Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:12]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cccc(N)c1

Procedure:
A mixture of 3.3 g of N-(3-nitrobenzoyl)-N-(2-ethoxy-2-oxoethyl) glycine ethyl ester and 0.5 g of 10% palladium on carbon in 40 ml THF and 40 ml ethyl acetate was stirred in a hydrogen atmosphere for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to an oil which was purified by HPLC using 50% ethyl acetate-hexane to remove an impurity and ethyl acetate to elute 3.1 g of N-(3-aminobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:19])[CH2:7][CH2:6]2.BrBr>C(OCC)(=O)C>[Br:1][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:11]([S:12](=[O:17])(=[O:18])[NH:13][CH2:14][CH2:15][CH3:16])=[C:3]([Cl:2])[CH:4]=2)[C:8]1=[O:19]
Reactant: Br
Reactant: CCCNS(=O)(=O)c1cc2c(cc1Cl)CCC2=O
Agent: BrBr
Solvent: CCOC(C)=O
Product: CCCNS(=O)(=O)c1cc2c(cc1Cl)CC(Br)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 L Milliliter of 48% aqueous HBr is added to a solution of 5.76 g (20 mmoles) of 5-chloro-6-n-propylsulfamoyl-1-indanone in 50 ml of ethyl acetate. Thereafter a solution of 3.20 g (20 mmoles) of bromine in 20 ml of ethyl acetate is added dropwise. The mixture is stirred for 1 hour at room temperature, then the solution is concentrated to dryness, and 50 ml of water are added to the residue. The crystalline precipitate is filtered off with suction and washed with water. 2-Bromo-5-chloro-6-n-propylsulfamoyl-1-indanone is obtained which has a melting point of from 150° to 154° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21]C4CCCCO4)=[O:19])[CH:11]=3)[O:6]2)[CH2:3]1.Cl>C(Cl)Cl.CCOCC>[CH3:1][N:2]1[CH2:5][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]([NH:20][OH:21])=[O:19])[CH:11]=3)[O:6]2)[CH2:3]1
Reactant: CN1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CC2(CC(=O)c3cc(/C=C/C(=O)NO)ccc3O2)C1
Yield: 84.3 %

Procedure:
(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (320 mg, 0.86 mmol) in DCM (4 ml) was treated with 1 M HCl in Et2O (4 ml) as described in Example 31, Step C, giving (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (209 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:40]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:41])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)N2CCOCC2)CC1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Under a N2 atmosphere, a solution of of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl]-ethyl}-methyl-amine (0.17 g, 0.48 mmole described as intermediate 12 above) and triethylamine (0.15 mL, 1.0 mmole) in dichloromethane (10 mL) was cooled to 0° C. 4-Morpholinecarbonyl chloride (0.06 mL, 0.51 mmole) was added and the resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated to give a brown residue. Flash chromatography (elution with 7:3 EtOAc-hexane) gave 0.17 g (74% yield) of morpholine-4-carboxylic acid {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydro-4H-pyridin-1-yl]-ethyl}-methyl-amide. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]=[C:10]3[C:9]2=[O:25])=[CH:4][CH:3]=1>C(Cl)Cl.CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]=[C:10]3[C:9]2=[O:25])=[CH:6][CH:7]=1
Reactant: O=c1c2nc(COc3ccccc3)nn2ccn1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C1c2nc(COc3ccccc3)nn2CCN1c1ccc(F)cc1
Yield: 6.3 %

Procedure:
A solution of 7-(4-fluoro-phenyl)-2-phenoxymethyl-7H-[1,2,4]triazolo[1,5-a]pyrazin-8-one (26 mg, 0.08 mmol) in a mixture of DCM (1 mL) and MeOH (1 mL) was hydrogenated in a H-Cube reactor (1.0 mL/min, 30 mm Pd/C 10% cartridge, full H2 mode, 100° C., 3 cycles). The solvent was evaporated in vacuo and the residue was purified by RP HPLC, mobile phase (gradient from 80% 0.1% NH4CO3H pH=7.8 solution in H2O, 20% MeOH to 0% 0.1% NH4CO3H pH=7.8 solution in H2O, 100% MeOH) to yield 7-(4-fluoro-phenyl)-2-phenoxymethyl-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-8-one (1.7 mg, 6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 4.11-4.24 (m, 2H), 4.44-4.58 (m, 2H), 5.42 (s, 2H), 6.95-7.02 (m, 2H), 7.04 (t, J=7.4 Hz, 1H), 7.13 (t, J=8.6 Hz, 2H), 7.29-7.49 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1-c1ccc(Cl)cc1Cl
Temperature: 75 °C

