Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)=[O:15])C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)=[O:15]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nccn3Cc3ccccc3)c3ncccc23)c1Cl
Agent: [Pd]
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ncc[nH]3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 2.9 %

Procedure:
A suspension of 5-(2,6-dichloro-3,5-dimethoxy-phenyl)quinoline-8-carboxylic acid (1-benzyl-1H-imidazol-2-yl)-amide (Example 160) (100 mg, 1.16 mmol) and palladium hydroxyde (75 mg) in MeOH (5 mL) was stirred for 72 h at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 1:4) followed by trituration in Et2O to provide 15 mg of the title compound as a yellow solid: ES-MS: 442.9 [M+H]+; tR=4.05 min (System 1); TLC: Rf=0.08 (Hex/EtOAc, 1:4).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:30])[C:16](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1)[C:17](=O)[CH3:18]>CO>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:16]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[NH:1][C:17]=1[CH3:18])=[O:30]
Reactant: NC1=CC(=O)CCC1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCCl
Solvent: CO
Product: CC1=C(C(=O)CCCCCCl)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1

Procedure:
37 g (0.33 mol) 3-aminocyclohex-2-en-1-one and 42 g (0.13 mol) 1-chloro-7-(3-nitrophenyl-methylene)-nonane-6,8-dione are boiled under reflux in 400 ml methanol for 38 h. The mixture is concentrated and the residue is chromatographed with toluene/acetone=8/2. The title compound is obtained as a yellow oil. Yield: 18 g (34%).
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[CH3:16][N:17]([CH2:22][C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[C:24]=1[CH3:32])[C:18](=[O:21])[CH:19]=[CH2:20].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[C:7](=[O:13])[NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:20]=[CH:19]/[C:18]([N:17]([CH3:16])[CH2:22][C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[C:24]=3[CH3:32])=[O:21])=[CH:3][C:4]=2[CH2:10][NH:9]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1sc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)sc2ccccc12
Reaction time: 0.17 h
Yield: 54.8 %

Procedure:
A suspension of 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.17 g, 0.63 mmol) in propionitrile (4 mL) and DMF (1 mL) was de-oxygenated with Ar for 10 min. The mixture was treated with N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide (0.20 g, 0.81 mmol) and (i-Pr)2EtN (0.24 mL, 1.3 mmol) and was de-oxygenated with Ar for 5 min. Pd(OAc)2 (14 mg, 0.062 mmol) and P(o-tol)3 (38 mg, 0.12 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux for 4 h, then allowed to cool. The resulting precipitate was isolated by filtration, washed with EtOAc, dissolved in CH2Cl2, and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2) gave the title compound (0.15 g, 56%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.97 (s, 1H), 8.45 (s, 1H), 7.77-7.65 (m, 3H), 7.53 (s, 1H), 7.40-7.29 (m, 2H), 6.98-6.84 (m, 1H), 4.94-4.89 (m, 2H), 4.02 (s, 2H), 3.15-3.10 (m, 3H), 2.43 (s, 3H), 1.70 (s, 1H), 1.49 (s, 6H); MS (ESI) m/e 435 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[OH:30])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:33][CH2:34][O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[O:30][CH2:33][CH2:34][O:35][CH3:36])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCOC)c1
Yield: 97.9 %

Procedure:
A solution of 200 mg (0.47 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate, 200 mg (1.36 mmol, 3 eq) of 2-bromoethylmethyl ether and 390 mg (2.82 mmol, 6 eq) of potassium carbonate in the presence of 28 mg (0.188 mmol, 0.4 eq) of sodium iodide in 8 ml of methyl ethyl ketone is refluxed for 15 hours. The insoluble matter is filtered off and the solvent is evaporated off. The oil obtained is chromatographed on silica gel (10 g FlashSmart column) eluted with 40/60 heptane/ethyl acetate. 223 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(2-methoxyethoxy)biphenyl-4-yl]propanoate are obtained in the form of a yellowish oil. Yield=98%
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19](Br)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/B(O)O)=[CH:33][CH:32]=1.O>COC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19](/[CH:38]=[CH:37]/[C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cnc(Br)cn2)sc1C(=O)NCc1ccccc1
Reactant: OB(O)/C=C/c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: O
Product: Cc1nc(-c2cnc(/C=C/c3ccc(F)cc3)cn2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
Part A. To a solution of 2-(5-bromo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (35 mg, 0.09 mmol, 1.0 equiv) in dimethyl ether (1 mL) was added, Na2CO3 (19 mg, 0.18 mmol, 2.0 equiv), trans-2-(4-fluorophenyl)vinyl boronic acid (37 mg, 0.22 mmol, 2.5 equiv), PdCl2(dppf) (3.0 mg, 5 mol %) and water (0.1 mL) in a sealed tube. The reaction was heated in microwave oven at 100° C. for 1 hr. The reaction mixture was cooled and the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 15:85, v/v] to afford 2-{5-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (25 mg, 64%). MS (M+H)+=431.1, Rt=1.66 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])([O-])=O.CO>[Fe].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)Cc1ccccc1Oc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1ccccc1Oc1cccc(N)c1
Yield: 96.8 %

