Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]([CH2:49][CH3:50])[C:46]([NH2:48])=[O:47])#[CH:38].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:48][C:46](=[O:47])[CH:45]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37]#[C:38][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1)[CH2:49][CH3:50]
Reactant: C#Cc1ccccc1C(CC)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 68.2 %

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K3) (193 mg, 0.422 mmol), PdCl2(PPh3)2 (15 mg, 0.021 mmol), t-Bu3PH.BF4 (6 mg, 0.021 mmol), CuI (4 mg, 0.021 mmol) and 2-(2-ethynylphenyl)butanamide (K1) (87 mg, 0.47 mmol) in DMF (3.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes. The volatiles were removed under reduced pressure and the residue was adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A1 as a yellow solid (175 mg, 68%); 1H NMR (400 MHz, d6-DMSO) δ 10.39 (s, 1H), 8.88-8.76 (m, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.63-7.47 (m, 3H), 7.37 (td, J=7.4, 1.6 Hz, 1H), 7.27-7.17 (m, 3H), 7.01 (s, 1H), 4.07 (s, 2H), 3.89 (dd, J=8.6, 6.4 Hz, 1H), 2.80 (br, 2H), 2.64 (J m, 1H), 1.98-1.90 (m, 1H), 1.74 (d, J=12.7 Hz, 2H), 1.70-1.60 (m, 1H), 1.55-1.44 (m, 2H), 1.42 (s, 9H), 0.87 (t, J=7.3 Hz, 3H). LCMS-A: rt 6.726 min; m/z 606 [M−H]−.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Na].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][CH2:19][CH:18]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:17]=2[CH:39]=1>C(COC)OC>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:17]=2[CH:39]=1
Reactant: CCOC(=O)CC1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)cc21
Agent: [Na]
Solvent: COCCOC
Solvent: c1ccc2ccccc2c1
Product: CCOC(=O)CC1CCCNc2ccc(Cl)cc21
Reaction time: 1 h
Yield: 36.8 %

Procedure:
To a solution of naphthalene (15.5 g) in dimethoxyethane (100 ml) was added sodium metal (2.79 g) in portions at 0° C. and the solution was stirred at the same temperature for 1 hour. The naphthilide was added to a solution of 7-chloro -5-ethoxycarbonylmethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (9.89 g) in dimethoxyethane (400 ml) at -60° C. and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water and the solution was extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oil and the crude oil was purified by silica gel column to give 7-chloro-5-ethoxycarbonylmethyl -2,3,4,5-tetrahydro-1H-1-benzazepine (2.31 g).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]CC(=O)C(C1C=CC=CC=1)C1C=CC=CC=1.[NH:34]1[CH2:39][CH2:38][CH2:37][NH:36][C:35]1=[S:40]>CC(C)=O>[BrH:17].[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2([OH:10])[N:36]3[CH2:37][CH2:38][CH2:39][N:34]=[C:35]3[S:40][CH2:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: S=C1NCCCN1
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: Br
Product: OC1(C(c2ccccc2)c2ccccc2)CSC2=NCCCN21
Reaction time: 48 h

Procedure:
A 2.1 g. portion of 1,1-diphenyl-2-propanone is converted to 1-bromo-3,3-diphenyl-2-propanone by the procedure of Example 22. The 1-bromo-3,3-diphenyl-2-propanone is dissolved in 15 ml. of acetone and added to a boiling mixture of 0.80 g. of tetrahydro-2-pyrimidinethione in 70 ml. of acetone. This mixture is allowed to stand for 48 hours and the resulting solid is collected by filtration, giving the desired product, m.p. 196°-198° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CC(=O)Nc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CC(=O)Nc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from N-{3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-phenyl}-acetamide (A-34) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=390.1 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[N:24]([CH:25]=2)[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:28][CH:27]=2)[S:21]3)=[CH:14][CH:13]=1)C.CO.[OH-].[Na+].Cl>O1CCCC1>[CH2:33]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2[S:21][C:20]3=[N:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:11]([OH:37])=[O:10])=[CH:13][CH:14]=4)=[CH:25][N:24]3[N:23]=2)=[CH:31][CH:30]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)OCC)cc4)nc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)O)cc4)nc3s2)cc1
Yield: 102.5 %

