Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30].CNCCNC.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:24][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22]
Reactant: O=C1NCCO1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(N3CCOC3=O)c2)Nc2c(C(=O)O)cc(Cl)cc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1 g, 2.5 mmol), oxazolidin-2-one (230 mg, 2.63 mmol), copper(I) iodide (95 mg, 0.5 mmol), N,N′-dimethyl-ethane-1,2-diamine (0.11 mL, 1 mmol), and potassium carbonate (1.04 g, 7.5 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×50 mL), washed with water (2×20 mL) and saturated aqueous ammonium chloride solution (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-4,4-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.8 g, 80%) as a white solid: MS (ESI) M+1=400.1.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([I:10])[CH:8]=1)[C:3](=[O:14])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1)[CH2:12]2
Reactant: COC(=O)c1c(I)cc(Cl)cc1CBr
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-iodo-benzoic acid methyl ester (0.389 g, 1.0 mmol), 4-chloro-benzylamine (0.158 mL, 1.2 mmol), and K2CO3 (0.276 g, 2.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5-chloro-7-iodo-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.115 g, 28%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.15 (s, 2H), 4.74 (s, 2H) 7.22-7.38 (m, 5H), 7.92 (s, 1H). GC-MS: m/z 417 (M−1)+, 382 (M−36)+.
Reaction SMILES: [Na+].[Na+].[Na+].[Na+].[O-:5][P:6]([O:9][P:10]([O:13][P:14]([O:17][P:18]([OH:21])([OH:20])=[O:19])([O-:16])=[O:15])([O-:12])=[O:11])(=[O:8])[O-:7].[C@@H:22]1([N:31]2[CH:38]=[CH:37][C:35](=[O:36])[NH:34][C:32]2=[O:33])[O:30][C@H:27]([CH2:28][OH:29])[C@@H:25]([OH:26])[C@H:23]1[OH:24].[C@@H:39]1([N:48]2[CH:55]=[CH:54][C:52](=[O:53])[NH:51][C:49]2=[O:50])[O:47][C@H:44]([CH2:45][OH:46])[C@@H:42]([OH:43])[C@H:40]1[OH:41].[Na+].[Na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
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)(O)O
Agent: CCCC[NH+](CCCC)CCCC
Agent: O=C([O-])O
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: CCCCN(CCCC)CCCC
Product: O=P(O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)O

Procedure:
The present invention provides the synthesis of diuridine tetraphosphate tetrasodium salt via the tetraammonium salt. In this process, uridine 5′-diphosphate disodium salt is first converted to the tributylammonium salt using a sulfonic acid resin to generate UDP as the free acid, followed by salt formation with excess tributylamine. After isolation by evaporative water removal, the anhydrous UDP tributylammonium salt is activated with 1,1-carbonyldiimidazole in DMF solution, during which time coupling to form U2P4 also occurs. Concentration of the solution in vacuo, followed by ion-exchange chromatography on Sephadex DEAE-A25 using an increasing gradient of aqueous ammonium bicarbonate yielded a solution of pure diuridine tetraphosphate in ammonium bicarbonate buffer. The volatile buffer is removed by repeated evaporation with water on a rotary evaporator to generate the tetraammonium salt of U2P4 as oil. The oil is dissolved in deionized water to give a ca. 10% solution, and this solution is charged to a Dowex 50Wx4 Na+ (Dow) column and eluted with deionized water. The fractions containing U2P4 are pooled, concentrated and lyophilized to yield U2P4 tetrasodium salt as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:36]1([CH2:42][CH2:43][CH2:44]O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:44][CH2:43][CH2:42][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2cc(O)ccc2n1
Reactant: OCCCN1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2cc(OCCCN3CCCCC3)ccc2n1
Temperature: 35 °C

Procedure:
A mixture of 0.400 g (0.002 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 0.966 g (0.004 mmol) of triphenylphospine (Fluka), 0.396 g (0.003 mmol) of 3-piperidin-1-yl-propan-1-ol and 0.68 ml (0.004 mmol) of di-tert.-butyl azadicarboxylate 40% in toluene in 40 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH/NH4OH from 97/3/0.5 to 90/10/0.5. The product fractions were evaporated and the residue was triturated with diethyl ether to yield after drying under vacuum 0.600 g (93%) of the title compound as white solid. MS (m/e): 343.3 (M+H)+.
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.[OH-].[K+].CS(C)=O>C1(C)C=CC=CC=1>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 86.8 %