Procedure:
A mixture of methyl 2-(3-nitrophenoxy)phenylacetate (15 g), methanol (100 ml), glacial acetic acid (100 ml), and iron powder (15.0 g) was gently heated with stirring to reflux. After 30 minutes the mixture was cooled and the excess iron powder was filtered off. This filtrate was poured into water (700 ml) and extracted with ether (2×200 ml). The ether extracts were neutralized by stirring with aqueous sodium bicarbonate then dried, filtered and concentrated to give methyl 2-(3-aminophenoxy)phenylacetate (13.0 g, 97% yield) as a pale yellow oil.
Reaction SMILES: [C:1](/[N:3]=[C:4](\SC)/[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)#[N:2].C[Si](C)(C)[NH:18][O:19][Si](C)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:12][C:10]1[CH:11]=[C:6]([NH:5][C:4]2[O:19][N:18]=[C:1]([NH2:2])[N:3]=2)[CH:7]=[C:8]([Cl:13])[CH:9]=1
Reactant: C[Si](C)(C)NO[Si](C)(C)C
Reactant: CS/C(=N\C#N)Nc1cc(Cl)cc(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1noc(Nc2cc(Cl)cc(Cl)c2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
In a 5 mL microwave vial, (Z)-methyl N′-cyano-N-(3,5-dichlorophenyl)carbamimidothioate (156 mg, 0.6 mmol, Eq: 1.00) and N,O-bis(trimethylsilyl)hydroxylamine (160 mg, 900 μmol, Eq: 1.5) were combined with CCl4 (1 ml) to give a colorless suspension which was capped and heated in a 80° C. oil bath for 2.5 hr. The mixture was concentrated in vacuo and MeOH added. The mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo and the crude material was purified by preparative TLC (silica gel, 1.0 mm, 9:1 DCM/MeOH) to give product which was recrystallized from MeOH and dried in vacuo (89° C., 2 torr, overnight) to give 32 mg (22%) of desired product as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:5].Cl.[NH2:30][OH:31]>>[OH:31][NH:30][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])[C:2]=1[CH3:1])=[O:13]
Reactant: COc1ccc(-c2cccc(C(=O)NCCCCCC(=O)O)c2C)c(OC)c1
Reactant: NO
Agent: Cl
Product: COc1ccc(-c2cccc(C(=O)NCCCCCC(=O)NO)c2C)c(OC)c1
Yield: 35 %

