Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].Br[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:1][CH:2]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:3])[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CC(N)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(Cc1ccccc1)NCCCCN1C(=O)c2ccccc2C1=O
Yield: 32 %

Procedure:
A mixture of 2.00 g of amphetamine (AP), 4.17 g of N-bromobutylphthalimide (manufactured by Aldrich Chemical Company Inc.) and 3.14 g of sodium hydrogen-carbonate was refluxed in 10 ml of benzene for 16 hours. After the solvent was removed from the reaction solution, the residue was purified by preparative thin layer chromatography (TLC, manufactured by Merck and Co. Inc.) using silica gel as the carrier. As an elution solvent, a mixture of methanol and chloroform in a volume ratio of 5:95 which had been previously saturated with ammonia was used the Rf value of the product was 0.7. Extraction of the product on silica gel with methanol gave 1.59 g of N-(4-phthalimidylbutyl)amphetamine (PIBAP).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([O:14][C:20]1[CH:21]=[C:16]([Cl:15])[N:17]=[C:18]([NH2:23])[N:19]=1)[C:10]([F:11])([F:12])[F:13]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O[C@H](c1ccc(Cl)cc1Br)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Nc1nc(Cl)cc(O[C@H](c2ccc(Cl)cc2Br)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 43) (400 mg, 1.4 mmol) in dioxane (25 mL) was added 4,6-dichloropyrimidin-2-amine (1.1 g, 7 mmol) and Cs2CO3 (1.3 g, 4 mmol). The mixture was heated for 24 h at 80° C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH2Cl2 and heptane was added. The solvent volume was reduced until a solid precipitated out. The solid was filtered and the procedure repeated several times to provide (R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[CH:17][CH:16]=1)=[O:13].[ClH:29].O1CCOCC1>ClCCl>[ClH:29].[OH:1][CH2:2][CH2:3][N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:13]
Reactant: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-({8-[(2-hydroxyethyl)(methyl)amino]octanoyl}amino)-benzoate (28.4 g, 72.4 mmol, e.g. which can be as prepared in Intermediate 38) in dry dichloromethane (225 ml) was added a 4M hydrogen chloride solution in 1,4-dioxane (145 ml, 579 mmol, 8 equivalents). The mixture quickly became cloudy and was stirred overnight resulting in a uniform white suspension. The solvents were evaporated off in vacuo, using a high vacuum at the end, to give the title compound (23.45 g) as a white solid. LCMS showed positive ion at m/z 336; TRET=2.01 min. NMR (d6-DMSO) appeared to show a trace of dichloromethane and 1,4-dioxane in the product.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:30])[N:6]2[C@H:22]1[CH2:27][CH2:26][C@H:25]([O:28][CH3:29])[CH2:24][CH2:23]1.I[CH3:32]>>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:32])[C:5](=[O:30])[N:6]2[C@H:22]1[CH2:23][CH2:24][C@H:25]([O:28][CH3:29])[CH2:26][CH2:27]1
Reactant: CI
Reactant: CO[C@H]1CC[C@H](n2c(=O)[nH]c3c(Cl)nc(-n4cnc5ccc(C#N)cc54)nc32)CC1
Product: CO[C@H]1CC[C@H](n2c(=O)n(C)c3c(Cl)nc(-n4cnc5ccc(C#N)cc54)nc32)CC1

Procedure:
Dark brown solid (76% crude yield). Synthesized using 3-(6-chloro-9-(trans-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile (0.7 g, 1.65 mmol) and iodomethane (0.61 mL, 10 mmol, 6 equiv.). MS (EI) m/z 438 (MH)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:32](=S)=[S:33].[Cl-].[NH4+]>C(O)C>[F:24][C:2]([F:23])([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:32]([SH:33])=[N:22][N:21]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(S)o4)cc23)c1

