Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=O)[C:5]#[N:6].[C:12]([CH2:14][C@@H:15]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:18]=[C:17](C2C=CC(C#N)=CC=2)[C@H:16]1C)#[N:13]>>[C:12]([CH2:14][C@@H:15]1[N:19]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[N:18]=[C:10]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[F:1])[C@H:16]1[CH3:17])#[N:13]
Reactant: C[C@@H]1C(c2ccc(C#N)cc2)=NN(c2ccc(O)cc2)[C@H]1CC#N
Reactant: N#Cc1ccc(C=O)c(F)c1
Product: C[C@@H]1C(c2ccc(C#N)cc2F)=NN(c2ccc(O)cc2)[C@H]1CC#N

Procedure:
4-((4S,5S)-5-(Cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)-3-fluorobenzonitrile was prepared from 3-fluoro-4-formylbenzonitrile following the procedure for the preparation of 4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (91G): LC-MS [M+H] 335.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.[I:22]N1C(=O)CCC1=O>CCCCCC.C1COCC1>[I:22][C:8]1[N:7]([CH3:6])[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[N:9]=1
Reactant: Cn1cnc2cc(CN3CCCC3)ccc21
Reactant: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(I)nc2cc(CN3CCCC3)ccc21
Reaction time: 0.17 h

Procedure:
0.80 mL (1.28 mmol) 1.6 M n-butyllithium solution in hexane are added to a solution, cooled to −75° C., of 250 mg (1.16 mmol) 1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole in 8 mL THF. The reaction mixture is stirred for 10 min at this temperature and then 288 mg (1.28 mmol) N-iodosuccinimide in 5 mL THF are added. The cooling bath is removed and the reaction stirred for 1 h at RT. 12 mL 0.1 M HCl are added and the aqueous phase is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH/NH3 9:1:0.1).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Temperature: 80 °C
Yield: 26.2 %

Procedure:
A mixture of 3-methyl-1H-1,2,4-triazole (5.0 g, 60.2 mmol), 1-chloro-2-methoxy-4-nitrobenzene (11.3 g, 60.2 mmol), and KOH flakes (3.4 g, 48.1 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 6 h. The reaction mixture was allowed to cool to rt and was poured into 800 mL of water with vigorous stirring. The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified using silica gel chromatography (0-2% MeOH/chloroform, linear gradient) to afford 1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (3.7 g, 26% yield). LC-MS (M+H)++235.2.
Reaction SMILES: C(O)C.C(O[C:7](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH2:8][CH3:9])C.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][SH:20])[CH3:16].C([O-])(=O)C.[K+]>O>[CH2:15]([O:17][C:18]([C:19]1[S:20][C:7]([CH2:8][CH3:9])=[C:10]([C:11]#[N:12])[C:13]=1[NH2:14])=[O:21])[CH3:16]
Reactant: CCOC(CC)=C(C#N)C#N
Reactant: CCOC(=O)CS
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(CC)c(C#N)c1N
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 85.3 %

