Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[CH:9]=[C:10]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.Br[C:24]1[CH:25]=[C:26]([C:33]([F:36])([F:35])[F:34])[C:27](=[O:32])[N:28]([CH2:30][CH3:31])[CH:29]=1.C(Cl)Cl.C1CCN2C(=NCCC2)CC1.C1C[O:54][CH2:53]C1>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]>[CH2:30]([N:28]1[C:27](=[O:32])[C:26]([C:33]([F:36])([F:35])[F:34])=[CH:25][C:24]([C:53]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]3[CH:9]=[C:10]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=3)[CH:7]=2)=[O:54])=[CH:29]1)[CH3:31]
Reactant: CCn1cc(Br)cc(C(F)(F)F)c1=O
Reactant: C1CCOC1
Reactant: Cc1ccc(N)cc1-c1cc(N2CCOCC2)c(=O)n(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)Nc2ccc(C)c(-c3cc(N4CCOCC4)c(=O)n(C)c3)c2)cc(C(F)(F)F)c1=O
Temperature: 150 °C
Yield: 15 %

Procedure:
In a microwave tube was added 5-(5-amino-2-methylphenyl)-1-methyl-3-morpholinopyridin-2(1H)-one (1.0 equiv.), 5-bromo-1-ethyl-3-(trifluoromethyl)pyridin-2(1H)-one (2.0 equiv.), PdCl2(dppf).CH2Cl2 adduct (0.1 equiv.), Mo(CO)6 (1.0 equiv.), and THF (0.3 M). The mixture was capped and stirred while DBU (3.0 equiv.) was added, fizzing occurred and the tube was subsequently heated in the microwave at 150° C. for 15 min at which time LCMS indicated full conversion to product (M+H=517). The reaction was filtered, concentrated, and purified via preparative HPLC to yield 1-ethyl-N-(4-methyl-3-(1-methyl-5-morpholino-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (15% yield). 1H NMR (400 MHz, <cd3od>) δ ppm 1.42 (t, J=7.24 Hz, 3H) 2.30 (s, 3H) 3.08-3.21 (m, 4H) 3.64 (s, 3H) 3.80-3.92 (m, 4H) 4.16 (q, J=7.04 Hz, 2H) 6.93 (d, J=1.96 Hz, 1H) 7.28 (d, J=8.22 Hz, 1H) 7.34 (d, J=1.96 Hz, 1H) 7.47-7.60 (m, 2H) 8.48 (d, J=1.96 Hz, 1H) 8.70 (d, J=2.35 Hz, 1H). LCMS (m/z) (M+H)=517.1, Rt=0.81 min.
Reaction SMILES: [CH:1]1([C@H:7]([OH:20])[CH2:8][CH2:9][C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][C@H:11]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[CH:1]1([C@H:7]([O:20][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][O:21]2)[CH2:8][CH2:9][C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][C@H:11]2[O:19][CH:26]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@@H](O)C3CCCCC3)[C@H](O)C[C@@H]2O1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](CC[C@@H](OC3CCCCO3)C3CCCCC3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of the diol 7 (6.0 g, 21.2 mmol) and dihydropyran (7.80 mL, 84.8 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. A catalytic amount of p-TsOH (0.05 g, 0.26 mmol) was added and the mixture was stirred for 30 min at 0° C. The reaction was then quenched by adding sat. aqueous NaHCO3 (10 mL). Layers were separated and the aqueous phase was extracted with 2×25 mL of CH2Cl2. Combined organic layers were dried over anhydrous K2CO3, filtered and concentrated to afford a colorless oil which was purified by passage through a short column of silica (Rf 0.46, 1:1 EtOAc/hexanes). The bis-THP ether 8 (8.59 g, 89% yield) was isolated as a colorless oil which solidified upon standing. 1H NMR (CDCl3) δ (characteristic peaks only) 5.00 (m, 1H), 4.75-4.45 (m, 2H), 3.85 (m, 2H), 3.60-3.30 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[OH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]cc(C(O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 98.7 %