Procedure:
A mixture of the obtained 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide, triethylamine (5.6 mL, 40.4 mmol), carbon disulfide (18.2 mL, 303 mmol) and ethanol (70 mL) was heated under reflux for 5 hr. After cooling, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/2) and recrystallized from hexane/ethyl acetate to give 5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol.
Reaction SMILES: FC(F)(F)C(O)=O.C([S:11][CH2:12][CH:13]([CH2:24][CH2:25][CH2:26][NH2:27])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=O)C>O.N>[NH2:27][CH2:26][CH2:25][CH2:24][CH:13]([CH2:12][SH:11])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15]
Reactant: CC(=O)SCC(CCCN)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCCC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-(2-Acetylthiomethyl-5-aminopentanoyl)-L-proline trifluoroacetate (1 g) is dissolved in a mixture of water (12 ml) and concentrated ammonia (12 ml) under a blanket of argon. The solution is stored twenty minutes at room temperature concentrated to 5 ml and applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle. The column is washed with water and 1-(5-amino-2-mercaptomethylpentanoyl)-L-proline is eluted with a buffer of pyridine-acetic acid at pH 6.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([NH2:12])([CH3:11])[CH2:6][CH2:5]2.[F:13][C:14]([F:25])([F:24])[C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([NH:12][C:21]([C:18]1([NH:17][C:15](=[O:16])[C:14]([F:13])([F:24])[F:25])[CH2:19][CH2:20]1)=[O:22])([CH3:11])[CH2:6][CH2:5]2
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Reactant: CC1(N)CCc2cc(Br)ccc21
Product: CC1(NC(=O)C2(NC(=O)C(F)(F)F)CC2)CCc2cc(Br)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], (rac)-5-bromo-1-methyl-indan-1-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to yield the title compound as light brown solid. MS: 402.9 (M−H−, 1Br).
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:2]([CH:22]3[CH2:24][CH2:23]3)[C:3]([CH3:21])([CH3:20])[O:4]2)=[CH:9][CH:8]=1
Reactant: OB(O)C1CC1
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1C1CC1

Procedure:
A mixture of 3-bromo-7-chloro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen (a compound obtained in Reference Example 8(1); 200 mg), cyclopropylboronic acid (100 mg), potassium phosphate (410 mg) and tetrakis(triphenylphosphine)palladium(0) (65 mg) in dioxane (5 mL) was heated under reflux for 23 hours. After cooling, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and filtered through a column of porous diatomite (Chem Elut), and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/chloroform=100/0 to 95/5) to give the titled compound (114 mg) as a colorless viscous oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][N:11]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH3:10]
Reactant: N#Cc1cccc(F)c1
Reactant: CNCCO
Product: CN(CCO)c1cccc(C#N)c1