Procedure:
Ethanol, (11.0 L), 2-(1-ethoxy-propylidene)-malononitrile, (2.003 kg, 13.34 moles, 1.0 eq), ethyl-2-mercaptoacetate (1.652 kg, 13.34 moles, 1.0 eq.), and potassium acetate (1.983 kg, 20.0 moles, 1.5 eq.) are charged to a 22L 3-neck reaction flask equipped with an addition funnel, thermocouple, overhead stirrer, and condenser. The reaction mixture becomes dark red and exotherms to 72° C. The mixture is stirred for 1.25 hours while cooling to 60° C. Deionized water (2.6 L), is added to the reaction mixture over 30 minutes while cooling to 53° C. The reaction mixture is then cooled to 10° C. over 3.5 hours. The resulting suspension is filtered to recover the precipitate, and the filter cake is rinsed with a chilled mixture of 1.1 L ethanol and 3.9 L water. The filter cake is vacuum dried at room temperature, affording the title compound (2.552 kg) in 85.3% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16](COCC[Si](C)(C)C)[CH:17]=[CH:18][C:11]=12)[NH2:5].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc(N)cc3F)ccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Cc2ccnc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
477 mg (1.00 mmol) of 3-fluoro-4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]aniline are dissolved in 4 ml of dichloromethane. 4.0 ml of trifluoroacetic acid are added, and the mixture is stirred at RT for 2 hours. The solution is concentrated to dryness. The residue is taken up in 15 ml of THF, and 15 ml of an aqueous 1 M lithium hydroxide solution are added. The solution is stirred at RT for 20 hours and then concentrated, and water is added. The mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: [Br:1][CH:2]([C:4]1[N:5]=[C:6]2[S:13][CH:12]=[CH:11][N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:9]1[C:8](=[O:10])[N:7]2[CH:11]=[CH:12][S:13][C:6]2=[N:5][C:4]=1[CH:2]([Br:1])[CH3:3]
Reactant: CC(Br)c1cc(=O)n2ccsc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(Br)c1nc2sccn2c(=O)c1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 7-(1-bromoethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (17.5 g, 67.5 mmol) and N-bromosuccinimide (14.2 g, 79.8 mmol) in acetonitrile (400 mL) was stirred at 80° C. under N2 overnight. After removal of the solvent under reduced pressure, the resulting solid was dissolved in dichloromethane, washed sequentially with water, saturated aqueous Na2S2O3 and NaHCO3 solution and brine, dried over Na2SO4, and then concentrated to give crude product (3.7 g), which was used in the next step without further purification. LCMS calculated for C8H7Br2N2OS (M+H)+: m/z=336.9. Found: 336.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.Cl>O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(N)cc1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Agent: Cl
Solvent: O
Product: COCc1cc(Nc2ccc(OC)cc2)nc(-c2cccc(C)c2)n1
Yield: 40.8 %

Procedure:
A mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (100 mg, 0.402 mmol), p-anisidine (50 mg, 0.402 mmol), water (5 ml) and 2N HCl (300 μl) was refluxed overnight. The resulting yellow solid was collected by filtration, washed with water and then dried under vacuum to give the title compound (55 mg, 41%). 1H NMR (CDCl3): 8.28 (d, J=8.7 Hz, 2H), 7.43-7.35 (m, 4H), 6.96 (d, J=9.0 Hz, 2H), 6.83 (s, 1H), 4.64 (s, 2H), 3.85 (s, 3H), 3.45 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>C(N(CC)CC)C.C(O)(=O)C>[C:16]([O:19][CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1)(=[O:18])[CH3:17]
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc2sc(S(N)(=O)=O)cc2c1
Yield: 87.6 %

Procedure:
To a mixture of 5-bromomethyl-2-sulfamoylbenzo[b]thiophene (3.06,0.01 mol), anhydrous sodium acetate (0.98 g, 0.01 mol) and glacial acetic acid (15 ml) was added three drops of triethylamine. The mixture was heated and the resulting solution was stirred at reflux for 6 hours and was left at room temperature over night. The acetic acid was removed in vacuo and the residual gum was diluted with 25 ml of ice water. The product was extracted into 3×50 ml of ether. The combined extracts were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 2.5 g of yellow solid (88% yield). Recrystallization from chloroform gave material with a m.p. of 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:6](=[O:21])[N:5]([CH2:22][CH3:23])[C:4]=2[N:3]=1.O.[OH-].[Li+]>CO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:6](=[O:21])[N:5]([CH2:22][CH3:23])[C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCCn1c(=O)c2[nH]c(Cl)nc2n(CC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Temperature: 40 °C
Reaction time: 17 h
Yield: 94.4 %

Procedure:
A solution of ethyl 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (2.3 g, 6.7 mmol) in methanol (75 ml) was treated with water (3 ml) and lithium hydroxide (0.481 g, 20.1 mmol) and the mixture stirred at 40° C. for 17 h. The mixture was evaporated to dryness and the residue treated with 50 ml of ethyl acetate and 50 ml of water. The 2 phases were separated and the aqueous phase adjusted to pH5 using 2M aqueous hydrochloric acid. The precipitated product was filtered off and dried to yield 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid as a white solid (1.99 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12](=O)[CH3:13])[CH:6]=1.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@H:12]([NH:24][C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[CH3:13])[CH:6]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)Cc1cccc(CC(C)=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(C[C@@H](C)N[C@H](C)c2ccccc2)c1
Yield: 41 %