Procedure:
To a solution of 4-[2-(4-butyloxyphenyl)imidazo[2,1-b]-[1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (2.05 g) in the mixture of methanol (41 ml) and tetrahydrofuran (20.5 ml) was added 2N NaOH aq. (19.1 ml) and refluxed for 17 hours. The reaction mixture was adjusted to pH 1-2 with 1N HCl and the resulting precipitate was collected by filtration to give 4-[2-(4-butyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (1.544 g).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]=[C:19]2[S:23][C:22](=[S:24])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]2=[O:29])[N:17]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:9][C:10](=[S:11])[NH:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]=[C:19]2[S:23][C:22](=[S:24])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]2=[O:29])[N:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC(=S)NC(=O)c3ccccc3)n2)SC1=S
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.6 g of benzoyl isothiocyanate were added dropwise, at room temperature, to a solution of 4 g of 5-(2-aminothiazol-4-ylmethylene)rhodanine-3-acetic acid in 70 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 6 hours. then ethyl acetate was added and precipitated solids were filtered off. The ethyl acetate solution was washed with water and concentrated under reduced pressure, and the crystalline solid thus obtained was separated by filtration and recrystallized from acetic acid, giving the title compound as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.Cl[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C>CCO>[CH3:17][N:16]1[C:12]([N:7]2[CH2:6][CH2:5][NH:4][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:8]2)=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[N:15]1
Reactant: FC(F)(F)C1CNCCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCNC(C(F)(F)F)C1
Temperature: 140 °C
Yield: 104 %

Procedure:
A mixture of (±)-2-(trifluoromethyl)piperazine (1 g, 6.2 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole (2.1 g, 13 mmol), DIPEA (2.4 g, 18.6 mmol) in EtOH (10 mL) was heated in a microwave oven at 140° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (10:1) as eluting solvents to afford (±)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-3-(trifluoromethyl)piperazine as a yellow oil (1.8 g, 99%). MS (ESI) m/z: 280 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])=O)=[CH:10][CH:9]=2)[C:3]=1[C:28]#[N:29].[OH2:30].[NH2:31][NH2:32].FC(F)(F)C(O)=O>>[NH2:29][C:28]1[C:3]2[C:4]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=4[O:26][CH3:27])=[O:30])=[CH:10][CH:9]=3)=[N:5][CH:6]=[CH:7][C:2]=2[NH:32][N:31]=1
Reactant: NN
Reactant: O
Reactant: COc1ccc(NC(=O)Nc2ccc(-c3nccc(Cl)c3C#N)cc2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=O)Nc2ccc(-c3nccc4[nH]nc(N)c34)cc2)c(OC)c1

Procedure:
1-[4-(4-Chloro-3-cyanopyrid-2-yl)phenyl]-3-(2,4-dimethoxyphenyl)urea is treated with hydrazine hydrate and then with trifluoroacetic acid under conditions similar to those described in Example 27. 1-[4-(3-Amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2,4-dimethoxyphenyl)urea is obtained in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([S:24][CH3:25])=[N:18][C:19]=2[NH2:23])(=O)C1C=CC=CC=1>CN>[OH:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([S:24][CH3:25])=[N:18][C:19]=2[NH2:23]
Reactant: CSc1nc(N)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Agent: CN
Product: CSc1nc(N)c2ncn(COCCO)c2n1

Procedure:
A mixture of 2.20 g (6.12 mmol) of 9-(2-benzoyloxyethoxymethyl)-2-methylthioadenine and 100 ml of 40% aqueous methylamine was heated on a steam bath with occasional agitation for one hour. The solution was cooled and spin evaporated in vacuo. The resultant oil was leached with five 40 ml portions of hot ether to give a solid; yield, 1.31 g (84%), m.p. 174°-176°. Recrystallization from ethanol gave the analytical sample of 9-(2-hydroxyethoxymethyl)-2-methylthioadenine; λmax (ε×10-3) (10% EtOH in solvent) pH 1-270 (16.7),291 (sh) (11.9), H2O and pH 13-276 (15.2) nm; nmr (DMSO-d6), 2.49 (3H, S), 3.55 (4H, S), 4.65 (1H, br S), 5.55 (2H, S), 7.31 (2H, S), 8.15 (1H, S) δ.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:13])(=O)=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Na+].S(Cl)([Cl:17])=O>CN(C)C=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([Cl:17])(=[O:13])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C

Procedure:
A suspension of 100 g. of sodium 4-acetylbenzenesulfonate in 225 ml. of dimethylformamide is treated with 31 ml. of thionyl chloride and the mixture is stirred at room temperature for 5 minutes, then poured into 1 l. of ice water. The resulting precipitate of 4-acetylbenzenesulfonyl chloride is collected by filtration and washed with ice water. The still-damp product may be used as such without further purification. However, if purification is desired, the following procedure may be used: The product is dissolved in methylene chloride and the solution is dried and evaporated at reduced pressure. Th residual sulfonyl chloride is crystallized from benzene/hexane; m.p. 83°-85° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=[CH:23][CH:22]=1>>[C:14]([O:13][C:11]1[CH:10]=[CH:9][C:3]2[C:4](=[O:5])[C:6]([C:7]#[N:8])=[C:22]([CH3:23])[O:1][C:2]=2[CH:12]=1)(=[O:16])[CH3:15]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC(=O)c1ccc(O)cc1O
Product: CC(=O)Oc1ccc2c(=O)c(C#N)c(C)oc2c1
Reaction time: 8 h