Procedure:
By treating 3-fluorobenzonitrile with N-methylethanolamine under heating, 3-(N-2-hydroxyethyl-N-methylamino)benzonitrile was obtained (F: 177). This benzonitrile was treated in the same manner as in Reference Example 2 to obtain 3-(N-2-hydroxyethyl-N-methylamino)benzylamine. F: 181.
Reaction SMILES: [CH2:1]([Cl:4])[CH2:2][OH:3].CCOCC.[CH2:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]([CH3:13])[CH3:12]>C(N(CC)CC)C>[CH2:10]([S:14]([O:3][CH2:2][CH2:1][Cl:4])(=[O:16])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: OCCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)CS(=O)(=O)OCCCl
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture was formed containing 6.7 ml. of ethylene chlorohydrin, 70 ml. of ether and 15.6 g. of isobutane sulfonyl chloride. Then, 14 ml. of triethylamine was added dropwise to the mixture with stirring in an ice bath over a period of 30 minutes at 12°-14° C. While stirring the mixture was allowed to warm to 23° C. (1 hour) and was then washed with water (100 ml.), dried over magnesium sulfate and evaporated to yield 19.7 g. of a colorless oil. nD30 1.4502.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2([CH2:13][CH2:12]2)[O:10][C:9](=[O:14])[C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:17][CH:16]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[N:35]1[CH:40]=[CH:39][C:38]([C:7]2[C:11]3([CH2:12][CH2:13]3)[O:10][C:9](=[O:14])[C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:17][CH:16]=2)=[CH:37][CH:36]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1OC2(CC2)C(OS(=O)(=O)C(F)(F)F)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1OC2(CC2)C(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
To a stirred solution of 5-oxo-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-7-yl trifluoromethanesulfonate (200 mg, 0.4 mmol) in 1,4-dioxane (10 mL) were added pyridin-4-ylboronic acid (74 mg, 0.6 mmol), Na2CO3 (102 mg, 1.2 mmol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 minutes, and then Pd(PPh3)4 (46 mg, 0.04 mmol) was added and the reaction mixture was then refluxed for 16 h, diluted with water and extracted with EtOAc (2×40 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to afford 7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (30 mg, 18%) as white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.64-8.61 (m, 2 H), 8.40 (d, J=7.2 Hz, 1 H), 8.02-7.99 (m, 2 H), 7.81-7.77 (m, 1 H), 7.67- 7.51 (m, 3 H), 7.38-7.24 (m, 5 H), 5.36 (s, 2 H), 1.88-1.85 (m, 2 H), 1.24-1.21 (m, 2 H). MS: M+H: m/z=421.2; M+Na: m/z=443.2. HPLC: 92%, (Condition-I).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)[CH:9]=[CH:8]2>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:15][CH2:16][C:17]([CH3:1])([OH:20])[CH2:18][CH2:19]1)[CH:9]=[CH:8]2
Reactant: O=C1CCC(n2ccc3cc(Br)ccc32)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCC(n2ccc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methylmagnesium bromide (1.4 M solution in toluene/THF) (3.667 ml, 5.134 mmol) was added dropwise to a cooled solution (at 0° C.) of intermediate D30 (0.5 g, 1.711 mmol) in THF (20 ml) under a N2 atmosphere. The resulting reaction mixture was warmed to room temperature and further stirred for 4 h. After cooling in an ice bath, the mixture was carefully quenched with NH4Cl (aqueous sat. solution), and was subsequently extracted with DCM. The organic layer was separated, dried (Na2SO4), and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; 0-30% EtOAc/heptane as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield cis-D33 (0.096 g, 18.2%) and trans-D33 (0.12 g, 22.7%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:33])[N:24]([CH2:29][CH2:30][C:31]#[N:32])[CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:20]=[C:19]([Cl:34])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:31]([CH2:30][CH2:29][N:24]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:23](=[O:33])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=[C:19]([Cl:34])[CH:20]=1)(=[O:39])[NH2:32]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)CC2CC2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)CCN(CC1CC1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 18 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-cyclopropylmethyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.07 g) in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 18 h and then concentrated under reduced pressure to give the title compound as a light brown oil (0.071 g).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:18]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([CH:31]([NH2:41])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])[CH2:25][CH2:24]1)=[O:22])[CH3:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]([CH:31]([NH:41][C:1]([C:4]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])[CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Reactant: COC(=O)c1cc(C(=O)O)nc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)OC)c3ccccc3n2)CC1
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a mixture of 2,4-dicarboxyquinoline (1.085 g, 5 mmol) in methanol (40 mL) was added chlorotrimethylsilane (TMSCl) (1.41 mL), and the reaction mixture was stirred overnight. The reaction mixture turned into a clear solution. The solvents were evaporated to yield a crude product, 2-carboxy-4-methoxycarbonylquinoline. To a solution of 2-carboxy-4-methoxycarbonylquinoline (151 mg, 0.65 mmol) in THF (10 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (181 mg, 1.05 eq.), EDCI (161 mg, 1.2 eq. ), and HOBt (75 mg, 1.1 eq.), and the resulting reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (146 mg) which was treated with trifluoroacetic acid (TFA) and CH2Cl2 (TFA/CH2Cl2, 1:1, 1.5 mL) and the resulting reaction mixture was stirred at ambient temperture for 1 hour. Evaporation of the solvents gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (74 mg). To this was added a mixture of THF:H2O (2:1, 2 mL) and LiOH (4 eq.). The resulting mixture was stirred at ambient temperature for 1.5 hours. The pH value was adjusted to between pH 3 and pH 4 with 1N HCl solution. Extraction of the organic layers with ethyl acetate was followed by evaporation of the solvents to yield 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-carboxyquinoline (39 mg); NMR (CD3OD) 1.25 (t, 3), 1.99 (m, 1), 2.2 (m, 1), 2.5 (m, 2), 3.4–3.9 (m, 8), 4.16 (q, 2), 5.25 (m, 1), 7.75 (m, 1), 7.86 (m, 1), 8.25 (m, 3) ppm.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:8])[CH:6]=[CH2:7])[CH2:2]C.[CH:9](N1CCCC1=O)=[CH2:10]>>[CH2:1]([N:4]([CH2:9][CH3:10])[C:5](=[O:8])[CH:6]=[CH2:7])[CH3:2]
Reactant: C=CC(=O)NCCC
Reactant: C=CN1CCCC1=O
Product: C=CC(=O)N(CC)CC