Procedure:
The procedure of the step 3 in Example 80 was repeated except that 6-(2-methyl-3-(2,4-dimethoxyphenyl)-benzamido)hexanoic acid instead of 6-(3-bromo-2-methylbenzamido)hexanoic acid, and hydroxylamine hydrochloride instead of 1,2-phenylenediamine were used and purified by a preparative HPLC (C18, 20% H2O/CH3CN, 20 ml/min) to obtain the title compound (27 mg, 35%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([O:30][CH3:31])=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:39])C(=O)C1.O>CN(C)C=O>[Br:39][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:18]([C:17]1[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=1)=[CH:14][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][CH:11]=3)[CH2:19][CH2:20][CH2:21]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccccc43)nc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(Br)ccc43)nc2c1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (300 mg, 0.73 mmol) in N,N-dimethylformamide (20 ml) was added NBS (193 mg, 1.08 mmol) under an inert atmosphere of nitrogen. The resulting solution was stirred for 1.5 h at −10° C. Then water (150 ml) was added and the reaction was extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel chromatography eluting with 1%-2% ethyl acetate in petroleum ether to afford methyl 3-(6-bromo-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (200 mg, 56%).
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH3:9])[CH:4]([OH:8])[CH2:5][CH2:6][OH:7])#[N:2].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]([CH:4]1[CH2:5][CH2:6][O:7][C:11]([CH3:16])([CH3:12])[O:8]1)([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)(C#N)C(O)CCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)OCCC(C(C)(C)C#N)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Optically active 4-cyano-4-methyl-3-hydroxy-1-pentanol (500 mg) was dissolved in acetone (5 mL) and p-toluenesulfonic acid (50 mg) and powder molecular sieve 4A (100 mg) were added. The mixture was stirred at room temperature for 1 hr. Thereto was added a powder of potassium carbonate to neutralize the reaction mixture, which was filtrated and concentrated under reduced pressure to give optically active 4-(1-cyano-1-methylethyl)-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)O1.[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:21]1[C:26]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: Clc1nccnc1Cl
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(-c2nccnc2Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 0.10 g (0.38 mmol) [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid in 1.2 ml of dioxane was added 0.17 g (1.15 mmol) of 2,3-dichloropyrazine, 2.57 mg (0.009 mmol) of tricyclohexylphosphine, 3.5 mg (0.004 mmol) of Pd2(dba)3, and 0.51 ml (1.27 M, 0.65 mmol) of aqueous potassium phosphate solution. The resulting suspension was degassed for 10 minutes. After 30 min in the microwave at 100° C., the reaction mixture was cooled, acidified with 1N HCl, extracted with ethyl acetate, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford crude [4-(3-chloropyrazin-2-yl)phenyl]acetic acid. ES-MS M+1=249.1.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([C:15]([OH:17])=O)[C:8]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:14]=1)(=[O:4])(=[O:3])[NH2:2].O1CCOCC1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N>O.C(N(CC)CC)C>[CH2:12]1[CH2:11][O:10][C:9]2[C:8](=[C:7]([CH:6]=[C:5]([S:1](=[O:3])(=[O:4])[NH2:2])[CH:14]=2)[C:15]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[N:24]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)=[O:17])[O:13]1
Reactant: NS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Reactant: c1cnc(N2CCNCC2)nc1
Agent: N
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cc2c(c(C(=O)N3CCN(c4ncccn4)CC3)c1)OCCO2
Temperature: 10 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
146 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid, 300 ml of dioxane and 57 g of triethylamine were introduced into a 1-liter 3-neck flask provided with an agitator, a thermometer and an introduction funnel. The mixture was heated to 40°-50° C. and 80 ml of water was added. The solution was cooled to a temperature of from 5°-10° C. and 61.5 g of ethyl chloroformiate was added. Agitation of the mixture was maintained for one hour at 10° C. and 93 g of 1-(2-pyrimidinyl)-piperazine was added without the temperature rising above 15° C. Agitation of the mixture was continued for one hour at ambient temperature and then, after the addition of 1,500 ml of water, the mixture was rendered alkaline to a pH of 10 with ammonia. The crystals produced after distillation under vacuum of the solvents and cooling were dried off, washed with water, dried in a drying oven at 50° C. and then purified by treatment with 120 ml of chloroform. After filtration and drying, 92 g of 1-(2,3-ethylenedioxy-5-sulfamoylbenzoyl)-4-(2-pyrimidinyl)-piperazine was produced (M.P.: 239° C.; yield: 40.2%). The structure was confirmed by nuclear magnetic resonance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(C)[CH:13]=[CH:12]C([Mg]Br)=[CH:10][CH:9]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[CH3:10][CH2:9][CH2:8][CH2:13][CH2:12][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:2]
Reactant: Clc1ccccc1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCCCCCCCC
Yield: 50 %

