Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.N1CCC(C2CC3C(=CC=CC=3)NC2=O)CC1>>[NH:15]1[CH2:16][CH2:17][CH:12]([N:3]2[C:2](=[O:1])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3ccccc3CC2=O)CC1
Agent: O=C1Nc2ccccc2CC1C1CCNCC1
Product: O=C1Cc2ccccc2CN1C1CCNCC1
Yield: 96 %

Procedure:
tert-Butyl 4-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate (730 mg, 2.2 mmol) was reacted in a manner analogous to the preparation of 3-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one. Title compound was obtained as yellow solid in 96% yield. MS m/e (M+H)+=231.4.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([O:13]CC)=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:17]>CO>[CH2:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([NH2:17])=[O:13])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCn1nc(C(=O)OCC)cc1C
Agent: [OH-]
Solvent: CO
Product: CCCCn1nc(C(N)=O)cc1C

Procedure:
A solution of ethyl 1-butyl-5-methyl-1H-pyrazole-3-carboxylate (18.1 g, 86.1 mmol) in methanol (25 mL) was treated with ammonium hydroxide (25 mL) according to a modification of the method described in Part D of Examples 1-4. At the end of the reaction, the methanol was removed under reduced pressure, and the remaining solution was cooled in a refrigerator. A precipitate formed, was isolated by filtration, and was washed with water. The solid (9 g) was recrystallized from hexane (300 mL) and ethyl acetate (30 mL), isolated by filtration, washed with hexane, and air-dried to provide 6.95 g of 1-butyl-5-methyl-1H-pyrazole-3-carboxamide as colorless plates, mp 113.5-114.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH2:8][CH2:7]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCN(c2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 1.85 g (6.33 mmol) of [1-(2-nitro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester in methanol (100 mL) is added 0.65 g (0.61 mmol) of 10% palladium on carbon. The mixture is placed under an atmosphere of hydrogen and shaken at room temperature overnight. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide 1.60 g (96.4%) of [1-(2-amino-phenyl)-piperidin-4-yl]-acetic acid ethyl ester as an orange oil.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[NH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=2[N:10]=1)C.[OH-].[Na+].Cl>CCO>[F:25][C:21]1[CH:20]=[C:19]([C@@H:6]([NH:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[N:10]=2)[CH2:5][C:4]([OH:26])=[O:3])[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C[C@H](NCc1ccc2c(n1)NCCC2)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@H](NCc1ccc2c(n1)NCCC2)c1cccc(F)c1
Reaction time: 1 h

Procedure:
To a solution of ester 9-2 (450 mg, 1.26 mmol) in EtOH (3 mL) was added 1N NaOH (1.39 ml, 1.39 mmol). After stirring for 1 h, the solvents were evaporated and the residue was dissolved in 1N HCl (1.39 ml, 1.39 mmol). The solution was concentrated and then azeotroped with CH3CN to give the acid 9-3 as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[CH3:13][CH:14]([CH3:34])[C:15]([O:17][C@H:18]([C@@H:21]1[CH2:25][C@@H:24]([O:26][C:27](=[O:29])[CH3:28])[C@@H:23](OC(=O)C)[O:22]1)[CH2:19][CH3:20])=[O:16].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[CH3:34][CH:14]([CH3:13])[C:15]([O:17][C@H:18]([C@@H:21]1[CH2:25][C@@H:24]([O:26][C:27](=[O:29])[CH3:28])[C@H:23]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:22]1)[CH2:19][CH3:20])=[O:16]
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Reactant: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@@H](OC(C)=O)[C@@H](OC(C)=O)O1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (63 mg, 0.34 mmol) in ACN (5 mL) was added BSA (252 μL, 1.02 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 0.5 hour to form a clear solution. After the solution was cooled to room temperature, [(1S)-1-[(2S,4R,5R)-4,5-diacetoxytetrahydrofuran-2-yl]propyl] 2-methylpropanoate (compound 42b, 105 mg, 0.34 mmol) and TMSOTf (113 μL, 0.51 mmol) were added in sequence. After being heated with stirring at 70° C. for 14 hours, the resulting mixture was concentrated in vacuo to remove the solvent and the residue was purified by column chromatography on silica gel (eluting with 0-5% methanol in DCM) to afford 75 mg of [(1S)-1-[(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]propyl] 2-methylpropanoate (compound 42c) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8](/[CH:30]=[CH:31]/[CH2:32][O:33][CH3:34])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:35]1([C@H:41]([NH:43][C:44]([NH2:46])=[O:45])[CH3:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CC(N(C)C)=O>[CH3:34][O:33][CH2:32]/[CH:31]=[CH:30]/[C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:46][C:44]([NH:43][C@@H:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:42])=[O:45])=[CH:3][C:4]=2[N:10]([C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:9]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: COC/C=C/c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: CC(=O)N(C)C
Product: COC/C=C/c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 100 °C

