Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C1COCC1>[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:1][CH2:2][C:3]2[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=c1[nH]cccc1CO
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccc[nH]c1=O)c1ccc(I)cc1
Temperature: -80 °C
Reaction time: 0.33 h

Procedure:
A 25 mL round bottom flask was charged with 0.209 g (1.67 mmole) of 3-(hydroxymethyl)pyridine-2(1H)-one and suspended in 15 mL of THF under the presence of argon gas. The solution was cooled to −80° C. in a methanol bath and 1.05 mL (1.68 mmol) of butyl lithium (BuLi) was added dropwise, and the solution stirred for 20 min. 0.4454 g (1.67 mmol) of 4-iodobenzoyl chloride was dissolved in 15 mL of THF, cooled to −80° C. in a methanol bath, then added dropwise into the alcohol reaction mixture. The reaction was stirred for 48 hours at −80° C. under the presence of argon gas. The reaction was then returned to room temperature and was quenched with 20 mL of water. The reaction was washed with ethyl acetate (4×20 mL), the organic layers combined, washed with Brine (3×20 mL), and finally dried over MgSO4. The solvent was removed in vacuo to produce a dull brown solid. The compound was purified by crystallization from toluene. The yield of the product was 0.0652 g (10.99% Yield). MP: 203-205° C. IR: (cm−1): 3415.21 (m, broad), υ (O—H), 3128.97 (m, broad), υ (N—H), 1720.30 (m), υ (C═O), 1613.77 (m), υ (C═C aromatic). 1H NMR (DMSO-d6, 500 MHz) δ: 5.13 (s, 2H), 6.23 (t, J=6.6 Hz, 1H), 7.40 (dd, J=4.5, 2.1 Hz, 1H), 7.59 (dd, J=4.7, 2.1 Hz, 1H), 7.74 (d, J=4.8 Hz, 2H), 7.94 (d, J=4.8 Hz, 2H), 11.78 (s, 1H). 13C NMR (DMSO-d6) δ: 165.76, 161.84, 139.75, 138.29, 135.79, 131.41, 129.58, 126.43, 105.09, 102.35, 62.81. HRMS: m/e, found 377.9583 (M+Na+). Calc. for C13H10INO3Na: 377.9603.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:20]([C:22]1[C:23](=[C:30]([C:33]#[N:34])[C:31]#[N:32])[O:24][C:25]([CH3:29])([CH3:28])[C:26]=1[CH3:27])#[N:21].C([O-])(=O)C.[NH4+]>C(O)C>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:27][C:26]2[C:25]([CH3:28])([CH3:29])[O:24][C:23](=[C:30]([C:31]#[N:32])[C:33]#[N:34])[C:22]=2[C:20]#[N:21])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)c(OC)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
In 5 ml of ethanol were dissolved 170 mg (0.65 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 141 mg (0.71 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 50 mg of ammonium acetate, and the mixture was stirred at 50° C. for 4 hours. Ethanol was evaporated off and the residue was purified by silica gel column chromatography to give 273 mg of a dark brown crystal (yield: 95.1%; mp: 222-226° C.)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9][N:8]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:7]1=[O:23]>C(#N)C.O>[N:1]([CH:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9][N:8]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:7]1=[O:23])=[N+:2]=[N-:3]
Reactant: O=C1C(Br)CC(c2ccccc2)CCN1CC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: [N-]=[N+]=NC1CC(c2ccccc2)CCN(CC2CC2)C1=O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Sodium azide (0.24 g, 3.72 mmol) was added to a solution of 3-bromo-1-(cyclopropylmethyl)-5-phenylazepan-2-one (0.3 g, 0.93 mmol) in acetonitrile (4 mL) and water (1 mL), and the mixture heated to 100° C. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with water (3×), saturated brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=O)=[CH:4][C:3]=1[O:15][CH3:16].CO>O1CCCC1>[CH3:16][O:15][C:3]1[CH:4]=[C:5]([CH2:8][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COc1cc(C(=O)N2CCCC2)ccc1N
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CN2CCCC2)ccc1N
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 49A (220 mg, 3.64 mmol) in tetrahydrofuran (20 mL) at 0° C. was added borane tetrahydrofuran complex (18 mL, 18 mmol) and the mixture was stirred at 0° C. for 2 hours and at 60° C. for 4 hours. After cooling to ambient temperature, methanol (20 mL) was added and stirring was continued for 30 minutes. The organic phase was concentrated and the residue was purified via preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. MS: 207 (M+H+).
Reaction SMILES: C[Si](C#C[Si](C)(C)C)(C)C.C1(CC(Cl)=O)CCCCC1.[CH:21]1([CH2:27][C:28](=[O:31])[C:29]#[CH:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCCCCCCCC>>[CH:21]1([CH2:27][C@H:28]([OH:31])[C:29]#[CH:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C#CC(=O)CC1CCCCC1
Agent: C[Si](C)(C)C#C[Si](C)(C)C
Agent: O=C(Cl)CC1CCCCC1
Solvent: CCCCCCCCC
Product: C#C[C@@H](O)CC1CCCCC1