Procedure:
A solution of 5-cyanoindole (2.84 g, 20 mmol) and benzaldehyde (4.24 g, 40 mmol) in MeOH (100 mL) was treated with powdered NaOH (0.8 g, 20 mmol) and stirred at rt for 4 days. The solvent was partially removed in vacuo and the residue diluted with CH2Cl2, washed with water (3×), and dried over Na2SO4, filtered and evaporated to a solid which was triturated with hexanes to provide 3-(hydroxyphenylmethyl)indole-5-carbonitrile as a light yellow solid (4.9 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:24])[CH2:19][C:20](=[O:23])[CH2:21][CH3:22]>>[CH3:16][O:17][C:18](=[O:24])[CH:19]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:12][C:11](=[O:14])[CH2:10][C@@H:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: CCC(=O)CC(=O)OC
Reactant: C[C@@H](CC(=O)CBr)OCc1ccccc1
Product: CCC(=O)C(CC(=O)C[C@H](C)OCc1ccccc1)C(=O)OC
Yield: 46.8 %

Procedure:
After (4S)-4-(benzyloxy)-1-bromopentan-2-one (15 g, 52 mmol) was prepared from the compound of Comparative Example 1 in the process similar to Comparative Example 2, it was reacted with 3-oxopentanoic acid methyl ester (6.5 mL, 52 mmol) to give the title compound (7.8 g, 47%).
Reaction SMILES: C(O[C:9]1[C:10](CO)=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)C1C=CC=CC=1.C(Cl)Cl.C(N(CC)CC)C.CS(Cl)(=O)=O>O>[O:16]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:17][C:13]=2[CH2:14][CH2:15]1
Reactant: OCc1cc2c(cc1OCc1ccccc1)CCO2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: c1ccc2c(c1)CCO2
Temperature: 10 °C
Reaction time: 15 h

Procedure:
A flame dried 1-liter, 3-neck flask fitted with a dropping funnel, mechanical stirrer, N2 inlet, and an internal thermometer was charged with 5-benzyloxy-6-hydroxymethyl-2,3-dihydrobenzofuran (28.90 g, 0.11 moles), methylene chloride (250 ml) and triethylamine (16 ml, 0.11 moles). The reaction mixture was chilled to 10° C. and methanesulfonyl chloride (8.9 ml, 0.11 mole) was added dropwise, while maintaining an internal reaction temperature of 10° C. The resultant yellow-green mixture was warmed to room temperature and stirred for 15 hours. Water (100 ml) was added to the reaction, the layers partitioned and separated. The organic phase was washed sequentially with saturated sodium bicarbonate solution (2×100 ml) and brine (1×100 ml) to remove some greenish color. The yellow organic layear was dried over MgSO4, suction filtered and the filtrate concentrated in vacuo to afford 5-benzyloxy-6-methanesulfonyloxymethyl)-2,3-dihydrobenzofuran a yellow precipitate (33.0 g, 88%). The crude product was used in the next step without further purification which was not necessary for the subsequent reaction.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:28][C:29]1[CH:30]=[C:31]([C:35](=[N:37]O)[NH2:36])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:25]3[O:26][N:37]=[C:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=4)[N:36]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1
Reactant: NC(=NO)c1cccc(F)c1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCC(C#N)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-cyanopiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 60A) and 50 mg (0.33 mmol, 1.5 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 81 mg (77% of theory)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+].N[CH:14]([C:18]([NH2:20])=[O:19])[C:15]([NH2:17])=[O:16].C(O)(=O)C>CO>[C:18]([C:14]1[N:2]=[C:1]([C:3]2[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=2)[NH:17][C:15]=1[OH:16])(=[O:19])[NH2:20]
Reactant: N#Cc1cc[n+]([O-])cc1
Reactant: NC(=O)C(N)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1nc(-c2cc[n+]([O-])cc2)[nH]c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of 4-cyanopyridine N-oxide (600 g) in ahydrous methanol (250 ml) was added sodium methoxide (1.35 g), and this solution was stirred for 0.5 hour at room temperature. To this solution were added aminomalonamide (3.51 g) and acetic acid, and this mixture was stirred for 2 hours under reflux. After cooling the reaction mixture to 0°-5° C., the precipitated product was separated by filtration, washed with ethanol, isopropylether and dried under vacuum to give yellow crystal of 4-(4-carbamoyl-5-hydroxyimidazole-2yl)-pyridine-N-oxide (5.96 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>CCOCC.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:17])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: COc1nc(O)cc(O)n1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1cc(O)nc(OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
142 g (1 mol) of 2-methoxy-4,6-dihydroxypyrimidine are added while stirring to 500 cc of sodium hydroxide solution 2N and the mixture is stirred at 50° for 1 hour. Subsequently it is cooled to room temperature and 139 g (1.1 mol) of dimethyl sulphate are added dropwise while stirring; by the addition of sodium hydroxide solution 2N the pH value is kept at between 8.0 and 8.2. The mixture is stirred at 50° for a further 2 hours, cooled to room temperature and extracted with chloroform. After drying the chloroform phase over sodium sulphate the solvent is decanted in a vacuum. A white powder is obtained. After decomposition with ether/chloroform (1:1), the substance has a M.P. of 197°-201°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[C:26](Cl)(=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:7][C:8]3[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:9]=3)[CH:24]=2)=[O:35])=[CH:28][CH:29]=1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc(C)c(Nc3cc(C(F)(F)F)nc(-c4ccncc4)n3)c2)cc1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (10 mg, 0.029 mmol) and p-anisoyl chloride (6 mg, 0.035 mmol) similar to Example 139 and isolated as a tan solid (10 mg, 71%). 1H NMR (CDCl3): 8.77 (dd, J=1.5, 4.8 Hz, 2H), 8.29 (dd, J=1.5, 4.8 Hz, 2H), 7.99 (s, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.79 (s, 1H), 7.36 (dd, J=1.8, 8.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.02 (s, 1H), 6.99 (d, J=8.7 Hz, 2H), 3.88 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@H:10]2[CH2:23]OS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:29]1([C:32]2[CH:36]=[C:35]([C:37]([O:39]CC)=[O:38])[NH:34][N:33]=2)[CH2:31][CH2:30]1>>[ClH:1].[CH:29]1([C:32]2[N:33]([CH2:23][C@H:10]3[C@H:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[O:15][CH2:14][CH2:13][NH:12][CH2:11]3)[N:34]=[C:35]([C:37]([OH:39])=[O:38])[CH:36]=2)[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COS(C)(=O)=O)C1
Reactant: CCOC(=O)c1cc(C2CC2)n[nH]1
Product: Cl
Product: O=C(O)c1cc(C2CC2)n(C[C@@H]2CNCCO[C@H]2c2ccc(Cl)c(Cl)c2)n1

