Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][O:33][C:28]3=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:34][N+:23]1[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][O:33][C:28]3=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])[N:22]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCO3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])OCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 12.7 %

Procedure:
H2O2 (70%, 0.67 mL, ca. 13.5 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.5 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 223 (374 mg, 1.4 mmol) and TFA (0.52 mL, 6.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-20%) of MeOH/DCM, to give 1,4-dioxide 224 (52 mg, 13%) as a red solid: mp (MeOH/EtOAc) 175-179° C.; 1H NMR δ 7.60 (s, 1H, H-9), 7.59 (s, 1H, H-5), 7.35 (br s, 1H, NH), 6.21 (s, 2H, H-7), 3.61 (br t, J=6.0 Hz, 2H, CH2N), 2.62 (br t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2]; 13C NMR δ 155.9, 149.7, 148.9, 137.8, 126.7, 103.5, 97.9, 94.1, 57.4, 45.1 (2), 38.8. Anal. calcd for C12H15N5O4.½CH3OH: C, 48.5; H, 5.5; N, 22.6. Found: C, 48.7; H, 5.3; N, 22.6%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:29])([F:28])[C:9]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][CH2:26][CH3:27])[CH:19]=1)([O:14][CH2:15][O:16][CH3:17])[C:10]([F:13])([F:12])[F:11].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.O>CN(C)C=O>[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]([O:14][CH2:15][O:16][CH3:17])([C:10]([F:12])([F:11])[F:13])[C:8]([F:28])([F:29])[F:7])=[CH:19][C:20]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCCBr
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Potassium carbonate (132.4 mg, 0.96 mmol) was added to a mixed solution of 4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenol (221.1 mg, 0.64 mmol) and 1,4-dibromobutane (1.38 g, 6.39 mmol) in N,N-dimethylformamide (20 mL), followed by stirring overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin-layer chromatography (hexane:ethyl acetate=10:1) to obtain 219.5 mg of the title compound (yield: 71%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[C:11]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:24][CH:23]=3)[C:10]=2[F:38])=[CH:6][C:5]=1[O:41]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:40]=[CH:39][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]([F:20])([F:18])[F:19])=[C:11]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=3)[C:10]=2[F:38])=[CH:6][C:5]=1[OH:41]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c(F)c(F)c2C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)c(C(F)(F)F)c(Oc3ccc(C(=O)O)cc3)c2F)cc1O
Reaction time: 8 h
Yield: 95 %

Procedure:
40.4 g of the 4-(4-nitro-3-benzyloxyphenoxy)-2-(4-benzyloxycarbonylphenoxy)-1-trifluoromethyl-3,5,6-tri-fluorobenzene (0.06 mol) prepared as described in Example 10 are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 4 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The orange solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:34]2[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:36][CH2:35]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: COc1ccc(CCN2CCNCC2)cc1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Product: COc1ccc(CCN2CCN(C(=O)c3ccc(N(CCOC(C)C)C(=O)CCl)cc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.88 g of [2-(4-methoxyphenyl)ethyl]piperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-methoxyphenyl)ethyl]piperazine. The hydrochloride thereof melts at 139°-140°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=3)(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:44])(=[O:43])[N:20]=1.[OH-].[Na+:46]>O>[CH3:17][C@@:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH:34]=4)(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:44])(=[O:43])[N:20]=2)[C:4]1=[O:18].[Na+:46]
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccc5ccccc5c4)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccc5ccccc5c4)ccc3N2)=C([O-])c2ccccc21
Yield: 95.9 %

Procedure:
A mixture of Example 103A (10.0 mg, 0.016 mmol) and 0.998 M sodium hydroxide (0.016 mL, 0.016 mmol) in water (1 mL) was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo to give the title compound (10.0 mg, quant. yield). 1H NMR (300 MHz, DMSO-d6) δ 0.40 (m, 1H) 0.65 (d, J=6.62 Hz, 3H) 0.67 (m, 3H) 0.76 (m, 1H) 1.27 (m, 1H) 1.34 (s, 3H) 1.69 (m, 1H) 2.11 (m, 1H) 7.26 (m, 4H) 7.43 (m, 2H) 7.64 (m, 2H) 7.75 (dd, J=8.46, 1.84 Hz, 1H) 8.03 (m, 4H) 8.38 (s, 1H) 10.54 (s, 1H) 15.37 (s, 1H). MS (ESI+) m/z 630.0 (M+H−Na)+, 647.1.0 (M−Na+NH4)+.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[N:8]=[C:9]([O:14][CH2:15][CH2:16][CH3:17])OCCC)#[N:2].[NH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:19]([N:18]1[C:1](=[NH:2])[C:3]2[CH:7]=[CH:6][S:5][C:4]=2[N:8]=[C:9]1[O:14][CH2:15][CH2:16][CH3:17])[CH2:20][CH3:21]
Reactant: CCCOC(=Nc1sccc1C#N)OCCC
Reactant: CCCN
Product: CCCOc1nc2sccc2c(=N)n1CCC