Procedure:
As directed by D. R. M. Walton and F. Waugh, J. Organomet. Chem. 37, 45 (1972), bis(trimethylsilyl)acetylene is acylated with cyclohexylacetic acid chloride and hydrolysed with aqueous/methanolic borax solution to 1-cyclohexyl-3-butyn-2-one. Reduction with (S)-B-(3-pinanyl)-9-borabiccyclo[3.3.1]nonane ((S)-Alpine-BoraneR, Aldrich, 88% ee) as directed by M. M. Midland et al., Tetrahedron 40, 1371 (1984) yields 1-cyclohexyl-3-butyn-2(S)-ol.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:29])[N:11]3[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH2:2]1.[CH2:30]([O:37][CH:38]1[CH2:41][CH:40]([N:42]2[CH:46]=[C:45](I)[CH:44]=[N:43]2)[CH2:39]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.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].ClCCl.O>[CH2:30]([O:37][CH:38]1[CH2:39][CH:40]([N:42]2[CH:46]=[C:45]([C:15]3[C:6]([O:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:25]([O:27][CH3:28])=[O:26])[C@@H:10]([CH3:29])[CH2:9][CH2:8]4)[CH:44]=[N:43]2)[CH2:41]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: Ic1cnn(C2CC(OCc3ccccc3)C2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3cnn(C4CC(OCc5ccccc5)C4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A 25-mL round-bottom flask was charged with (S)-methyl 5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.100 g, 0.25 mmol), 1-(3-(benzyloxy)cyclobutyl)-4-iodo-1H-pyrazole (0.106 g, 0.30 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.020 g, 0.02 mmol), sodium carbonate (0.053 g, 0.50 mmol), 1,4-dioxane (10 mL) and water (3 mL). The resulting mixture was stirred overnight at 80° C., and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 1-10% ethyl acetate/petroleum ether) to afford (S)-methyl 6-(1-(3-(benzyloxy)cyclobutyl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.060 g, 48%) as a yellow solid. MS (ESI, pos. ion) m/z 502 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][OH:17])[C@@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:13]([C:27]([O:29][CH3:30])=[O:28])[C@@H:12]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:42](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][O:17][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:13]([C:27]([O:29][CH3:30])=[O:28])[C@@H:12]1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Yield: 117.1 %

Procedure:
To a stirred and ice-cooled solution of crude (2R*,3S*,4S*,5S*)-1-benzyloxycarbonyl-4-benzyloxymethyl-5-hydroxymethyl-3-methoxycarbonyl-2-phenylpyrrolidine (15.9 g, ca.29.0 mmol) and imidazole (Im, 7.90 g, 116 mmol) in DMF (32.0 ml) was added t-butyldimethylsilyl chloride (8.74 g, 58.0 mmol)in one portion. The cooling bath was removed immediately after the addition, and the stirring was continued at room temperature for ca.5 hours. The reaction mixture was diluted with PhMe--AcOEt (2:1, 300 ml), washed with H2O (×3), and sat. NaCl aq. solution (×2), dried (MgSO4), and concentrated in vacuo to give a colorless oil (20.5 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 200 g). Elution with n-hexane-AcOEt (50:1→20:1→15:1) gave title compound (16.8 g, 96%) as a colorless viscous oil: IR νmax (film): 1743(s), 1705(vs), 1495(m), 1100(s), 780(s), 745(s), 737(s), 700(s) cm-1 ; 1H-NMR δ: 7.48-7.37(m, 3H), 7.37-7.14(m, 11H), 6.90(br.s, 1H), 5.27(br.d,J=6.1 Hz, 1H), 5.02(br.s, 2H), 4.51-4.41(m, 1H), 4.47(s, 2H), 3.97(dd, J=10.3, 2.6 Hz, 1H), 3.94-3.83(m, 1H), 3.60(d, J=3.7 Hz, 2H), 3.54(dd, J=11.8, 9.5 Hz, 1H), 3.33-3.15(m,1H), 3.28(s, 3H), 0.90(br.s, 9H), 0.05(br.s, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(F)ccc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 28 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a stirred solution of 2,5-difluorotoluene (0.544 g, 4.25 mmol, Aldrich, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.430 g, 4.25 mmol) was added in one portion. The resulting pale yellow solution was warmed to 28° C. and stirred at that temperature overnight. It was then poured into ice (25 g) and extracted with ethyl acetate (40 mL). The extract was dried over Na2SO4 and evaporated to afford 0.555 g (91%) of the title compound as a light red oil; 1H NMR (CDCl3): 2.369 (d, 3H, J=1.8 Hz), 7.127 (dd, 1H, J1 =8.1 Hz, J2 =6.0 Hz), 7.734 (dd, 1H, J1 =8.4 Hz, J2 =6.3 Hz).
Reaction SMILES: CN([C:7]1[CH:8]=[C:9]2[S:15](=[O:17])(=[O:16])[NH:14][C:13](=[O:18])[N:10]2[CH2:11][CH:12]=1)S(C)(=O)=O.[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1>ClCCl>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[N:21]=[C:20]([NH:19][C:13](=[O:18])[NH:14][S:15]([C:9]2[C:8]([N:14]([CH3:13])[S:15]([CH3:9])(=[O:17])=[O:16])=[CH:7][CH:12]=[CH:11][N:10]=2)(=[O:16])=[O:17])[N:25]=1
Reactant: CN(C1=CCN2C(=O)NS(=O)(=O)C2=C1)S(C)(=O)=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2N(C)S(C)(=O)=O)n1