Procedure:
10.92 g (0.03 mole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 11.0 g (0.197 mole) of freshly powdered KOH in 40 ml of toluene were heated to reflux for 30 min. as indicated sub letter (b). After addition of 6 ml (0.085 mole) of DMSO, the reaction mixture was heated to reflux for 12 further hours, then cooled, extracted and finally distilled as indicated hereinabove to afford 5.32 g (87% yield) of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>C1(C)C=CC=CC=1>[N:18]1([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cc(N3CCNCC3)nc3ccccc23)cc1
Yield: 91.1 %

Procedure:
A solution of 2-chloro-4-phenylquinoline (4.0 g) and anhydrous piperazine (8.0 g) in toluene (4 ml) is heated under reflux for 5 hours. To the reaction mixture is added water and the resulting mixture is extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (40 g) using chloroform as an eluent. Fractions containing the title compound are pooled and concentrated to give the title compound (4.4 g), m.p. 133°-134° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]([S:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:8]([CH3:18])(CC(O)=O)[NH:9]2)(=[O:3])[CH3:2].Cl.CN([CH2:31][C:32](Cl)=[O:33])C>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:1](=[O:3])[CH2:2][N:9]([CH3:10])[CH3:8])[N:9]([CH2:2][C:1]([O:33][CH2:32][CH3:31])=[O:3])[C:8]=2[CH3:18])=[CH:21][CH:22]=1
Reactant: CC(=O)Nc1cccc2c1C(Sc1ccc(Cl)cc1)C(C)(CC(=O)O)N2
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(=O)CN(C)C)cccc21

Procedure:
The sub-title compound was prepared by the method of Example 1 part (iv) using the product from Example 1 part (iii) and (dimethylamino)-acetyl chloride, hydrochloride. The product was purified using column chromatography (33% EtOAc/hexane as eluent).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]#[N:15])[C:3]=1[Cl:16].N([O-])=O.[Na+].N#N.[ClH:23]>O.Cl[Cu]>[C:14]([C:4]1[C:3]([Cl:16])=[C:2]([Cl:23])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)#[N:15]
Reactant: Cl
Reactant: N#Cc1c(Cl)c(N)cc2[nH]c(=O)c(=O)[nH]c12
Agent: Cl[Cu]
Agent: N#N
Agent: O=N[O-]
Solvent: O
Product: N#Cc1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred solution of 7-amino-6-chloro-5-cyanoquinoxaline-2(1H),3(4H)-dione (0.035 g, 0.15 mmol, as prepared above) in concentrated HCl (1.5 mL) at 0° C., an aqueous solution of NaNO2 (0.060 g, 0.87 mmol) in water (0.20 mL) was added and the resulting turbid solution was stirred in an ice bath for 2 h. A solution of CuCl (0.100 g, 1.01 mmol) in concentrated HCl (1.0 mL) was added to it while cooling the flask in an ice bath. Instant evolution of N2 ensued and the resulting dark green suspension was stirred at 0° C. for 2 h. Water (1.0 mL) was added to it followed by stirring overnight at room temperature. To the light green suspension so formed, water (4.0 mL) was added with further stirring at room temperature for 1 h. The precipitated solid was filtered, washed with water (2.0 mL), and dried under vacuum to furnish 0.029 g (77%) of the title compound as a cream colored solid; m.p. 327-335° C. (decomposed); 1H NMR (DMSO-d6): δ 7.463 (d, 1H, J=1.2 Hz), 12.306 (s, 2H). The coupling of aromatic signal disappeared upon addition of 3 drops of methanol-d4 indicating that the aromatic proton had coupled with peri N--H proton; IR (KBr, cm-1); 3574, 3479, 2237, 1737, 1710, 1392, 1271, 1183.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:8][O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Crude tert-butyl (S)-3-cyclopentyl-1-hydroxypropan-2-ylcarbamate from the previous step was dissolved in CH2Cl2 (30 mL). Et3N (3.2 mL, 24.3 mmol) was added and the mixture was cooled to 0° C. A solution of MsCl (1.1 g, 9.7 mmol) in CH2Cl2 (10 mL) added dropwise. After stirring for an additional 2 h, water (30 mL) was added and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic layers were washed with brine, dried over MgSO4, and evaporated to give crude tert-butyl (S)-3-cyclopentyl-1-(methanesulfonyloxy)propan-2-ylcarbamate that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHZ) δ 1.09 (m, 2 H), 1.46 (s, 9 H), 1.50 (m, 3 H), 1.60 (m, 3 H), 1.81 (m, 3 H), 3.02 (s, 3 H), 3.86 (m, 1 H), 4.17 (dd, J=10, 4 Hz, 1 H), 4.27 (dd, J=10, 3.2 Hz, 1 H), 4.59 (brs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(C2(C(F)(F)F)CCN(C3C=CC(C(Cl)=[O:45])=C([N+]([O-])=O)C=3)C2)C=C(Cl)C=1.FC(C1C=CC=CC=1C1(C(F)(F)F)CC(C2C=CC=CC=2C(F)(F)F)N(C2C([N+]([O-])=O)=C(C=CC=2)C(Cl)=O)C1)(F)F>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:23]([F:25])([F:26])[F:24])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:19])=[O:45])=[CH:21][CH:22]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(Cl)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Agent: O=C(Cl)c1cccc(N2CC(c3ccccc3C(F)(F)F)(C(F)(F)F)CC2c2ccccc2C(F)(F)F)c1[N+](=O)[O-]
Product: O=C(O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1