Procedure:
N-n-propylacrylamide (NnPAM) and vinylpyrrolidone were purchased from a commercial vendor and used as received. Anhydrous methanol was degassed by vigorously bubbling dry nitrogen through it.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:3]2[C:4]([NH:8][C@H:9]([C:11]3[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15](=[O:23])[C:14]4=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]4[N:12]=3)[CH3:10])=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])=[CH:38][N:39]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cnc(N)nc3)n(-c3ccccc3)c(=O)c12
Yield: 19.1 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (34 mg, 0.15 mmol), 1,1% bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.43 mol) according to the method described in Example 3 to give 13 mg (28% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH2:10](N)[CH2:11][NH2:12].[Cl-].[Na+]>C(Cl)(Cl)Cl.O>[NH:9]1[CH2:10][CH2:11][N:12]=[C:8]1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: NCCN
Reactant: N#Cc1cnc(N)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1cnc(C2=NCCN2)cn1
Temperature: 120 °C
Yield: 48.1 %

Procedure:
A mixture of 2-amino-5-cyanopyrazine (500.0 mg, 4.163 mmol), ethylenediamine (3.0 mL, 44.88 mmol), and phosphorous pentasulfide (185.1 mg, 0.416 mmol) was placed in a sealed tube and heated at 120° C. for 3 h. At this time, the reaction was poured onto ice. The resulting reaction mixture was diluted with chloroform (50 mL), water (10 mL), and a saturated aqueous sodium chloride solution (20 mL). The layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 5-(4,5-dihydro-1H-imidazol-2-yl)-pyrazin-2-ylamine (327.0 mg, 48.1%) as a white solid which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([OH:26])=[O:25].[C:27]1([C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N+]=[N-])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([O:26][CH:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:25]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OCC(=O)O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OCC(=O)OC(c5ccccc5)c5ccccc5)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-methyl-5α-4-azaandrostan-3-on-17β-yloxyacetic acid (3.5 mg) in CH2Cl2 (0.2 ml) under N2 was added diphenyldiazomethane (ca. 20 mg) in portions during 15 minutes. The reaction stirred at room temperature for 2 hours, then additional diphenyldiazomethane (ca. 5 mg) was added and the reaction was allowed to stir overnight. The mixture was purified via preparative TLC on a silica gel plate (1000μ) developed with EtOAc to yield diphenylmethyl 4-methyl-5α-4-azaandrostan-3-on-17β-yloxyacetate, (Rf=0.4/EtOAc).
Reaction SMILES: C(OC(N[CH:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][CH:11]([OH:39])[CH:12]([NH:20][C:21](=[O:38])[C@H:22]([CH2:34][C:35](=[O:37])[NH2:36])[NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.CO.C([NH2:51])(C)C.C(Cl)(Cl)Cl>>[NH2:51][CH:10]([CH:11]([OH:39])[CH:12]([NH:20][C:21](=[O:38])[C@H:22]([CH2:34][C:35](=[O:37])[NH2:36])[NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)NC(CC(O)C(Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)c1ccccc1
Reactant: CC(C)N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Yield: 95 %

Procedure:
Using the procedure of Example 11 with the resultant compound of Example 66 gave, after silica gel chromatography using methanol/isopropylamine/chloroform, the desired compound (RF 0.3; 2.5% methanol/2% isopropylamine/chloroform) in 95% yield. Mass spectrum (M+H)+ =519.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]=[C:15]3[C:10](=[N:11][CH:12]=[N:13][C:14]3=[O:17])[N:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]=[C:15]3[C:10](=[N:11][CH:12]=[N:13][C:14]3=[O:17])[N:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1cc(N)ccc1C1=NC2=NC=NC(=O)C2=N1
Product: CC(=O)Nc1ccc(C2=NC3=NC=NC(=O)C3=N2)c(N(C)C)c1

Procedure:
A quantity of 0.6 gm of 8-(4-amino-2-dimethylamino-phenyl)purin-6-one is heated to 150° C. in 5 ml of acetic anhydride for one hour. The mixture is evaporated to dryness in vacuo and recrystallized from acetone/ether.