Procedure:
The mixture containing 1-bromo 5-fluoro 2-nitrobenzene (1 g, 4.5 mmol), 2,4-dichloro benzeneboronicacid (907 mg, 4.7 mmol), sodiumcarbonate (1.44 g, 13.5 mmol) in benzene and 3 ml of water was purged with nitrogen for 30 mins. Tetrakis(triphenylphosphine)-palladium(0) (264 mgs, 0.2 mmol) was added to the mixture and was heated to 75° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. Organic layer was separated and washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a brown solid which was recrystallized to give 1 g (yield, 80%) of white solid. The product gave satisfactory NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH3:25])[C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]#[C:15][CH2:16][CH2:17][O:18]C2CCCCO2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1>CO>[C:1]([O:5][C:6](=[O:26])[N:7]([C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]#[C:15][CH2:16][CH2:17][OH:18])[CH2:12][CH2:13]1)[CH3:25])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCOC2CCCCO2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCO)CC1

Procedure:
A solution of 3.45 g (9.44 mmol) of trans-Methyl-{4-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-cyclohexyl}-carbamic acid tert-butyl ester and 0.7 g (2.83 mmol) of pyrimidium toluene-4-sulfonate in 25 ml MeOH was stirred at 55° C. for 1.5 h. The reaction was partitioned between aqueous solution of 10% KHSO4/ether (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl, dried over Na2SO4 and evaporated to give 2.85 g (quantitative) of trans-[4-(4-Hydroxy-but-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 281 (M).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH:22]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:27]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:28])=[CH:17][CH:16]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C2CCCC2)nn1
Yield: 78 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using cyclopentanecarbonyl chloride instead of methoxyacetyl chloride, to the title compound (295 mg, 78%) which was obtained as a white solid. MS: m/e=379.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14](C)C)=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:8]=1)#[N:2].[CH3:17][O:18][C:19](=[O:42])[C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][CH:28]=2)=[C:22](N)[CH:21]=1.C(OCC)(=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH3:17][O:18][C:19](=[O:42])[C:20]1[CH:21]=[CH:22][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[CH:29][CH:28]=2)=[C:24]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH:9]([CH3:10])[CH3:11])=[N:5][C:4]=3[N:12]=[CH:13][N:14]=2)[CH:25]=1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Temperature: 25 °C

Procedure:
A suspension of N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine (2.00 g, 9.3 mmol) and the product from Example 1C (3.46 g, 9.3 mmol) in Acetic acid (40 mL) was heated at 120° C. for 20 minutes under N2. After cooling to room temperature, the reaction mixture was portioned between ethyl acetate (150 mL) and H2 (200 mL), and then made basic to pH 9 with K2CO3 under stirring. The organic layer was separated, washed with 10% NaHCO3, H2O and brine, dried over MgSO4, and evaporated to give a pale brown oil. The oily residue was separated by silica gel column chromatography (ethyl acetate/n-hexane=5/1) gave yellow crystal. Further purification by washing with cold ethyl acetate (15 mL) gave the title compound as slightly yellow crystal (3.27 g, 65% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[CH2:11][C@@H:10]3[C:21](=[O:30])[N:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][C:24](=[O:25])[N:9]23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C1COCC1>[C:38]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[CH2:11][C@@H:10]3[C:21](=[O:30])[N:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][C:24](=[O:25])[N:9]23)=[CH:4][CH:3]=1)(=[O:40])[CH3:39]
Reactant: CCCCN1CC(=O)N2[C@@H](c3ccc(N)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN1CC(=O)N2[C@@H](c3ccc(NC(C)=O)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 98 (0.2 g) in THF (15 mL) was added triethylamine (76 μL) and acetyl chloride (39 μL) and the resulting solution was stirred at room temperature for 2 hours. After evaporation of THF, the resulting residue was taken up in CH2Cl2 (100 mL), washed with water (2×50 mL) and dried over Na2SO4. After evaporation of CH2Cl2, the resulting solid was recrystallised from MeOH/H2O to give the title compound as a cream powder (120 mg) m.p.: 246° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28]O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.[ClH:30]>>[Cl:30][CH2:28][CH2:27][NH:26][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5](=[O:8])[NH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:25]
Reactant: Cl
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCO)c2n1
Product: O=C(NCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 85 °C