Procedure:
In a sulfonation flask, 5.7 g (0.023 mol) 3-cyano-2-(1,1-dipropoxymethylenamino)thiophene and 35 ml 1-aminopropane are heated at reflux temperature for 5 hours. Then the excess of 1-aminopropane is distilled off and the residue purified by column chromatography over silica gel (eluant: hexane/ethylacetate 1:1). Yield: 5.1 g of 3-propyl-2-propoxy-3H-thieno[2,3-d]pyrimidine-4-ylideneamine in the form of brownish crystals; m.p. 61-63° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[NH2:18][C:16]([C@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH3:35])=[O:17]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H](C)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting D-alanine amide HCl for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ 8.32 (s, 1H), 7.96 (m, 1H), 7.82 (m, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.54 (q, 1H, J=6.0 Hz), 2.20 (s, 3H), 1.45 (d, 3H, J=6.0 Hz). ESHRMS m/1477.1104 (M+H calculated for C22H20ClF2N4O4 requires 477.1136).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:53][C@@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]1[OH:60]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:53][C@@H:54]2[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]2[OH:60])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
5-(4-Chloro-phenyl)-6-cyclopropylmethoxy-nicotinic acid (21.5 g, 0.071 mol) was dissolved in DMF (655 mL). To the solution was added TBTU (25 g, 0.078 mol), N,N-diisopropylethyl amine (60.5 mL, 0.35 mol) and (1R,2R)-2-amino-cyclohexanol (11.8 g, 0.078 mol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 21.7 g of the title compound as a white solid, MS (ISP) 401.2 (M+H)+.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([NH2:27])=[N:24][N:23]=2)=[CH:18][CH:17]=1.[CH2:28]([NH:30][S:31]([C:34]1[CH:35]=[C:36]([F:44])[C:37]([F:43])=[C:38]([CH:42]=1)[C:39](O)=[O:40])(=[O:33])=[O:32])[CH3:29].CN(C=O)C>>[CH2:28]([NH:30][S:31]([C:34]1[CH:35]=[C:36]([F:44])[C:37]([F:43])=[C:38]([CH:42]=1)[C:39]([NH:27][C:25]1[S:26][C:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)=[N:23][N:24]=1)=[O:40])(=[O:33])=[O:32])[CH3:29]
Reactant: Nc1nnc(-c2ccc(F)cc2)s1
Reactant: CCNS(=O)(=O)c1cc(F)c(F)c(C(=O)O)c1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCNS(=O)(=O)c1cc(F)c(F)c(C(=O)Nc2nnc(-c3ccc(F)cc3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a 20 ml scintillation vial was added EDC (54 mg, 0.283 mmol), HOAt (38 mg, 0.283 mmol) and commercially available 5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (55 mg, 0.283 mmol). To this was added 5-[(ethylamino)sulfonyl]-2,3-difluorobenzoic acid as a solution in 2 ml DMF (75 mg, 0.283 mmol based on theoretical yield of preceding). The reaction mixture was stirred at room temperature overnight with a Teflon covered magnetic stir-bar. The reaction mixture was then concentrated to ˜1 ml and the residue was purified using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 30% B to 60% B in 10 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-[(Ethylamino)sulfonyl]-2,3-difluoro-N-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzamide as a white solid (12 mg, 19%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C)c(NCC=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C)c(N(CC=O)C(=O)CCl)c1
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-methoxyanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-methoxyanilino)acetaldehyde.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([CH2:12][C:13]2[C:14](=[O:18])[O:15][CH2:16][CH:17]=2)=[CH:10][CH:9]=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]=1[CH3:26])(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO>[C:1]([O:4][CH2:5][C:6]1[C:11]([CH2:12][C@H:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[CH:10][CH:9]=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(CC2=CCOC2=O)ccc(C(=O)OC(C)(C)C)c1C
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OCc1c(C[C@H]2CCOC2=O)ccc(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-2,5-dihydrofuran-3-yl)methyl)benzyl acetate (280 mg, 0.75 mmol) was dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL). A catalytic amount of (−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 16 hours. A fresh portion of (−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate was added to the mixture. Reaction vessel was charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 24 hours. Reaction mixture was concentrated in vacuo. Residue was passed through a plug of silica gel eluting 80% ethyl acetate-hexanes. Filtrate was concentrated in vacuo. Title compound was obtained as clear colorless oil in 69% yield. MS m/e (M−H)−=376.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:31][CH2:32][C:33]1[O:37][C:36](=[O:38])[NH:35][N:34]=1.C(NC(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15]([NH:31][CH2:32][C:33]3[O:37][C:36](=[O:38])[NH:35][N:34]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: NCc1n[nH]c(=O)o1
Reactant: COc1cc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc(OC)c1OC
Solvent: CC(=O)N(C)C
Solvent: CC(C)NC(C)C
Product: COc1cc(-c2cc3ncccc3c(NCc3n[nH]c(=O)o3)n2)cc(OC)c1OC
Temperature: 70 °C
Reaction time: 6 h

