Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH2:15])=[N:4][CH:3]=[N:2]1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[S:1]1[C:5]([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:15][S:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:22])=[N:4][CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1cccc2cc(-c3ncns3)[nH]c12
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cc(-c3ncns3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a mixture of 2-(1,2,4-thiadiazol-5-yl)-1H-indole-7-amine (0.35 g) and pyridine (8 ml) was added thiophene-2-sulfonyl chloride (0.34 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (0.25 g, yield 43%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 232-233° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11]O)[C:6]=2[CH:13]=1.[Br:14]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:14][CH2:11][CH2:10][C:7]1[C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1coc2ccc(F)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Fc1ccc2occ(CCBr)c2c1
Reaction time: 0.25 h
Yield: 105.5 %

Procedure:
A solution of 2-(5-fluorobenzofuran-3-yl)ethanol (5.2 g) and tetrabromomethane (11.6 g) in acetonitrile (175 mL) was treated with triphenylphosphine (8.3 g) at 0° C. After stirring for 15 min, the mixture was concentrated in vacuo an the resulting oil was applied to a silica gel flash column (eluent: heptane/ethyl acetate 65:35) resulting in an oil, 3-(2-bromoethyl)-5-fluorobenzofuran (7.4 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:31][CH:32]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:40])([F:25])[F:39])=[CH:32][N:31]=4)[CH2:34][CH2:35]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1)N1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine to give the title compound as a colorless solid. MS: 566.2 ([M+H])
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([CH2:45][C:46]([OH:48])=[O:47])([CH3:44])[C:25]1=[O:49])[CH:21]1[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:50][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([CH2:45][C:46]([O:48][CH3:50])=[O:47])([CH3:44])[C:25]1=[O:49])[CH:21]1[CH2:22][CH2:23]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (1400 mg, 1.96 mmol; Example 263, Step A) in a mixture of MeOH (3.1 mL) and benzene (12.5 mL) was added 2.0 M (trimethylsilyl)diazomethane in hexanes (1.96 mL, 3.92 mmol) at 0° C. dropwise. After being stirred at 0° C. for 1 h, the reaction was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (40 g SiO2, 10%, and 20% EtOAc/Hex) provided the title compound as a pale yellow foam.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:42])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:40]>>[CH3:42][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:40]
Reactant: CC(C)(N)CCn1c(=O)[nH]c2ccccc21
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Product: CC(C)(CCn1c(=O)[nH]c2ccccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
The target compound is prepared according to General Method 2 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 219 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-1,3-dihydro-benzimidazol-2-one. Yield: 187 mg (44%); mass spectroscopy: [M+H]+=427.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:20]=[C:21](CCN)[CH:22]=[CH:23][CH:24]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:22]=[CH:21][CH:20]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: NCCc1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCCc1cccc(Cl)c1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 14.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(3-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.24 g (14%) of the titled product as a white solid: mp 171°-177° C.; IR (KBr, cm-1) 3387, 1574, 1539, 1461, 1426, 1237, 1175, 734, 699, 477; 1H NMR (300 MHz, DMSO-d6) δ 11.18 (m, 2H), 7.28 (m, 8H), 7.06 (m, 1H), 3.83 (m, 2H), 2.94 (t, J=7 Hz, 2H); MS (FD) m/e 330 (M+); UV (EtOH) 293 nm (ε=17219), 266 nm (ε=9969), 260 nm (ε=9196), 240 nm (ε=8196), 203 nm (ε=27483).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH:6]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])([CH3:8])[CH3:7]>CN(C=O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([NH:9][CH:6]([CH3:8])[CH3:7])(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: CC(C)NS(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Reaction time: 18 h