Procedure:
(E)-6-chloro-3-(3-methoxyprop-1-en-1-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (111 mg, 0.239 mmol), (R)-1-(1-phenylethyl)urea (59 mg, 0.359 mmol), Cs2CO3 (194 mg, 0.597 mmol), BrettPhos precatalyst (19.06 mg, 0.024 mmol) and DMA (1.5 ml). The mixture was evacuated and purged with nitrogen six times and heated at 100° C. for 35 min. The mixture was diluted with EtOAc and washed with water, brine, dried (Na2SO4) and concentrated to afford crude (R,E)-1-(3-(3-methoxyprop-1-en-1-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea, which was used in the next step. MS ESI calc'd. for C38H36N5O2 [M+H]+ 594, found 594.
Reaction SMILES: [Br:1][C:2]1[C:11]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:9]([Cl:21])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>O1CCCC1>[Br:1][C:2]1[C:11]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:9]([Cl:21])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCN(c1cc(Cl)cc(C(=O)OC)c1Br)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(c1cc(Cl)cc(C(=O)O)c1Br)C1CCOCC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 93.9 %

Procedure:
To a solution of methyl 2-bromo-5-chloro-3-[ethyl(oxan-4-yl)amino]benzoate (122 mg, 0.32 mmol) in tetrahydrofuran (3 ml) was added 4M NaOH (3.2 ml). The reaction mixture was stirred at 50° C. for 20 hours. The reaction mixture was acidified to pH 2-3 with 6M HCl and extracted with DCM (3×100 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 109 mg (93%, 83% corrected yields) of 2-bromo-5-chloro-3-[ethyl(oxan-4-yl)amino]benzoic acid as a pale yellow foam. LC-MS 89%, m/z=361.9/364.2/365.8, 1H NMR (500 MHz, Chloroform-d) δ 7.50 (d, J=2.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 4.00 (d, J=11.5 Hz, 2H), 3.49-3.27 (m, 2H), 3.21 (t, J=7.4 Hz, 1H), 3.14 (q, J=7.0 Hz, 2H), 1.78 (dd, J=7.4, 3.4 Hz, 4H), 0.93 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26](Br)[CH:27]([CH3:29])[CH3:28]>>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CBr
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2cn(CC(C)C)c3ccccc23)cc(OC)c1OC

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (1.69 g) obtained in Example 1 and isobutyl bromide (0.82 ml) to give Compound 5 (1.32 g).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][C@H:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH3:20])[C:10]2=[O:21])[CH2:6][CH2:5][NH:4]1)#[N:2].[O:22]=[S:23]1(=[O:39])[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[C:25](=[O:33])[N:24]1[CH2:34][CH2:35][CH2:36][CH2:37]Br.[I-].[K+]>>[O:39]=[S:23]1(=[O:22])[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[C:25](=[O:33])[N:24]1[CH2:34][CH2:35][CH2:36][CH2:37][N:4]1[CH2:5][CH2:6][C@@H:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH3:20])[C:10]2=[O:21])[CH2:8][C@@H:3]1[C:1]#[N:2]
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Reactant: CCCn1c(=O)n([C@@H]2CCN[C@@H](C#N)C2)c2ccccc21
Agent: [I-]
Agent: [K+]
Product: CCCn1c(=O)n([C@@H]2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)[C@@H](C#N)C2)c2ccccc21
Temperature: 80 °C

Procedure:
From (±) cis/trans-2-cyano-4-(3-n-propyl-2-oxo-1-benzimidazolinyl)-piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one using a modification of the procedure described in Example 1, Step 4, wherein one equivalent of potassium iodide was added and the reaction was warmed at 80° C. for 24 hours, there was obtained a white solid after chromatographic purification, melting point 159-160° C. The NMR was consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31](OC)=[O:32])=[CH:29][CH:28]=3)[CH3:26])[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:28]=[CH:29][C:30]([CH2:31][OH:32])=[CH:35][CH:36]=3)[CH3:26])[CH:24]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc([C@@H](C)n2cc(C[C@@H]3C(=O)NC=CN3S(=O)(=O)c3ccc(Cl)c(Cl)c3)nn2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@H](c1ccc(CO)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Methyl 4-((R)-1-(4-(((R)-1-(3,4-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-pyrazin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)ethyl)benzoate (1.38, 2.51 mmol) was dissolved in CH2Cl2 (200 mL) and cooled to −78° C. under N2. Dibal (1.5M solution in toluene, 8.4 mL, 12.6 mmol) was then added over 10 min. After 30 min, the cold bath was removed and the reaction was stirred for 4 h. To the solution was added MeOH (20 mL), followed by Na2SO4 (25.1 g) and saturated NH4Cl (2.5 mL). The reaction mixture was stirred overnight. The solids were removed by filtration, and washed with CH2Cl2/MeOH (10/1). The filtrate was concentrated and the residue was chromatographed on silica (100% CH2Cl2 to 5% MeOH in CH2Cl2) to yield the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16](=[O:27])[NH:17][CH:18]1[C:25]2[CH:24]=[CH:23][S:22][C:21]=2[CH2:20][CH:19]1[OH:26])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]([NH:17][CH:18]1[C:25]2[CH:24]=[CH:23][S:22][C:21]=2[CH2:20][CH:19]1[OH:26])=[O:27]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1c2ccsc2CC1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NC(Cc1ccccc1)C(=O)NC1c2ccsc2CC1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 24a was dissolved in chloroform (400 mL) and TFA (100 mL) was added and the mixture was stirred for three hours at room temperature. The organic phase was washed two times with 15% ammonia solution (300 mL) and with brine. The organic phase was dried over sodium sulphate and evaporated. The product was purified by silica gel chromatography with DCM with three to ten percent methanol.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:14]=[C:13]([O:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:9]=1[NH2:10]>>[Br:7][C:8]1[CH:14]=[C:13]([O:15][C:16]([F:18])([F:19])[F:17])[CH:12]=[CH:11][C:9]=1[NH:10][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1]
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1ccc(OC(F)(F)F)cc1Br