Procedure:
To (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (77 mg, 0.192 mmol) in a pressure reaction tube was charged hydrogen chloride (4 N dioxane, 4.8 mL, 19.2 mmol) and the resulting white suspension was heated at 85° C. overnight. After cooling to ambient temperature, the reaction mixture was decanted to yield the crude product as brownish oily residue, which was dried in vacuo and directly used in the next step without further purification. MS (apci) m/z=405.0 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4]1)[CH3:2].Cl.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18])[CH3:13].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]([NH:18][CH2:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:19])=[O:10])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)CCN
Reactant: CCn1ccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccn(CC)c1

Procedure:
Into a suspension of 3.33 g (23.9 mmol) of 1-ethyl-3-pyrrolecarboxylic acid, 4.41 g (28.7 mmol) of β-alanine ethyl ester hydrochloride and 5.50 g (28.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in 40 ml of methylene chloride, 4.0 ml (28.7 mmol) of triethylamine were added dropwise under ice cooling and stirring. The reaction mixture was stirred at room temperature for 2.5 hours.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]([N:15]2[CH2:19][C@@H:18]([N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[O:22])[CH2:17][C@H:16]2[C:35]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[O:36])=[O:14])[C@H:10]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)[CH2:9]1)(OC(C)(C)C)=O.Cl>C(Cl)Cl>[Cl:50][C:47]1[CH:46]=[CH:45][C:44]([C@@H:10]2[CH2:9][NH:8][CH2:12][C@H:11]2[C:13]([N:15]2[C@H:16]([C:35]([N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)=[O:36])[CH2:17][C@H:18]([N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[O:22])[CH2:19]2)=[O:14])=[CH:49][CH:48]=1
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)[C@H]3CC[C@@H](C)CC3)CN2C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)[C@H]3CC[C@@H](C)CC3)CN2C(=O)[C@@H]2CNC[C@H]2c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-BOC-(3R,4S)-3-(4-chlorophenyl)-4-({(2S,4S)-4-{(cis-4-methylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidin-1-yl}carbonyl)pyrrolidine (1.18 g, 1.65 mmol) obtained in Step A was dissolved in DCM (1 mL). 4M HCl (1 mL) was added dropwise thereto. The reaction solution was stirred for 1 hour at room temperature, concentrated in vacuo to give the title compound (1.01 g, 99.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd].O>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Reaction time: 144 h
Yield: 103.3 %

Procedure:
A mixture of 5% palladium on carbon paste (3.44 g), 7-nitro-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (19.15 g, 0.05 mol), ethanol (791 ml) and water (69 ml) was hydrogenated at 50 psi and 30° C. for 6 days. The reaction mixture was then filtered through Kieselguhr and evaporated in vacuo to give the title compound as an oil (18.04 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH3:18])[C:11]=1[NH2:23].[C:24](OCC)(=[O:28])[C:25]([CH3:27])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:23]=[C:25]([CH3:27])[C:24](=[O:28])[N:16]([C@H:17]([CH:19]3[CH2:20][CH2:21][CH2:22]3)[CH3:18])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)C(C)=O
Reactant: COc1ccc(-c2ncnc(N[C@@H](C)C3CCC3)c2N)c(Cl)c1
Solvent: CCO
Product: COc1ccc(-c2ncnc3c2nc(C)c(=O)n3[C@@H](C)C2CCC2)c(Cl)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
(S)-6-(2-Chloro-4-methoxy-phenyl)-N4-(1-cyclobutyl-ethyl)-pyrimidine-4,5-diamine (0.23 g, 0.69 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.78 ml, 6.9 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (S)-4-(2-chloro-4-methoxy-phenyl)-8-(1-cyclobutyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 567a). 1H NMR (300 MHz, CDCl3) δ ppm 9.06 (s, 1 H), 7.46 (d, J=8.79 Hz, 1 H), 7.09 (d, J=2.56 Hz, 1 H), 6.97 (dd, J=8.79, 2.56 Hz, 1 H), 5.82 (m, 1 H), 3.91 (s, 3 H), 2.51 (s, 3 H), 2.22 (m, 2 H), 1.87 (m, 4 H), 1.74 (s, 3 H), 1.55 (m, 1 H). MS (AP) 385.3 [(M+H)+, 100].
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[C:24](=[O:29])C=CCC)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+].S(=O)(O)[O-].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[CH:24]=[O:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC=CC(=O)[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])O
Solvent: O
Solvent: CC(C)=O
Product: Cc1cn([C@H]2C[C@H](C=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 69.6 %

