Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH2:28][CH2:27]3)=[C:22]([C:23]#[N:24])[CH:25]=2)=[O:16])[CH:10]=[N:9]1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1Cl
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccccc1Cl
Yield: 37.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(2-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.2 g), the title compound (0.79 g) was obtained, melting point: 218° C.
Reaction SMILES: [CH2:1](N1C2C(=CC=CC=2)C(=O)C1=O)[CH2:2][CH3:3].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][C:20](=[O:26])[C:19]2=[O:27].BrCCC>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[N:21]([CH2:1][CH2:2][CH3:3])[C:20](=[O:26])[C:19]2=[O:27]
Reactant: O=C1Nc2c(Cl)cc(Cl)cc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CCCBr
Product: CCCN1C(=O)C(=O)c2cc(Cl)cc(Cl)c21

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione using 5,7-dichloroisatin (purchased from Fisher Scientific) and 1-bromopropane (purchased from Fisher Scientific). 1H NMR δ 7.53 (d, 1H), 7.51 (d, 1H), 4.05 (t, 2H), 1.78 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH2:32][O:33]C)[CH:4]=[CH:5]2.O.[C:36](O)(=O)C>>[C:32]([O:31][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:11][CH2:10][C@@H:9]35)(=[O:33])[CH3:36]
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCCC(=O)OC)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: CC(=O)O
Solvent: O
Product: COC(=O)CCCCC(=O)O[C@H]1CC[C@H]2[C@H]3Cc4ccc(OC(C)=O)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 100 °C
Reaction time: 6 h

Procedure:
4,5α-epoxy-6α-((5-methoxycarbonyl-valeryl)-oxy)-3-methoxymethoxy-17-methyl-morphinane (0.43 g, 0.91 mmol) was mixed with H2O (15 ml) and glacial acetic acid (15 ml) and stirred for 6 hours at 100° C. The mixture was then evaporated down at 40° C. using a Rotavapor and the residue obtained was purified by flash chromatography (60 g silical gel; CH2Cl2 /MeOH=9/1). The product was dissolved in H2O (6 ml) and glacial acetic acid (0.6 ml) and lyophilised. Yield: 0.221 g (0.45 mmol, 49.7%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:5]=2[CH:6]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.CCOCC.[NH4+].[Cl-]>CCOC(C)=O.O1CCCC1>[Br:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)([OH:11])[C:5]=2[CH:6]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C1CCCc2sc(Br)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccc(Cl)cc2)CCCc2sc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In a 250 mL round bottomed flask was placed 2-bromo-6,7-dihydro-1-benzothiophen-4(5H)-one (1.9 g, 8.2 mmol) and tetrahydrofuran (30 mL). To the solution was added 4-chlorophenylmagnesium bromide in ether (1 M, 8.2 mL, 8.2 mmol) and the mixture was stirred for 30 min at rt. To the mixture were added 10% NH4Cl aq (50 mL) and EtOAc (50 mL). The mixture was vigorously stirred for 10 min and then the aqueous phase was discarded. The organic phase was dried over anhydrous MgSO4 and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified pre-packed silica gel (40 g) column chromatography eluted with 0% to 50% EtOAc/hexane to yield the title compound (2.4 g; 85%) as a colorless syrup. 1H NMR (300 MHz, d-chloroform) δ ppm 7.26-7.29 (m, 4H), 6.56 (s, 1H), 2.68-2.86 (m, 2H), 1.81-2.17 (m, 5H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18]([NH:19][C:20](=[O:28])[CH2:21][CH2:22]1)=[CH:17][CH2:16]3)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.C(Cl)Cl>[C:29]([N:19]1[C:20](=[O:28])[CH2:21][CH2:22][C@@:23]2([CH3:24])[C:18]1=[CH:17][CH2:16][C@@H:15]1[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:11])[C@H:12]1[CH2:13][CH2:14][C@@H:9]2[O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 17β-t-butyldimethylsilyloxy-4-azaandrost-5-en-3-one (2 g) in pyridine (5 ml) at 5°-10° C. was added benzoyl chloride (2 ml) in CH2Cl2 (10 ml) dropwise. After the addition, the mixture was stirred at 60° C. for 3 hours and poured onto ice-water. The mixture was extracted with methylene chloride, and dried (Na2SO4). Removal of solvent gave the crude product which was recrystallized from CH2Cl2 -hexane to afford the title product.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([O:24]C)=[O:23])[CH2:17]1.[Li+].[OH-]>CO.O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17]1
Reactant: COC(=O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 30 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Methyl (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetate a13-1 (500 mg, 0.87 mmol, 1 eq) is dissolved in MeOH/H2O (4 ml/1 ml) and LiOH (47 mg, 1.7 mmol, 2 eq) is added. The reaction mixture is stirred at 30° C. for 1 hour, then quenched with HCl 1M (100 μl). The resulting mixture is diluted with n-butanol (15 ml), and stirred overnight at room temperature. After phase separation the organic layer is dried on Na2SO4, filtered and the filtrate is concentrated under reduced pressure to afford 229 mg of (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetic acid a14-1 as a colorless oil which is used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:15][CH2:14]3)[C:8]2=[O:16])=[CH:4][CH:3]=1.[CH:19]1([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27](B4OC(C)(C)C(C)(C)O4)[CH:28]=3)[C:23]2=[O:40])[CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH:13]1([N:9]2[C:10](=[O:12])[CH2:11][N:7]([CH2:6][C:5]3[CH:17]=[CH:18][C:2]([C:27]4[CH:28]=[C:29]5[C:24](=[CH:25][CH:26]=4)[C:23](=[O:40])[N:22]([CH:19]4[CH2:21][CH2:20]4)[CH2:30]5)=[CH:3][CH:4]=3)[C:8]2=[O:16])[CH2:15][CH2:14]1
Reactant: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1C1CC1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1c2ccc(-c3ccc(CN4CC(=O)N(C5CC5)C4=O)cc3)cc2CN1C1CC1
Yield: 53.1 %