Procedure:
2.9 g (10 mmol) of the compound (II-1) (Example 1) and 1.55 g (10 mmol) of 2-amino-4,6-dimethoxypyrimidine are combined in 30 ml of dichloromethane and refluxed for 8 hours. After the solvent has been removed in vacuo, 4.45 g (100% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-[3-(N-methyl-N-methylsulfonylamino)-2-pyridylsulfonyl]-urea of m.p. 168°-173° C. (decomp.) are obtained in a purity of approx. 90%.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:20][CH:21]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:23][OH:24].[H-].[Na+]>O1CCOCC1>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:24][CH2:23][CH2:22][CH:21]([CH3:20])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(CCO)CC(C)(C)C
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(COCCC(C)CC(C)(C)C)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (7.0 g, 25.6 mmol) is partly solved in dioxane (190 mL) at 80° C. 3,5,5-Trimethyl-hexan-1-ol (124.1 g, 731 mmol) and sodium hydride (1.7 g, 42 mmol, 60% in mineral oil) are added subsequently. The orange reaction mixture is stirred at 80° C. for one hour and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 4.8 g of 2-(2H-Benzotriazol-2-yl)-4-methyl-6-(3,5,5-trimethylhexyloxymethyl)-phenol.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])[CH3:4].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>CN(C=O)C>[C:3]([C:6]1[N:7]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:5])[CH3:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccn1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.32 g, 33 mmol) in DMF (30 ml) was added at an ice bath temperature a solution of 2-acetylpyrrole (3.27 g, 30 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 15 minutes and cooled again. To the solution was added dropwise a solution of 4-fluorobenzylbromide (6.24 g, 33 mmol) in DMF (2 ml). The reaction solution was stirred at room temperature for 1 hour and poured into ice-water, and then extracted with ethylacetate. The ethyl acetate was washed with water and dried. The solvent was evaporated to give 2-acetyl-1-(4-fluorobenzyl)pyrrole (6.5 g) as an oil quantitatively.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[C:4]#[C:3][CH2:2][CH2:1][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH3:17]
Reactant: C#CCCOC1CCCCO1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)C#CCCOC1CCCCO1

Procedure:
The title compound was prepared from 2-but-3-ynyloxy-tetrahydro-pyran and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]=[C:6]([CH:13]2[C:21]3[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:23])[N:5]=1)[CH3:2].CN1C=CN=C1.[F:30][CH:31]([F:36])[S:32](Cl)(=[O:34])=[O:33].Cl>ClCCl.O>[CH2:11]([O:10][C:8]1[N:9]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=[C:6]([CH:13]2[C:21]3[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=3)[N:15]([S:32]([CH:31]([F:36])[F:30])(=[O:34])=[O:33])[C:14]2=[O:23])[N:7]=1)[CH3:12]
Reactant: CCOc1nc(OCC)nc(C2C(=O)Nc3c(F)cccc32)n1
Reactant: O=S(=O)(Cl)C(F)F
Agent: Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: CCOc1nc(OCC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3c(F)cccc32)n1
Temperature: 0 °C