Procedure:
A solution of methyl[3-(2-oxopropyl)phenyl]acetate (Preparation 65) (45.3 g, 236 mmol), (R)-α-methyl benzylamine (27.6 ml, 214 mmol), sodium triacetoxyborohydride (68.1 g, 321 mmol) and acetic acid (14.7 ml, 257 mmol) in dichloromethane (1500 ml) was stirred at room temperature for 18 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (600 ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with further dichloromethane (2×100 ml). The combined organic extracts were washed with brine (100 ml), dried (sodium sulfate), filtered through celite and reduced in vacuo. The oil was dissolved in methanol (200 ml), treated with 1M hydrogen chloride in methanol (300 ml) and reduced in vacuo to give a 4:1 mixture of diastereomers (R,R major) as an off-white, hydrochloride salt. Two successive crystallisations (diisopropylether/methanol) gave the title compound (27.3 g) as a colourless crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11].F>[Cr].[Co]>[CH3:8][C:4]1[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=[C:6]([C:10]([CH3:11])=[O:12])[CH:5]=1
Reactant: Cc1cccc(C)c1O
Reactant: CC(=O)OC(C)=O
Agent: [Co]
Agent: [Cr]
Agent: F
Product: CC(=O)c1cc(C)c(O)c(C)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(36.6 g, 0.30 mol) of 2,6-dimethylphenol are mixed in an Hastelloy C autoclave with 0.315 mol of acetic anhydride and 9 mols of hydrogen fluoride. The temperature is raised to 50° C. and the reaction runs for 3 hours. After extraction and wash, 47.4 g of a gray to purple solid mass of 3,5-dimethyl-4-hydroxyacetophenone is obtained. This solid is then esterified by refluxing with 4 mols of acetic anhydride for 19 hours. After removal of acetic acid and acetic anhydride by vacuum distillation the 3,5-dimethyl-4-acetoxyacetophenone is flash distilled to yield 47.7 g of a slightly yellow liquid. 0.1 mol of the 3,5-dimethyl-4-acetoxyacetophenone, 1.2 g of 5% Pd/C as catalyst and 100 ml ethanol are mixed in an autoclave and the autoclave is charged with hydrogen gas at a pressure of 215-220 mm Hg PSIG and the reaction is run for about 21/2 hours at a temperature of about 25°-30° C. Additional catalyst is added as needed. The catalyst is then removed and the ethanol evaporated to yield 21.5 g of a colorless oil which is 1-(3',5'-dimethyl-4'-acetoxyphenyl)ethanol. 0.168 mol of 1-(3',5'-dimethyl-4'-acetoxyphenyl)ethanol is added to a flask with 0.35 g KHSO4 and 0.5 g t-butyl catechol. The flask is heated to 185° to 190° C. at 1.5 to 2.0 mm Hg. A colorless liquid is distilled. After the addition of 0.15 g of t-butyl catechol, and redistillation, 26.1 g of 3,5- dimethyl-4-acetoxystyrene monomer is produced. The compound has a boiling point of 90°-91° C. at 0.5 mm of Hg and the yield is 81.8%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](ON2C(=O)CCC2=O)=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[C:9]1[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])[CH:19]=[C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:40])[CH:8]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: NCCCC(=O)O
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)NCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1
Reaction time: 48 h