Procedure:
5'-O-tert-Butyldimethylsilyl-3'-deoxy-3'-formylthymidine (Compound 11, Table VII) was prepared by dissolving 5'-O-tert-Butyldimethylsilyl-3'-deoxy-3'-ethylacrylylthymidine (1 g, 2.3 mmole) and 4-methylmorpholine-N-oxide (0.52 g, 4.4 mmole) in a solution of 40 ml acetone and 4 ml water to give a clear pale yellow solution. Aqueous osmium tetroxide (11.2 ml, 0.050 g/ml, 2.2 mmole) was then added and the resulting pale yellow mixture stirred for 2 hours. After this time 1.17 g sodium periodate (5.47 mmole) was added to the reaction and stirring was continued for one more hour. The stirred mixture was then treated with 0.60 g sodium bisulfite and the reaction stirred for an additional hour. At this time the solvent was evaporated and the residue was redissolved in 30 ml ethyl acetate. The solution containing the redissolved residue was washed with water (3×20 ml) and then dried over anhydrous sodium sulfate. Evaporation of the solvent yielded 0.59 g 5'-O-tert-butyldimethylsilyl-3'-deoxy-3'-formylthymidine as a crude red foam that was generally used without further purification (71% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](Br)[CH3:16])=[CH:11][CH:10]=2)=[O:8])=[CH:4][CH:3]=1.[C-:18]#[N:19].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:16])[C:18]#[N:19])=[CH:11][CH:10]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CC(Br)c1ccc(C(=O)c2ccc(Cl)s2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C#N)c1ccc(C(=O)c2ccc(Cl)s2)cc1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
A mixture of 9.9 parts of α-bromo-α-methyl-p-tolyl 5-chloro-2-thienyl ketone, 1.96 parts of sodium cyanide, 12 parts of water and 48 parts of dioxane is stirred for 17 hours while heating at 90° C. The reaction mixture is evaporated and 36 parts of water are added to the residue. The product is extracted with ether. The extract is dried and evaporated. The residue is purified by column-chromatography over silica gel, using chloroform as eluent. The pure fraction is collected and the eluent is evaporated. The residue is triturated in n-hexane, yielding p-(5-chloro-2-thenoyl)hydratroponitrile; mp. 90° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[CH3:10][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O:6][CH3:10])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(CO)(CO)C(=O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(C)(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a suspension of 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (10.06 g, 75 mmol) in MeOH was dropped 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether and stirred at room temperature overnight. After solvent was concentrated under reduced pressure, the reaction was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate as an oil (3.79 g, 34%). 1H NMR (300 MHz, CDCl3) δ 3.81 (d, 2H), 3.67 (s, 3H), 3.60 (d, 2H), 2.89 (br, 2H), 0.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CC(=O)OCC>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Br:26])=[CH:28][CH:29]=2)[C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.7 %

Procedure:
A solution of 8.0 g (32.0 mmol) of 4-chloro-5-formyl-2-phenylimidazole (prepared according to Chem. Pharm. Bull. 24 (1976) 960-969) and 5.3 g (32.0 mmol) of K2CO3 in 200 ml of abs. DMF was stirred at RT for 20 min. A solution of 9.6 g (32.0 mmol) of 4-bromobenzyl bromide in 200 ml of abs. DMF was then added dropwise and the reaction solution was stirred at RT for 6 h. It was concentrated in vacuo, and the residue obtained was taken up in EA, washed with water, 10% strength KHSO4, 10% strength NaHCO3, and satd sodium chloride solution, and dried over Na2SO4. Chromatographic purification on SiO2 using EA/heptane (1:4) as eluent of the residue which remained after stripping off the EA yielded 11.5 g of the title compound in the form of a beige solid.