Procedure:
Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 2-bromo-4-(trifluoromethoxy)aniline: ESMS m/e: 325.9 (M+H)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[Br:5][C:6]#[C:7][C:8]([O:10][CH3:11])=[O:9]>S(=O)(=O)(O)O>[Br:5][C:6]([S:1][C:2]#[N:3])=[CH:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: N#C[S-]
Reactant: COC(=O)C#CBr
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: COC(=O)C=C(Br)SC#N
Reaction time: 0.08 h

Procedure:
To a stirred solution of ammonium thiocyanate (3.06 g., 0.04 mole) in 2M aqueous sulfuric acid (20 ml) at 0° C., methyl 3-bromopropiolate (3.26 g., 0.02 mole) was added dropwise, neat, over 5 minutes. After keeping the temperature at 0° C. for 1 hour, the mixture, consisting of a solid precipitate in the aqueous solution, was extracted with ether which was washed with water, dried (MgSO4), and concentrated. The residual solid was suspended in hexane and removed by filtration, yielding 2.4 g. of product. The solid recrystallized from ethanol as yellowish microcrystals; mp 139°-142.5° C.; IR (KBr) 2170, 1680 cm-1.
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd].C(O)C>[OH:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCOc1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCCOc1ccccc1O

Procedure:
A mixture of (3) (1.57 g, 5.0 mM), ethanol (50 mL), glacial acetic acid (7 drops) and 10% palladium on carbon (0.7 g) was reacted in a hydrogen atmosphere (40 p.s.i.) at room temperature until hydrogen uptake ceased. Concentration of the filtered mixture yielded the product (4) as an oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)[S:5][C:6]=1[C:7]1[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:10][N:11]=1.[CH2:30](N(CC)CC)[CH3:31].C([Sn](CCCC)(CCCC)C=C)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH3:17][Si:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][O:13][CH2:12][N:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:6]1[S:5][C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)=[N:3][C:2]=1[CH:30]=[CH2:31]
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1cc(-c2nc(Br)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C=Cc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1nccn1COCC[Si](C)(C)C
Yield: 72 %

Procedure:
N-(4-(4-bromo-5-(1((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazol-2-yl)pyridin-2-yl)acetamide (0.80 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.187 g, 0.162 mmol) were placed in a microwave vial and sealed under atmosphere of argon. Triethylamine (7.0 mL, 50 mM), THF (7 mL) and tributylethenyl stannane (0.708 mL, 2.43 mmol) were added and the mixture was irradiated at 95° C. for 3 hours. The solvent was evaporated and the residue was purified using column chromatography on silica gel (0 to 60% EA in hexane) to give the title compound (0.65 g, 72%). LCMS: (FA) ES+, 442. 1H NMR (400 MHz, CDCl3) δ: 8.80 (s, 1H), 8.41-8.31 (m, 1H), 8.09 (s, 1H), 7.70-7.40 (m, 3H), 6.81 (dd, J=17.2, 10.7 Hz, 1H), 6.38 (dd, J=17.2, 1.9 Hz, 1H), 5.54 (dd, J=10.7, 1.9 Hz, 1H), 5.27 (s, 2H), 3.48-3.34 (m, 2H), 2.25 (s, 3H), 0.90-0.84 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:17])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[OH:9])[CH:2]=1.[CH:18]([Mg]Br)=[CH2:19].[Cl-].[NH4+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[OH:9])[CH:18]=[CH2:19])[CH:2]=1
Reactant: C=C[Mg]Br
Reactant: O=C(c1cccnc1)C(O)c1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)(c1cccnc1)C(O)c1ccccc1Cl
Reaction time: 3 h