Procedure:
3-(4,6-Diethoxy-1,3,5-triazin-2-yl)-7-fluoro-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.51 g) are introduced as initial charge in 10 ml of dichloromethane and cooled to 0° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (0.46 g) is added dropwise and the mixture is after-stirred for 2 hours at 0° C. to 6° C. After adding 1-methyl-1H-imidazole (0.25 g) and difluoromethanesulfonyl chloride (0.23 g), the mixture is stirred for 2 hours at 0° C. to 10° C. After adding 5 ml of water, the mixture is adjusted to pH 2 using 10% strength hydrochloric acid, the organic solvent is largely distilled off in vacuo, and the solid is filtered off, washed with water and heptane and dried. This gives the title compound as a solid in an HPLC purity of 93% (1.19 g, 83% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[OH-].[Na+].CN(C)C=[O:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][CH:23]=[C:22]2[CH:26]=[O:27])=[CH:17][CH:16]=1>N1C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][CH:23]=[C:22]2[C:26]([OH:12])=[O:27])=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: O=Cc1cccn1-c1ccc(F)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(O)c1cccn1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Potassium permanganate (30.1 g) and sodium hydroxide (15.3 g) were added to a solution of dimethylformamide (380 ml) and pyridine (300 ml), and 1-(4-fluorophenyl)-2-formylpyrrole (30 g) was further added thereto under ice-cooling with stirring. The mixture was warmed to room temperature and stirred further for 3 h. The reaction mixture was filtrated and the filtrate was neutralized with hydrochloric acid. The precipitated crystals were recrystallized from hydrous ethanol to give 1-(4-fluorophenyl)pyrrole-2-carboxylic acid (20 g), melting point 195–196° C.
Reaction SMILES: Cl[C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:3]=1.C(N(CC)CC)C.[CH2:29]([SH:31])[CH3:30].Cl>CN(C)C=O.CCCCCC.O.C(OCC)(=O)C>[CH2:29]([S:31][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:3]=1)[CH3:30]
Reactant: CCS
Reactant: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCSc1nc(Nc2ccc(F)cc2F)c(C(=O)OC)cc1F
Yield: 81.9 %

Procedure:
In 7 ml of N,N-dimethylformamide was suspended 700 mg of methyl 6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and to the resulting suspension were added 340 mg of triethylamine and 210 mg of ethanethiol at room temperature, after which the resulting mixture was subjected to reaction at 50° C. for 4 hours. Subsequently, 40 ml of ethyl acetate and 30 ml of water were added to the reaction mixture, and the pH of the mixture was adjusted to 2 with 2N hydrochloric acid. The organic layer was separated, washed with successively with 20 ml of water and 20 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 10 ml of hexane, after which crystals were collected by filtration to obtain 620 mg (yield 81.9%) of methyl 6-ethylthio-2-(2,4-difluorophenylamino)-5-fluoronicotinate having a melting point of 113°-114° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:19][CH:18]=[CH:17][C:10]=2[N:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)=[O:7].O=S(Cl)Cl.CCN(CC)CC.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH:35][C:14]([C:12]1[N:13]=[C:8]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:9]2[S:19][CH:18]=[CH:17][C:10]=2[N:11]=1)=[O:16]
Reactant: O=C(O)c1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: CN(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)c1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A mixture of 4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidine-2-carboxylic acid ( 290 mg, 1.0 mmol) and SOCl2 (4 mL) was refluxed for 30 min, concentrated in vacuo, and treated with CH2Cl2 (10 mL), Et3N (208 μL, 1.5 mmol) and N,N-dimethylethylenediamine (120 μL, 1.1 mmol). The reaction mixture was stirred at room temperature for 1 h, poured into sat. NaHCO3, extracted with EtOAc (2×10 mL), dried (MgSO4), concentrated in vacuo then triturated with EtOAc and filtered to give the title compound (234 mg, 65%) as a cream solid.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:19][C:20]([F:50])([F:49])[C:21]1[CH:34]=[CH:33][C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][C:41]([O:45][CH2:46][CH2:47][OH:48])([CH3:44])[CH2:40][CH2:39]3)[C:23]=2[CH:22]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:49][C:20]([F:19])([F:50])[C:21]1[CH:34]=[CH:33][C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][C:41]([O:45][CH2:46][CH2:47][O:48][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:44])[CH2:42][CH2:43]3)[C:23]=2[CH:22]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC1(OCCO)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OCCOC1(C)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.7 %

Procedure:
A solution of 3.3 g of hexadecanoic acid chloride in 20 ml of anhydrous benzene was added dropwise at 10° C to a solution of 5 g of 2-trifluoromethyl-10-[3-(4-{2-hydroxyethoxy}-4-methyl-piperidino)-propyl]-phenothiazine in 50 ml of anhydrous benzene containing 1.2 g of triethylamine and the mixture was stirred for 20 hours at room temperature. The mixture was washed with water and then was stirred for 4 hours with 100 ml of an aqueous saturated sodium bicarbonate solution. The organic phase was decanted and concentrated. The oily residue was subjected to chromatography over silica gel with a 98-2 benzene-triethylamine mixture as eluant to obtain 6.4 g of 2-trifluoromethyl-10-[3-(4-{2-hexadecanoyloxyethoxy}-4-methyl-piperidino)-propyl]-phenothiazine in the form of a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:25]Br>>[CH3:31][O:30][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[CH:29]=1)[CH2:25][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: COc1cc(CBr)cc(OC)c1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(OC)cc(OC)c2)c(=O)[nH]c1=O
Yield: 68 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (279 mg, yield: 68.0%).