Procedure:
Using tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate and, ethyl 3-cyclopropyl-1H-pyrazole-5-carboxylate, and in the same manner as in Example 44, the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)([O-])=O.CO.O.NN>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(N)c1

Procedure:
15 g (0.043 mol) of the compound from Example XXVIII are dissolved in 100 ml of tetrahydrofuran and 100 ml of methanol and 4 g (0.08 mol) of hydrazine monohydrate are added. Raney nickel is added in portions under argon with stirring, the temperature rising to 50° C. After the evolution of gas has ended, the mixture is heated to boiling for a further hour and then filtered while hot. The filtrate is concentrated in vacuo and the residual oil is taken up using 250 ml of dichloromethane. After washing twice using water and drying with sodium sulphate, the solvent is evaporated in vacuo and a colourless oil is obtained which crystallises overnight.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[S:22][CH3:23]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[S:22][CH3:23]
Reactant: CSc1ccc(B(O)O)cc1Cl
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Product: COC(=O)c1ccc2occ(-c3ccc(SC)c(Cl)c3)c2c1
Yield: 84 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [3-chloro-4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 84%) was obtained as colorless crystals.
Reaction SMILES: C(OC([NH:8][S:9]([NH:12][C:13]1[C:14]([CH3:38])=[C:15]2[C:19](=[C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]=1[CH3:22])[N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16]2)(=[O:11])=[O:10])=O)(C)(C)C.[ClH:39].CC(O)C.C(OCC)C>C(O)=O>[ClH:39].[CH3:38][C:14]1[C:13]([NH:12][S:9](=[O:10])(=[O:11])[NH2:8])=[C:21]([CH3:22])[C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])=[C:19]2[C:15]=1[CH2:16][CH2:17][N:18]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCN1CCc2c(C)c(NS(=O)(=O)NC(=O)OC(C)(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: O=CO
Product: CCCCCCCCN1CCc2c(C)c(NS(N)(=O)=O)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 0.33 h