Procedure:
A solution of 13 g (0.0531 mol) of 1-(pyrid-3-yl)-2-(2-chlorophenyl)-2-hydroxyethanone in tetrahydrofuran (THF) was added dropwise to a freshly prepared solution of 0.18 mol of vinylmagnesium bromide in 80 ml of THF at room temperature. Stirring was carried out for three hours at room temperature, after which the solution was hydrolyzed by adding ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The collected organic phases were dried over Na2SO4 and then filtered, and the filtrate was evaporated down. The crude product was stirred with methyl tert-butyl ether, filtered off under suction and dried to give a product of melting point 110°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][S:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=[C:8]([NH2:20])[N:7]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[S:5][C:6]2[N:7]=[C:8]([NH2:20])[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=2[C:12]=1[NH2:13])=[O:21]
Reactant: COC(=O)CSc1nc(N)nc(-c2ccccc2)c1C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2nc(N)nc(-c3ccccc3)c2c1N
Reaction time: 16 h
Yield: 74 %

Procedure:
Following the method of Perez et al. (Synthesis 1983, 402), to a stirred solution of 0.27 g (0.9 mmol) (2-amino-5-cyano-6-phenyl-pyrimidin-4-ylsulfanyl)-acetic acid methyl ester in 25 ml methanol was added 0.17 ml (0.9 mmol) sodium methylate solutiuon (5.4M in methanol) and stirring continued for 16 hours at reflux. The reaction mixture was then concentrated in vacuo to ca 5 ml and the resulting crystals collected by filtration and washed with ether/methanol (10/1) to afford 0.2 g (74%) 2,5-diamino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester as a yellow crystalline solid. ES-MS m/e (%): 301 (M+H+, 100), 269 ([M+H-MeOH]+, 45).
Reaction SMILES: [OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].CS.Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].[CH2:22]([SH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([S:29][C:12]1[C:13]([N+:19]([O-:21])=[O:20])=[CH:14][CH:15]=[CH:16][C:17]=1[Cl:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1cccc(Cl)c1SCc1ccccc1
Yield: 56 %

Procedure:
It is known to convert chloronitrobenzenes containing activated chlorine atoms to the corresponding aryl methyl sulphides in alcoholic solution or suspension, in the presence of sodium hydroxide solution or potassium carbonate, by the introduction of methanethiol (Houben-Weyl, vol. E 11 (1985), p. 175). The yields achieved by this method, however, are only 52-78% of theory. The reaction of 2,3-dichloro-nitrobenzene with benzylmercaptan in the presence of a base gave 2-chloro-6-nitrophenyl benzyl sulphide in only 56% yield (Bull. 1951, 621-626).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([SH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]>>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[S:7][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]
Reactant: Cc1ccccc1S
Reactant: CC(C)=CCCC(C)=CCBr
Product: CC(C)=CCCC(C)=CCSc1ccccc1C

Procedure:
thio-o-cresol is reacted with 1-bromo-3,7-dimethyl-octa-2,6-diene to produce 3,7-dimethyl-octa-2,6-dienyl o-tolyl sulphide (boiling point = 125°C/0.08 mmHg);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[N:13]=[N:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18].N12CCN(CC1)CC2.O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[N:13]=[N:12][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Cc2ccccn2)nn1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(Cc2ccccn2)nn1)c1ccccc1
Yield: 41.2 %

Procedure:
A solution of 6-(2-pyridinylmethyl)-3-pyridazinol (100 mg, 0.53 mmol), N-methyl-N-phenylcarbamoyl chloride (91 mg, 0.53 mmol) and 1,4-diazabicyclo[2.2.2]octane (60 mg, 0.53 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate) yielding the title compound (70 mg, 41% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[C:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH:9]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[C:8]1[CH2:15][CH2:14][CH:11]([CH:12]=[O:13])[CH2:10][CH:9]=1
Reactant: CC1=CCC(C2=CCC3(CC2)CO3)C1(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1=CCC(C2=CCC(C=O)CC2)C1(C)C
Reaction time: 2 h

Procedure:
6-(2,2,3-Trimethyl-cyclopent-3-enyl)-1-oxa-spiro[2.5]oct-5-ene (XIV, 2.72 g, 12.5 mmol,), dissolved in toluene (5 ml), are added dropwise to a solution of BF3.OEt2 (1.7 ml) in toluene (20 ml). After 2 hours, the reaction solution is poured onto ice (10 ml), then the phases are separated and the organic phase is washed once with saturated NaCl solution. The organic phase is then dried over Na2SO4, filtered off and concentrated in a rotary evaporator. 2.07 g of crude product having a purity of 83% are obtained, which is used in the next step without being purified further.