Procedure:
1-(4-bromobenzyl)-3-cyclopropylimidazolidine-2,4-dione (7H5) (0.1 mmol, 30 mg), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (0.1 mmol, 31.0 mg), tris(dibenzylidineacetone)dipalladium (0.005 mmol, 4.59 mg), tricyclohexylphosphine (0.012 mmol, 3.37 mg) and potassium phosphate (0.17 mmol, 36.1 mg) were suspended in dioxane (1 ml) and water (0.5 ml) and heated to 130° C. in the microwave for 15 min. The reaction mixture was quenched with 2 ml of water and 3 ml of DCM and the organic phase separated using a hydrophobic fritted tube. The organic phase was concentrated and the residue purified by prep basic HPLC to give 3-cyclopropyl-1-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)imidazolidine-2,4-dione (Example 7a) 21.3 mg (53%); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, 1H) 7.63 (d, 1H) 7.58 (m, 3H) 7.35 (d, 2H) 4.59 (s, 2H) 4.37 (s, 2H) 3.71 (s, 2H) 2.96 (m, 1H) 2.64 (m, 1H) 1.01-0.86 (m, 8H) LCMS m/z (M+H) 402.2.
Reaction SMILES: C([O-])(=O)C.[NH4+].Cl.[CH3:7][O:8][C:9]1[C:14]([NH2:15])=[C:13]([O:16][CH3:17])[C:12]([NH2:18])=[CH:11][C:10]=1[Cl:19].O.C(N(CC)CC)C>[Pd].C(O)C.C(O)=O>[ClH:19].[NH2:15][C:14]1[C:13]([O:16][CH3:17])=[C:12]([NH2:18])[CH:11]=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: COc1c(N)cc(Cl)c(OC)c1N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=CO
Product: COc1ccc(N)c(OC)c1N
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
The mixture consisting of 77 g of ammonium acetate, 42 g of 10% palladium on charcoal, 0.25 mole (69 g) of 2,4-dimethoxy-3,5-diaminochlorobenzene hydrochloride in 420 ml of ethanol containing 50 ml of water was heated to 75° C. with stirring. 75 g of triethylamine were added and then, 31 g of formic acid were added dropwise. After 30 minutes of additional heating, the reaction mixture was filtered while hot. The filtrate was evaporated to dryness. Upon addition of ethyl acetate, the inorganic salts were precipitated and removed by thorough draining. 10 ml of an alcoholic solution of 7N hydrochloric acid were added to the filtrate which had been dried over sodium sulphate. The expected product precipitated, it was recrystallized from a mixture of water and a solution of hydrochloric acid in ethanol.
Reaction SMILES: FC1C=C([N+]([O-])=O)C(OC)=CC=1CO.[F:15][C:16]1[C:24]([O:25][CH3:26])=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[F:15][C:16]1[C:24]([O:25][CH3:26])=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=[CH:21][C:17]=1[CH2:18][OH:19]
Reactant: COc1c([N+](=O)[O-])ccc(C(=O)O)c1F
Agent: COc1cc(CO)c(F)cc1[N+](=O)[O-]
Product: COc1c([N+](=O)[O-])ccc(CO)c1F