Procedure:
288.8 mg (1.28 mmol) of tin(II) chloride dihydrate are added to a solution of 100 mg (0.26 mmol) of N-isopropyl-4′-nitrobiphenyl-4-sulfonamide (Example 11A) in 2.0 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated in vacuo and dried under high vacuum. 47 mg (63.2% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.Cl[Si](C)(C)C.[C:17]1(=[O:21])[CH2:20][CH2:19][CH2:18]1>C1COCC1>[NH2:1][C:2]1[S:3][C:4]([C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)=[CH:5][N:6]=1
Reactant: O=C1CCC1
Reactant: Nc1nccs1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ncc(C2(O)CCC2)s1
Temperature: -60 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A solution of 2-aminothiazole (7.1 g, 71 mmol) in THF (360mL) cooled to −78° C. was treated dropwise with n-BuLi (56.18 mL, 142 mmol) while maintaining an internal temperature less than or about equal to −60° C. After addition was completed, the solution was treated dropwise with chlorotrimethylsilane (18 mL, 142 mmol). The reaction solution was warmed to −10° C., then was cooled back to −78° C. n-Butyllithium (28.4 mL, 71 mmol) was added dropwise and after 10 minutes, cyclobutanone (5.33 mL, 71 mmol) was added dropwise. The solution was stirred for 1 hour at −78° C., was quenched with saturated ammonium chloride solution, and was warmed to 23° C. The reaction mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine, was dried (MgSO4), was filtered, and solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography (15:1→7:1 CHCl3—MeOH) to afford 7.24 g of 1-(2-amino-thiazol-5-yl)cyclobutanol. 1HNMR (400 MHz, DMSO-D6) δ 6.78 (s, 1H), 6.70 (s,2H), 5.58 (s,1H), 22 (m,4H), 1.69 (m, 1H), 1.50 (m,1H).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]1[NH:21][C:20](=O)[CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:20]3[CH2:19][CH2:18][CH:17]([CH3:16])[N:21]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c1Oc1ccccc1N2
Reactant: CC1CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3Oc3c(Cl)cccc32)=N1

Procedure:
Reaction of 4-chlorophenoxazine, 5-methyl 2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 4-CHLORO-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 120-122° C., from ethanol. Conversion of the free base to the hydrochloride salt affords 4-CHLORO-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 228-230° C., (dec.) (corr.), by trituration with hot benzene.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:33]2[N:32]=[CH:31][C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:39])[NH:19][C:9]5[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:35][CH:34]=2)[CH2:38][CH2:37]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M149) (310 mg, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (192 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([OH:22])[CH2:20][CH3:21]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:22][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: CCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1cc[n+]([O-])c(C)c1C
Temperature: 80 °C
Reaction time: 22 h