Procedure:
A mixture of 5 g of 2,4-dihydroxybenzoyl acetonitrile, 15 ml of pyridine and 7.5 ml of acetic anhydride was left overnight at room temperature. The next morning the crystals were filtered and recrystallized from ethanol, mp 140°-141° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[C:15]([NH:23][C:24]([NH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Product: COc1cc(NC(=S)NC(=O)c2ccccc2)c(C(N)=O)cc1OC
Yield: 96.3 %

Procedure:
To a stirred mixture of 4 g of 2-amino-4,5-dimethoxybenzamide and 200 ml of ether was added dropwise, a solution of 3.3 g of benzoyl isothiocyanate in 100 ml of ether over 15 minutes. After 24 hours the solid was collected, giving 7 g of 2-[[(benzoylamino)thioxomethyl]amino]-4,5-dimethoxybenzamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][C@@H:18]([NH:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][N:16]1C(=O)C(F)(F)F)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].C(O)(=O)C>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][C@@H:18]([NH:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:17][NH:16]1)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Yield: 95.1 %

Procedure:
(2S,5R)—N-(2-tert-butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (1.07 g, 2.06 mmol) was dissolved in 1,4-dioxane (4.2 mL), to which was added water (1.1 mL), and followed by ice cooling. To this was added 1M sodium hydroxide aqueous solution (6.3 mL), and followed by reaction at the same temperature for 2.5 h. pH was adjusted to ca. pH 7 by the addition of acetic acid to the reaction mixture. The organic solvent was distilled off under reduced pressure. The resulting aqueous solution was extracted with ethyl acetate. After the organic layer was washed with saturated brine, and dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to afford 0.80 g of the title compound (yield 93%).
Reaction SMILES: C(OC([N:11]1[CH2:16][C@H:15]([CH3:17])[C@:14]([OH:19])([CH3:18])[C@H:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:24]([O:23][C:21](=[O:22])[NH:20][C@H:13]1[C:14]([OH:19])([CH3:18])[C@@H:15]([CH3:17])[CH2:16][NH:11][CH2:12]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Benzyl-(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate (414 mg, 1.09 mmol) in a vial was dissolved in MeOH (10 mL) and 10% palladium on carbon (100 mg) was added. The vial was closed with septum and connected to a balloon filled with hydrogen. The reaction mixture was stirred at room temperature overnight. The solution was filtered to remove the palladium on carbon and solvent was evaporated under reduced pressure to give the sub-title compound as a colorless oil (245 mg, 92%), which was used in the next step without further purification. LCMS calc. for C12H25N2O3 (M+H)+ m/z=245.2. found 245.1.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](B(O)O)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([OH:16])[CH3:15].[C:17](=[O:20])([O-])[O-].[Na+].[Na+].Cl>C1COCC1.O>[CH2:14]([O:16][C:17](=[O:20])[CH2:1][C:5]1[CH:10]=[CH:9][C:8]([C:8]2[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH:7]=2)=[CH:7][CH:6]=1)[CH3:15]
Reactant: CC(C)(C)C1CC=C(B(O)O)CC1
Reactant: CCO
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(C2=CCC(C(C)(C)C)CC2)cc1
Temperature: 140 °C

Procedure:
To a mixture of 4-bromophenyl ethyl acetate (780 mg), 4-t-butyl-cyclohexen-1-yl boronic acid (897 mg), PdCl2(P(o-tolyl)3)2 (254 mg) in THF:ethanol:water (8 mL:4 mL:2 mL), added sodium carbonate (1.377 g). The sealed flask was heated at 140° C. for a 5 min period. The heterogeneous mixture was treated with an excess of 1M aqueous hydrochloric acid and filtered through a celite pad. The organic solvents were removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and chromatographed on silica gel using an ethyl acetate/hexanes gradient. The product was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:22])[CH2:12][C:13]1[N:18]=[C:17]([O:19]C)[CH:16]=[C:15]([Cl:21])[N:14]=1.C(#N)C.C[Si](C)(C)Cl>C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:22])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15]([Cl:21])[N:14]=1
Reactant: COc1cc(Cl)nc(CC(=O)N2CCc3c(F)cccc32)n1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21