Procedure:
104 mg Trifluoro-methanesulfonic acid 7-(3,4,5-trimethoxy-phenyl)-[1,6]naphthyridine-5-yl ester (6.1), 30 mg (0.261 mmol) of 5-aminomethyl-3H-[1,3,4]oxadiazole-2-one (2.33) and 0.132 mL (0.782 mL) N,N-diisopropylamine were placed in dimethylacetamide at ambient temperature. The reaction was then heated to 70° C. where it was maintained overnight and then cooled to ambient temperature. After this time 0.132 mL (0.782 mL) N,N-diisopropylamine was added and the reaction was heated to 90° C. where it was left for 6 h. The reaction was then cooled to ambient temperature and partitioned between water and ethyl acetate. The organic layer was separated and the aqueous phase was extracted with additional ethyl acetate (×2). The combined organic fractions were dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by silica gel chromatography (ethyl acetate/methanol: 100:0 to 90:10) and then a second purification by silica gel chromatography (dichloromethane/methanol: 100:0 to 95:5) gave the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH3:9][C:10]1([CH3:22])[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([OH:21])=[CH:15][CH:16]=2)[O:11]1.[Cl-].[NH4+]>O1CCCC1>[CH3:9][C:10]1([CH3:22])[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[C:12](=[CH:13][C:14]([OH:21])=[CH:15][CH:16]=2)[O:11]1
Reactant: Brc1ccccc1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccccc2)c2ccc(O)cc2O1
Yield: 57.4 %

Procedure:
Bromobenzene (141.3 g) in dry tethydrofuran (300 ml) was added to magnesium (23.7 g) in dry tetrahydrofuran (100 ml). 2,2-Dimethylchroman-4-one-7-ol (34.5 g) in dry tetrahydrofuran (250 ml) was then added and the solution refluxed for 48 hours. The mixture was poured into ammonium chloride solution, the tetrahydrofuran layer was separated and evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate and the organic layer and the residue from the tetrahydrofuran layer was shaken with 10% sodium hydroxide solution. The basic layer was acidified and re-extracted with ethyl acetate. The organic layers were dried (MgSO4). Removal of the solvent under reduced pressure gave an oil (26 g) which was chromatographed on silica. Elution with ether - petrol (1:1) gave the title compound (14 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: COCCOCCOCCO
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCCOCCOc1cc([N+](=O)[O-])ccc1-c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a stirred mixture of 2-(2-hydroxy-4-nitrophenyl)benzothiazole (0.15 g, 0.55 mmol), triphenylphosphine (0.216 g, 0.825 mmol) and triethylene glycol monomethyl ether (0.108 g, 0.66 mmol) in dry THF (10 ml) at 0° C. was added dropwise DIAD (0.167 g, 0.825 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, then left to rise to room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (1:1 Hexane/EtOAc) to give the title compound (0.176 g, 76%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3
Product: Cc1nccn1-c1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:21])=[C:4]([C:14]([OH:20])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].[CH:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>CC(C)=O>[CH2:34]([O:20][C:14]1[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:2]([F:1])=[C:3]([CH3:21])[C:4]=1[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])[C:31]1[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(F)cc([N+](=O)[O-])c(O)c1C(=O)Oc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(F)cc([N+](=O)[O-])c(OCc2ccccc2)c1C(=O)Oc1ccccc1
Yield: 98.7 %

Procedure:
A 30 L 4-neck flask equipped with mechanical stirrer, thermometer, addition funnel and gas inlet was charged with a solution of compound 64 (1423 g, 4.89 mol) in acetone (17 L). K2CO3 (1350 g, 9.8 mol) and KI (81 g, 0.49 mol) were added to the stirring reaction mixture and the resulting suspension was degassed with N2 for 5 min prior to adding BnBr (878.2 g, 5.13 mol) at 27˜29° C. over 8 mM. After the addition, the brown suspension was refluxed for 2.5 h, then allowed to cool to 20˜30° C. The suspension was filtered, and the filter cake was washed with acetone (3×900 mL). The filtrate was concentrated under reduced pressure and the residual oil was dissolved in MTBE (7.0 L) and successively washed with water (5×1.0 L) and brine (4×1.0 L). The organic layer was dried over Na2SO4 filtered then concentrated to dryness under reduced pressure to afford 1840 g of crude compound 65 (98.7% yield) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[F:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:29]2[CH2:30][CH2:31][CH:26]([F:25])[CH2:27][CH2:28]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: FC1CCNCC1
Product: O=C(NCCCN1CCC(F)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for step D of example 223 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (130 mg, 0.32 mmol) and 4-fluoropiperidine (59.0 mg, 0.38 mmol). The title compound was afforded as a solid (15.0 mg, 10% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.13 (1H, m), 8.41 (1H, s), 4.71 (1H, m), 3.32 (2H, m), 3.20 (2H, m), 2.27 (4H, m), 1.83 (2H, m), 1.65 (4H, m). MS m/z: 493.06, 495.05 [M+H]+.