Procedure:
In n-propanol (42 ml) was dissolved 2,3-dimethyl-4-nitropyridine-1-oxide (841 mg). To the solution was added anhydrous potassium carbonate (2.1 g), and the mixture was stirred at 80° C. for 22 hours, followed by filtration with celite. The filtrate was concentrated, and the residue was chromatographed on a column of silica-gel (50 g), which was eluted with 5% methanol.chloroform to yield 2,3-dimethyl-4-propoxypyridine-1-oxide (360 mg) as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][N:27]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40])[C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:32][CH2:31][CH2:30][CH2:29][C:28](=[O:34])[N:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
N-(tert-Butoxycarbonyl)-O-benzylhydroxylamine (4.2 g, 18.8 mmol) was dissolved in DMF (120 mL) and cooled to 0° C. Sodium hydride (80%, 0.564 g, 18.8 mmol) was added, and the mixture was stirred at 0° C. for 30 minutes. A solution of (3) (6.0 g, 18.6 mmol) in DMF (30 mL) was slowly added to the cold solution which was then allowed to stir at room temperature for 20 minutes and at 80° C. overnight. The DMF was removed under high vacuum, and the reside was quenched with H2O (50 mL) and extracted with CH2Cl2 (3×70 mL). Organic extracts were washed with saturated sodium chloride, and the solvent was removed by rotary evaporation. Silica gel column chromatography, eluting with 2:1 hexane/EtOAc produced 7.29 g (77%) of (4) as an oil: NMR δ 1.50 (s, 9 H), 1.40-1.90 (m, 8 H), 2.30 (t, 2 H, J=6), 2.40 (t, 2 H, J=6), 3.40 (t, 2 H, J=6), 3.63 (t, 2 H, J=6), 4.77 (s, 2 H), 4.80 (s, 2 H), 7.33 (s, 10 H) . Anal. (C29H39N3O5), C, H, N.
Reaction SMILES: N[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].N([O-])=O.[Na+].[ClH:15]>O.[Cu](Cl)Cl>[Cl:15][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1nccc(Cl)c1N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nccc(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
3-Amino-4-chloro-2-methoxypyridine (200 mg, 1.27 mmol), dissolved in conc. hydrochloric acid (4 mL) was stirred at −5° C. while a solution of sodium nitrite (437 mg, 6.33 mmol) in water (2 mL) was added dropwise over 10 min. The mixture was stirred for a further 10 min before copper chloride (1.25 g, 12.66 mmol) was added portionwise over 5 min. The dark effervescing mixture was stirred at −5° C. for 20 min and then the cooling bath was removed and the mixture stirred at ambient temperature for 1 h. The resultant green solution was basified by addition of 5N sodium hydroxide (aq.), diluted with water (100 mL) and extracted with diethyl ether (3×30 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound (218 mg, 97%).
Reaction SMILES: [CH2:1]([S:7][C:8]1[S:18][C:11]2=[N:12][C:13](I)=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cu](C#N)[C:20]#[N:21].[C-]#N.[Na+]>CN(C)C=O>[C:20]([C:13]1[N:12]=[C:11]2[S:18][C:8]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9][N:10]2[C:15](=[O:16])[CH:14]=1)#[N:21]
Reactant: CCCCCCSc1nn2c(=O)cc(I)nc2s1
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCSc1nn2c(=O)cc(C#N)nc2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
In 100 ml of dimethylformamide, 6 g of 2-hexylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. To this solution, 1.77 g of copper cyanide and 0.97 g of sodium cyanide were added and the solution was stirred at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was extracted with chloroform and water. The organic layer was washed with water and dried over anhydrous sodium sulfate. Florisil® was added to the organic layer and it was shaken. The solvent was distilled off, and 2.3 g of 7-cyano-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 51%.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[CH2:5][CH2:6][CH2:7][N:8]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:9](=O)[O:10]C1C=CC=CC=1>C(O)C>[NH2:2][N:3]1[CH2:5][CH2:6][CH2:7][N:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]1=[O:10]
Reactant: NN
Reactant: O=C(Oc1ccccc1)N(CCCCl)c1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: NN1CCCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (5.3 mL) was added to a solution of 3-(4-fluorophenylamino)propan-1-ol (2.37 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added to the residue, followed by extraction with ethyl acetate (100 mL). Heptane (100 mL) was added to the resulting extract, and the solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1) to obtain (3-chloropropyl)-(4-fluorophenyl)amine. Triethylamine (5.4 mL) and phenyl chlorocarbonate (1.9 mL) were added to a solution of (3-chloropropyl)-(4-fluorophenyl)amine (2.40 g) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (3.93 g). Hydrazine monohydrate (0.40 mL) was added to a solution of phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (500 mg) in ethanol (10 mL) at room temperature. The reaction solution was stirred at room temperature for one hour, stirred at 60° C. for one hour and heated under reflux for seven hours. Hydrazine monohydrate (0.40 mL) was added to the reaction solution, and the reaction solution was heated under reflux for 13 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 265 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:33]=[N:32][C:16]2[N:17]=[C:18]([NH:21][C:22]3[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:31])[N:19]=[CH:20][C:15]=2[CH:14]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:33]=[N:32][C:16]2[N:17]=[C:18]([NH:21][C:22]3[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:31])[N:19]=[CH:20][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cnc3nc(Nc4c(C)cccc4[N+](=O)[O-])ncc3c2)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2cnc3nc(Nc4c(C)cccc4N)ncc3c2)c1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0.168 mmol) in ethanol (4 mL) and water (4 mL) was added iron powder (75 mg, 1.344 mmol) and ammonium chloride (74 mg, 1.344 mmol). The mixture was stirred at 100° C. for 2 hrs, cooled to RT, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=4:1) to afford N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-yl)-6-methylbenzene-1,2-diamine (40 mg, 53%) as a yellow solid. MS (ES+) C22H19Cl2N5O2 requires: 455, 457. found: 456, 458 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.33 (br. s., 1H), 9.01 (s, 1H), 9.65 (br. s., 1H), 8.23 (s, 1H), 7.05 (s, 1H), 6.93 (br. s., 1H), 6.64-6.63 (m, 1H), 6.50-6.49 (m, 1H), 4.80 (s, 2H), 3.99 (s, 6H), 2.09 (s, 3H).
Reaction SMILES: [CH3:1]O.[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:6]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:6]=1[CH2:21][CH2:22][C:23]([O:25][CH3:1])=[O:24]
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CCC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1OC

Procedure:
To a solution of 50 ml of methanol in 50 ml toluene are added 7.0 g (0.02 mole) of 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid and 1 ml of concentrated sulfuric acid. The resulting solution is stirred, heated at reflux for 18 hours, then concentrated to 20 ml at reduced pressure, and extracted with ether. The resulting ether solution is washed with 5% sodium bicarbonate solution and water. The solution is dried with anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to obtain a residual solid which is recrystallized from petroleum ether to give 5.5 g of methyl 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoate having a melting point of 78°-80°.