Procedure:
The title compound was prepared using the procedure from Compound 130D ((2-fluoro-5-methoxy-4-nitrophenyl)methanol) with 2-fluoro-3-methoxy-4-nitrobenzoic acid (Compound 147E). 1H NMR (CDCl3, 400 MHz): δ=4.08 (d, J=1.77 Hz, 3 H), 4.85 (s, 2 H), 7.29-7.35 (m, 1 H), 7.64 (dd, J=8.46, 1.89 Hz, 1 H).
Reaction SMILES: [C:1]12([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[Cl:24][C:25]1[C:26](=[O:32])[NH:27][N:28]=[CH:29][C:30]=1Cl>C(O)C>[C:1]12([N:11]3[CH2:16][CH2:15][N:14]([C:30]4[CH:29]=[N:28][NH:27][C:26](=[O:32])[C:25]=4[Cl:24])[CH2:13][CH2:12]3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: C1CN(C23CC4CC(CC(C4)C2)C3)CCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]ncc(N2CCN(C34CC5CC(CC(C5)C3)C4)CC2)c1Cl
Yield: 73.7 %

Procedure:
A mixture of 1-(1-adamantyl)piperazine (2.2 g, 10 mmol), triethylamine (1.36 ml, 10 mmol) and 4,5-dichloro-3-oxo-2,3-dihydropyridazine (1.65 g, 10 mmol) in ethanol (25 ml) was heated under reflux for 5 hours. After cooling the precipitated solids were collected, washed with ethanol and dried to afford 2.57 g of the title compound, yield: 73.6%, mp. 292°-294° C.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:14][C@H:13]2[C:15]3[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4]1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH2:4]1[C:5]2=[C:15]3[C:9](=[CH:8][CH:7]=[CH:6]2)[CH2:10][CH2:11][CH2:12][C@H:13]3[CH2:14][C@@H:3]1[CH2:2][C:16]#[N:17]
Reactant: [C-]#N
Reactant: BrC[C@@H]1Cc2cccc3c2[C@@H](CCC3)C1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC[C@@H]1Cc2cccc3c2[C@@H](CCC3)C1

Procedure:
A solution of 1.6 g cis-2-bromomethyl-2,3,3a,4,5,6-hexahydro-1H-phenalene 13 and 330 mg NaCN in 7 ml DMSO (dimethylsulphoxide) was heated at 80°-85° C. for 4 hours. The reaction mixture was then poured into 50 ml water and the product extracted with ether. The organic layer was washed with water, dried and evaporated. This yielded 1.2 g of the nitrile 14.
Reaction SMILES: [Li]CCCC.[NH:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1.CCOC(C)=O>[F:24][C:12]([F:11])([F:23])[C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
n-BuLi (56 mL, 89.7 mmol) was added to a solution of 1H-pyrrole (6.02 g, 89.7 mmol) in THF (179 mL) at −78° C. over 10 minutes. 4-(trifluoromethyl)benzene-1-sulfonyl chloride (26.3 g, 107.6 mmol) was dissolved in THF (20 mL) and added to the reaction mixture over 30 minutes. The reaction was stirred for 30 minutes then allowed to warm to room temperature and stirred for a further 18 h. The solution was diluted with EtOAc washed with brine and the organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc 99/1 to 4/1, v/v) to give compound 111 (21.4 g, 77.7 mmol, 87%). MS (ESI) 276.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1)[CH2:15][CH3:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:18]3[CH2:19][CH2:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]3[CH2:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCCC1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCCC1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Propyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[N:9]=[C:8]([CH:10]=O)[CH:7]=[C:6]([CH3:12])[CH:5]=1)[CH3:2].Cl.NO.[N:18]1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[N:9]=[C:8]([C:10]#[N:18])[CH:7]=[C:6]([CH3:12])[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1cc(C)cc(C=O)n1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCN(CC)c1cc(C)cc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A solution of 6-diethylamino-4-methyl-pyridine-2-carbaldehyde (427 mg, 2.22 mmol) and hydroxylamine hydrochloride (232 mg, 3.33 mmol) in NMP (10 mL) is stirred at 80° C. for 3 h, then at 90° C. for 10 h under microwave irradiation. The solution is cooled to 0° C. before pyridine (1.10 g, 11.3 mmol) and trifluoromethane sulfonic anhydride (3.15 g, 11.2 mmol) is added. The mixture is warmed to rt and stirred for 18 h before it is diluted with DCM (100 mL) and washed with 10% aq. citric acid solution (50 mL) followed by sat. aq. Na2CO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 6-diethylamino-4-methyl-pyridine-2-carbonitrile (329 mg) as a pale yellow solid; LC-MS: tR=1.02 min, [M+1]+=190.02. 1H NMR (CDCl3): δ 1.19 (t, J=7.0 Hz, 6H), 2.28 (s, 3H), 3.52 (q, J=7.0 Hz, 4H), 6.44 (s, 1H), 6.74 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([CH3:28])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(OCC)C>[CH3:28][C:20]1[CH:19]=[C:18]([C@H:10]2[CH2:9][C@@H:8]([C:6]3[O:7][NH:32][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:22][C:21]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)c(C)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)c(C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.4 g, 3.37 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. NaOH (0.135 g, 3.37 mmol) dissolved in water (2 mL) was added during 10 min and the resulting colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.223 g, 3.37 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M HCl and the mixture continued to stir at 80° C. for 20 min. The mixture was dissolved between diethyl ether and water. The phases were separated and the organic phase was dried over Na2SO4, filtered through celite and the solvent removed. Purified by preparative HPLC. Gradient eluation using acetonitrile-acidic buffer, started 40-60 and ended 55-45. Cis-methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.37 g, 29%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.80-1.87 (m, 1H), 2.07-2.28 (m, 2H), 2.31-2.38 (m, 1H), 2.41 (s, 3H), 3.03-3.10 (m, 1H), 3.35-3.43 (m, 1H), 3.66 (s, 3H), 4.13-4.19 (m, 1H), 5.09 (t, 1H), 5.52 (s, 1H), 7.02-7.06 (m, 2H), 7.49 (d, 1H). MS m/z 385 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([O:20][C:21]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[O:38])[CH:32]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([O:20][C:21]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:38])[CH:32]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)c1cccc(-c2cccc(C=O)c2)c1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(-c2cccc(C(O)c3ccccn3)c2)c1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 2-bromopyridine (1.51 g, 9.58 mmol) in dry tetrahydrofuran (20 mL) was stirred under nitrogen at −78° C. and 2.5M n-butyllithium in hexanes (3.8 mL, 9.5 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 30 min. when a solution of 9 (2.1 g, 6.1 mmol) in tetrahydrofuran (15 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued at −78° C. for 20 min., then for 2 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (150 mL) and extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×100 mL), dried over sodium sulfate and stripped. The crude 10 was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH:14][CH3:15])=[N:12][CH:13]=2)[CH:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH:14][CH3:15])=[N:12][CH:13]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CNc1ncc(-c2cc(Cl)nc(Cl)n2)cn1
Reactant: C1COCCN1
Solvent: CC#N
Product: CNc1ncc(-c2cc(N3CCOCC3)nc(Cl)n2)cn1