Procedure:
The compound (1.86 g) obtained in Example 5 was dissolved in formic acid (7.5 mL) and 8.51 M hydrogen chloride—2-propanol solution (1.98 mL) was added under ice-cooling. The mixture was stirred at the same temperature for 20 min. Diethyl ether (50 mL) was added, and the precipitated crystals were collected by filtration to give the title compound as crystals (1.34 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To stirred solution of the (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (2.5 g, 10 mmol), benzyl bromide (1.8 gm,10 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and the mixture was refluxed for 24 hours At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethyl acetate: hexane. The product, 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester was isolated as a low melting solid. Yield: 3.0 gm 86%; Low melting solid; MS: 349 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10]O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>ClCCl>[ClH:14].[C:1]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][Cl:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccn(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccn(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.07 g of 3-t-butyl-1H-pyrazole-1-ylmethanol was dissolved to 140 ml of dichloromethane. 2 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.66 g of 3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride.
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH:20]([CH3:22])[CH3:21])[C:10]=2/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.[Mn]>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH:20]([CH3:22])[CH3:21])[C:10]=2/[CH:23]=[CH:24]/[CH:25]=[O:26])=[CH:7][CH:8]=1
Reactant: CC(C)c1nn(-c2ccccn2)c(-c2ccc(F)cc2)c1/C=C/CO
Agent: [Mn]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nn(-c2ccccn2)c(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
Manganese IV dioxide (72.2 g, 0.83 mol) was suspended in toluene and refluxed for four hours with azeotropic removal of water. The unsaturated alcohol (28 g, 0.083 mol, Step B) was added and heating to reflux continued for 24 hours. The suspension was then cooled to room temperature and filtered through a bed of silica. The filtrate was concentrated in-vacuo to give 27.0 g of pure product (98%), mp 105°-107° C.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:10][CH:9]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[O:25]=[C:24]1[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](=[O:26])[N:7]1[C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:12][CH:13]=1
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(N3C(=O)c4ccccc4C3=O)cc2)S1
Yield: 92.3 %

Procedure:
Into 30 ml of dioxane were dissolved 1,00 g of 5-(4-amino-phenyl)thiazolidine-2,4-dione and 0.74 g of phthalic anhydride, and the solution was refluxed for 2 hours. Thereafter, 30 ml of acetic acid and 0.5 g of sodium acetate were added and the mixture was refluxed for 2 hours. The reaction liquor was poured into 400 ml of water, and the crystals deposited were collected by filtration. These were recrystalized from ethanol to obtain 1.50 g of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([O:30][CH2:31][CH3:32])[N:25]=[C:24]([NH2:33])[CH:23]=1.NC1C(N)=NC=CC=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([O:30][CH2:31][CH3:32])[N:25]=[C:24]([NH:33][C:12](=[O:14])[CH2:11][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])[CH:23]=1
Reactant: COc1cccc(CC(=O)O)c1OC
Reactant: CCOc1nc(N)cc(N)c1C#N
Agent: Nc1cccnc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1nc(NC(=O)Cc2cccc(OC)c2OC)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To 67 mg (0.34 mmol) of (2,3-dimethoxyphenyl)acetic acid in 1 mL of CH2Cl2 was added 32 μL (0.37 mmol) of oxalyl chloride. The solution was stirred at ambient temperature for 20 minutes then added to a solution of 60 mg (0.28 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile in 0.5 mL of pyridine. The mixture was complete within 5 minutes though some diaminopyridine remained. The solvent was removed under reduced pressure, then the residue was taken up in 10 mL of ethyl acetate and extracted with water (2×5 mL), saturated NaHCO3(aq.) (1×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was recrystallized from 8 mL of methanol to provide 35 mg (35%) of white crystals. 1H NMR (300 MHz, d6-DMSO) δ 10.22 (s, 1H), 7.15 (s, 1H), 6.97 (m, 2H), 6.88 (s, 2H), 6.81 (dd, 1H, J=7.1, 2.0 Hz), 4.35 (q, 2H, J=7.1 Hz), 3.79 (s, 3H), 3.71 (s, 2H), 3.68 (s, 3H), 1.31 (t, 3H, J=7.1 Hz); MS (ESI) m/e=327 (M−Et+H)+, 357 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][OH:42])[CH:36]=2)[C:31]([F:43])=[CH:30][N:29]=1.C1COC2C=CC(N)=CC=2O1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:28]3[N:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][OH:42])[CH:36]=4)[C:31]([F:43])=[CH:30][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: OCc1cccc(Nc2nc(Cl)ncc2F)c1
Agent: Nc1ccc2c(c1)OCCO2
Product: OCc1cccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)c1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.92 (d, 1H, J=3.0 Hz), 7.78 (bs, 1H), 7.41-7.31 (m, 3H), 7.12 (d, 1H, J=7.2 Hz), 6.94 (bs, 1H), 6.81-6.75 (m, 3H), 4.68 (s, 2H), 4.25 (s, 4H); 19F NMR (CDCl3): −47438; LCMS: ret. time: 17.73 min.; purity: 100%; MS (m/e): 369 (MH+).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36]C1C=C(S)C=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:36][C:8]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(S)c1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2cccc(F)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 3-fluoro-thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.