Procedure:
Chlorobenzene (45.0 mg, 0.4 mmol) and a THF solution of p-tolylmagnesium bromide (0.98 mL, 1.02 M, 1.0 mmol) was added to CoF2.4H2O (3.38 mg, 0.02 mmol), and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (25.6 mg, 0.06 mmol) at 0° C. under argon atmosphere. The mixture was reacted at 60° C. for 24 hours. After cooled to the ambient temperature, 1.0 mL of saturated sodium potassium tartrate aqueous solution was added to the reaction mixture. The water layer was extracted five times using Et2O. The total organic extract was filtrated by Florisil pad (100-200 mesh, Nacalai Tesque, Inc.). As the internal standard, gas chromatographic analysis was performed using undecane (42.2 μL, 0.2 mmol) (yield=91%). After removing the solvent under reduced pressure, the crude product was purified by silica gel chromatography (pentane), thereby obtaining the above compound, which was a colorless liquid (0.059 g, yield=88%, purity=>99% (GC analysis)).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH2:9])=[O:8])[CH:2]=1.[N:11]([C@H:14]([C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1)[CH3:15])=[N+:12]=[N-:13].CN(C)CCN.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[N:11]([C@H:14]([C:16]1[CH:21]=[C:20]([NH:9][C:7](=[O:8])[C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=2)[CH:19]=[N:18][CH:17]=1)[CH3:15])=[N+:12]=[N-:13]
Reactant: Cc1cccc(C(N)=O)c1
Reactant: C[C@H](N=[N+]=[N-])c1cncc(Br)c1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)Nc2cncc([C@H](C)N=[N+]=[N-])c2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
A mixture of m-toluamide (164 mg, 1.21 mmol), 3-[(1S)-1-azidoethyl]-5-bromopyridine (227 mg, 1 mmol), copper (I) iodide (9.6 mg, 0.05 mmol), N,N-dimethylethylene diamine (0.011 mL, 0.1 mmol) and potassium carbonate (276 mg, 2 mmol) in dioxane (1 mL) was heated in a microwave reactor at 110° C. for 30 minutes then at 160° C. for a further 30 minutes. After this time the mixture was allowed to cool to room temperature, was diluted with ethyl acetate (5 mL) and was filtered through Celite. The filtrate was concentrated under reduced pressure to give a brown oil which was purified by flash chromatography (silica, ethyl acetate/dichloromethane) to give N-{5-[(1S)-1-azidoethyl]pyridin-3-yl}-3-methylbenzamide (80 mg, 28%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH:16]=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:16][CH:13]3[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12]3)[CH2:30][CH2:31]2)=[CH:23][CH:24]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)C1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(CN2CCC(Cc3ccc(F)cc3)CC2)C1
Reaction time: 2 h

Procedure:
A solution of (+/−)-N-(benzyloxycarbonyl)-3-pyrrolidinecarboxaldehyde (416 mg, 1.79 mmol) and 4-(4-flourophenylmethyl)piperidine (518 mg, 2.69 mmol) in dry CH2Cl2 (15 mL) were stirred for 15 min when sodium triacetoxyborohydride (759 mg, 3.58 mmol, Aldrich) was added. The reaction was stirred for 2 h and then quenched with 1M aqueous HCl (50 mL) and CH2Cl2 (200 mL). The reaction was brought to pH 11 with 1M aqueous NaOH. The organic layer was separated, washed with brine, dried over MgSO4, and conc. in vacuo to a pale yellow oil. The oil was purified by radial chromatography (SiO2, CH2Cl2:MeOH, 97:3) to yield the product as a colorless oil. MS (ESI) 411 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[N:31]=[C:30]3[S:32][C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])=[N:34][C:29]3=[CH:28][CH:27]=2)[CH:21]=[CH:22][C:23]=1[F:24].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[N:31]=[C:30]3[S:32][C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])=[N:34][C:29]3=[CH:28][CH:27]=2)[CH:21]=[CH:22][C:23]=1[F:24])=[O:5]
Reactant: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: CC(C)(C#N)Oc1cccc(C(=O)Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)Oc1cccc(C(=O)Nc2cc(Nc3ccc4nc(NC(=O)C5CC5)sc4n3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethoxy)benzoyl chloride synthesized above in N,N-dimethylacetamide (4.0 mL) was added N-{5-[(3-amino-4-fluorophenyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.582 mmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100) and crystallized from hexane/ethyl acetate to give the title compound (216 mg, 66%) as pale-purple crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[CH2:20]([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:21](=[CH2:23])[CH3:22]>C(O)CCC>[CH:25]1([N:24]([CH2:20][C:21](=[CH2:22])[CH3:23])[C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: C=C(C)CNC1CCCCC1
Solvent: CCCCO
Product: C=C(C)CN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)C1CCCCC1
Yield: 43 %

Procedure:
4.3 g. 6-chloro-9-(β-D-ribofuranosyl)-purine and 7.6 g. methallyl-cyclohexylamine were heated under reflux for 2 hours in 50 ml. butanol. The reaction mixture was evaporated in a vacuum and the residue obtained was dissolved in 50 ml. ethyl acetate and then extracted twice with 50 ml. amounts of water. The organic phase was dried, again evaporated and the residue recrystallized from methanol. 2.6 g. (43% of theory) N(6)-cyclohexyl-N(6)-methallyl-adenosine were obtained; m.p. 110°- 112° C.