Procedure:
5-[9-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (100 mg, 0.18 mmol) was dissolved in dry DMF (2 ml). 4-Aminobutyric acid (GABA, 23 mg, 0.2 mmol) and DIPEA (0.05 ml) was added. The mixture was stirred under nitrogen for 2 days. The mixture was concentrated. The residue was dissolved in EtOAc and washed with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: [CH:1]([P:3](=[O:14])([O-:13])[O:4][CH2:5][CH:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[CH2:2].[CH2:15]([NH2:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[H-].[Na+].O>C(OCC)(=O)C>[CH2:11]([CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][O:4][P:3]([CH2:1][CH2:2][NH:33][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:13])[O:14][CH2:5][CH:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: C=CP(=O)([O-])OCC(CC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCNCCP(=O)(OCC(CC)CCCC)OCC(CC)CCCC
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 2-ethylhexyl vinylphosphonate (49.90 g), octadecylamine (40.43 g) and sodium hydride 0.10 g was stirred at 140° C. for 6 hours. Water (100 ml) and ethyl acetate (200 ml) were added. The organic phase was separated, dried with sodium sulfate, filtered and the solvent evaporated under reduced pressure to give di(2-ethylhexyl)[2-(octadecylamino)ethyl]phosphonate, as colourless liquid nD40 =1.4541.
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12](COCC[Si](C)(C)C)[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(OC([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][C:43](O)=[O:44])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[NH:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][C:43]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5]1)=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CCNCC3)ccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc2c(cn1)[nH]c1nccc(N3CCN(C(=O)C[C@@H]4CCCN4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(piperazin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (100 mg, 0.2 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (220 mg, 1.0 mmol), 1-hydroxybenzotriazole (50 mg, 0.4 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrogen chloride (70 mg, 0.4 mmol), and triethylamine (0.1 mL, 0.7 mmol) in methylene chloride (2.5 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-70% ethyl acetate in heptane) to afford the title compound as a white foam, which was used in the next step without any further purification (140 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH3:20])([CH3:19])[NH:14]1.C(O)(=O)C(C)=[O:23].O>O1CCOCC1.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:19](=[O:23])[C:15]([CH3:20])=[N:14]1
Reactant: CC(C)Oc1cc(N2NC(C)(C)NC2=O)c(Cl)cc1Cl
Reactant: CC(=O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a stirred mixture of 1.0 g (0.0031 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3,3-dimethyl-1,2,4-triazolidin-5-one in 10 mL of p-dioxane was added 0.29 g (0.0031 mole) of pyruvic acid and one drop of concentrated sulfuric acid. The mixture was stirred at room temperature for one hour, then an additional 0.25 g (0.0029 mole) of pyruvic acid was added. The mixture was heated at 90° C. for three hours, then poured into water. The mixture was extracted with ethyl acetate, and the solvent was evaporated from the extract under reduced pressure to give an oil. The oil was purified by thin-layer preparative chromatography on silica gel, eluting with ethyl acetate:heptane (1:1). Extraction of the appropriate bands gave 0.6 g of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione as a solid (mp 163°-164° C.), Compound 10 in the tables.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[C:20]1[C:21]2[C:28]([CH3:29])=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:29][C:28]1[C:21]2[C:20]([N:16]3[CH2:15][CH2:14][N:13]([C:11](=[O:12])[CH2:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH2:18][CH2:17]3)=[N:25][CH:24]=[N:23][C:22]=2[NH:26][CH:27]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCN(C(=O)Cc4cccc([N+](=O)[O-])c4)CC3)c12
Temperature: 80 °C

Procedure:
2-(3-Nitrophenyl)-1-(piperazin-1-yl)ethanone from step A (0.32 g, 0.9 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.168 g, 1.0 mmol), and diisopropylethylamine (0.1 ml) were combined in isopropanol and heated at 80° C. for 24 hours. The product was isolated by prep HPLC to give 1-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-(3-nitrophenyl)ethanone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:41]=[CH:40][CH:39]=[CH:38][C:13]=1[C:14]([NH:16][CH2:17][C:18]1[C:19]([NH:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:20]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]2=[N:22][C:23]=1[CH2:24][CH3:25])=[O:15])=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]3[CH:38]=[CH:39][CH:40]=[CH:41][C:12]=3[NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])[C:19]([NH:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)CCCCCCCBr
Reactant: CNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)CCCCCCCN(C)CCO
Temperature: 60 °C

Procedure:
A solution of 2-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (68 mg, 0.11 mmol, e.g. which can be as prepared in Intermediate 46) in N,N-dimethylformamide (5 ml) was treated with 2-(methylamino)ethanol (0.0175 ml, 0.22 mmol, commercially available e.g. from Aldrich) and N,N-diisopropylethylamine (0.038 ml, 0.22 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (5 mg). LCMS showed MH+=622; TRET=2.15 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:30][CH2:29][C:11]2([N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][N:13]([CH2:23][C:24]([O:26]C)=[O:25])[C:12]2=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].CO>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([CH2:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:14][N:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12]2=[O:28])[CH2:29][CH2:30]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN1CN(CC2CCCCC2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(CC(=O)O)CN2CC1CCCCC1
Yield: 71.1 %

Procedure:
A stirred mixture of 4 g (9.45 mmol) of methyl 8-(t-butoxycarbonyl)-1-cyclohexylmethyl-4-keto-1,3,8-triazaspiro [4.5]decan-3-acetate, 4 g (72 mmol) carbonate 60 ml of methanol and 40 ml of water was heated at reflux for 3 hours. The resulting solution was concentrated to about one-half of its original volume and then it was carefully acidified with 2N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. After the extracts were dried over magnesium sulfate, they were concentrated. The residue solid was recrystallized from hexane to give the product as 2.75 g (69.5%) of colorless crystals, mp 148°-149° C.