Procedure:
According to Method 6, the reaction of 2,6-dichloro-N-methyl-4,5′-bipyrimidin-2′-amine with morpholine in acetonitrile gave 2-chloro-N-methyl-6-morpholino-4,5′-bipyrimidin-2′-amine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([NH:26][C:27]([NH:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:7]([F:14])=[CH:8][C:9]([F:13])=[CH:10][C:11]=1[F:12])=[O:4])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN=C=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F
Product: CCCCNC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F

Procedure:
Following the procedure of Example 58 only using the product of Example 50 and n-butylisocyanate, the title compound was obtained, mp 217°-218° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.[F:12][C@@H:13]1[C@H:17]([OH:18])[C@@H:16]([CH2:19][OH:20])[O:15][C@H:14]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:12][C@@H:13]1[C@H:17]([OH:18])[C@@H:16]([CH2:19][OH:20])[O:15][C@H:14]1[N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[O:2][CH3:1]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: COc1ncnc2nc[nH]c12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C

Procedure:
6-Methoxypurine (Sigma Chemical Company; 0.8 g, 5.3 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.4 g, 1.6 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 20 ml of 10 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (2,400 I.U.) and purine nucleoside phosphorylase (3,900 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 6 the reaction was diluted to 100 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. On day 16, 2,640 I.U. thymidine phosphorylase and 4,360 I.U. purine nucleoside phosphorylase were added. On day 45, the reaction was evaporated. The residue was suspended in warm methanol and the suspension was filtered. The filtrate was evaporated. The residue was dissolved in warm water and applied to a 2.5×7 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). After washing with water, the product was eluted with methanol/water (9/1). Product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain title compound which analyzed as a 0.3 hydrate.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>COCCO>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:27]
Reactant: NCCCCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NCCCCC(=O)O)c(O)c2cc(Oc3ccccc3)ccc12
Yield: 47.9 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (60 mg, 0.17 mmol) (prepared according to U.S. Pat. No. 7,928,120), 5-aminovaleric acid (970 mg, 8.28 mmol) and NaOMe (360 mg, 6.62 mmol) in 2-methoxyethanol (15 mL) was refluxed for 1.5 h. Solvent was evaporated, and the residue was partitioned between EtOAc and water. 1 M HCl was added with stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by preparative TLC (40% EtOAc/hexanes+2% AcOH) to give 33 mg of the title compound. MS: (+) m/z 406.13 (M+1).