Procedure:
2 g of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-chloropyrimidin-2-yl)ethanone are added to a microwave tube with 30 ml of acetonitrile. 3.1 g of KI and 2.4 ml of trimethylchlorosilane are added. After microwave irradiation for one hour at a temperature of 100° C., the reaction medium is diluted with 100 ml of ethyl acetate and 20 ml of water. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 95/05 dichloromethane/methanol, so as to give 1.13 of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](OCC)(OCC)(OCC)[CH3:13]>>[CH3:12][C:13]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2ccc(O)cc2)o1
Yield: 99 %

Procedure:
A mixture of 9.6 parts of 4-hydroxybenzoic acid hydrazide and 44 parts of 1,1',1"-[ethylidynetris(oxy)]trisethane is stirred and refluxed overnight. The precipitated product is filtered off and crystallized from 1-butanol, yielding 10.5 parts (99%) of 4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol; mp. 238.8° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:12]2[O:13][CH2:14][CH2:15][CH3:16])=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCC)[C@H]2[OH:36])=C(N)N=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>P([O-])([O-])([O-])=O.CS(C)=O>[CH2:14]([O:13][C@@H:12]1[C@H:17]([OH:18])[C@@H:19]([CH2:21][OH:22])[O:20][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:36])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH3:16]
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: CCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)nc(N)nc32)O[C@@H]1CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
A mixture of 2,6-Diamino-9-(2'-O-propyl-β-D-ribofuranosyl) purine and 2,6-Diamino-9-(3'-O-propyl-β-D-ribofuranosyl) purine (4.6 gm) and adenosine deaminase (200 mg, Sigma Chemicals Type II) were stirred at room temperature overnight in 0.1M tris buffer (150 ml, pH 7.4), DMSO (100 ml) and 0.1M sodium phosphate buffer (10 ml). A further aliquot of adenosine deaminase (140 mg) in 0.1M phosphate buffer (30 ml) and DMSO (20 ml) was added and the reaction stirred an addition 24 hrs. The solvent was evaporated in vacuo and the residue flash chromatographed on silica gel utilizing 5→20% MeOH/CH2Cl2. Product-containing fractions were evaporated in vacuo and the residue crystallized from H2O to yield 2.6 gm of product. m.p. dec>270° C. 1H NMR (DMSO-d6) δ0.75 (t, 3, CH3), 1.42 (tq, 2, CH2), 3.3-3.6 (m, 4, H-5', O--CH2), 3,85 (m, 1), 4.2 (m, 1), 4.23 (m, 1), 5.10 (t, 1, 5'-OH), 5.13 (d, 1, 3'-OH), 5.75 (d, 1, H-1'), 6.45 (br s, 2, NH2), 7.95 (s, 1, H-8) and 10.67 (br s, 1, NH). Anal. Calcd. for C13H19N5O5 : C, 47.99; H, 5.89; N, 21.53. Found: C, 47.90, H, 5.85; N, 21.44.
Reaction SMILES: Br[C:2]([CH3:30])([CH3:29])[C:3]([NH:5][C:6]1[C:11]2[NH:12][C:13](=[O:16])[CH2:14][O:15][C:10]=2[CH:9]=[C:8]([F:17])[C:7]=1[C:18]1[C:22]([Cl:23])=[C:21]([C:24]([F:27])([F:26])[F:25])[N:20]([CH3:28])[N:19]=1)=[O:4].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:23][C:22]1[C:18]([C:7]2[C:6]3[NH:5][C:3](=[O:4])[C:2]([CH3:30])([CH3:29])[N:12]4[C:13](=[O:16])[CH2:14][O:15][C:10]([C:11]=34)=[CH:9][C:8]=2[F:17])=[N:19][N:20]([CH3:28])[C:21]=1[C:24]([F:27])([F:26])[F:25]
Reactant: Cn1nc(-c2c(F)cc3c(c2NC(=O)C(C)(C)Br)NC(=O)CO3)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1nc(-c2c(F)cc3c4c2NC(=O)C(C)(C)N4C(=O)CO3)c(Cl)c1C(F)(F)F
Yield: 8.5 %

Procedure:
5-(2-Bromoisobutyrylamino)-6-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-7-fluoro-2H-1,4-benzoxazine-3(4H)-one (1.15 g, 2.24 mmol) was dissolved in anhydrous acetonitrile (50 ml) and potassium iodide (0.45 g, 2.70 mmol) and potassium carbonate (0.37 g, 2.70 mmol) were added. Solution was refluxed for 2 hr and water was added. Product was extracted with ethyl acetate and solvent evaporated. Column chromatography on silica gel using hexane-ethyl acetate (7:3) as eluent afforded the title compound (84.0 mg, 0.19 mmol).