Procedure:
Representative compounds of the formula (V) and formula (V-a), respectively, include: 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl)benzoyl chloride; 4-(3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoylchloride; 4-(3-[3,5-bis(trifluoromethylphenyl]-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoyl chloride and the like.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[C:10]([I:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C.[Fe]>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[C:10]([I:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1c(I)nn2Cc1ccccc1
Temperature: 75 °C
Yield: 99.9 %

Procedure:
1-Benzyl-3-iodo-4-nitro-1H-indazole (340 mg; 0.897 mmol) was dissolved in a mixture of ethanol (8 mL) and water (2 mL). Ammonium chloride (24 mg; 0.45 mmol) and iron powder (501 mg; 8.97 mmol) were added and the mixture was stirred with heating to 75° C. under a nitrogen atmosphere for 4 hours. The mixture was allowed to cool, diluted with ethyl acetate (50 mL) and filtered through a pad of Celite. The solution was concentrated under reduced pressure to give 1-benzyl-3-iodo-1H-indazol-4-amine (313 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:24][CH:25]([CH3:27])[CH3:26])=[C:4]([C:17]([CH2:22][CH3:23])=[C:18]([F:21])[CH2:19][OH:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1>>[Cl:1][C:2]1[C:3]([O:24][CH:25]([CH3:26])[CH3:27])=[C:4](/[C:17](/[CH2:22][CH3:23])=[C:18](/[F:21])\[CH:19]=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CCC(=C(F)CO)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: CC/C(=C(\F)C=O)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure M, 3-(8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-pent-2-en-1-ol (Compound 157, 0.90 g, 2.26 mmol), tetrapropylammonium perrunthenate (TPAP, 0.04 g, 0.11 mmol), and 4-methylmorpholine N-oxide (NMO, 0.40 g, 3.4 mmol) were reacted to give the title compound as a pale yellow solid after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH3:24]>O1CCCC1.CN(C)C=O>[F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:24])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a suspension of 5.70 g (20.8 mmol) 3-(4-pentafluorosulfanyl-phenyl)-acrylic acid in 30 ml tetrahydrofuran and 0.21 ml N,N-dimethyl formamide a solution of 3.47 ml (27.4 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to mixture of 300 ml ice and 120 ml of a 25% aqueous ammonia solution. The precipitated amide was collected, washed with water and n-heptane and dried at 40° C. in vacuo. Yield 5.17 g (91%) 3-(4-pentafluorosulfanyl-phenyl)-acrylamide.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[C:11]([C:22]([F:25])([F:24])[F:23])=[N:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7]=2[C:6]1=[O:26].P(Br)(Br)Br.[Br-].[CH3:32][NH:33][CH3:34]>C(Cl)Cl>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[C:11]([C:22]([F:23])([F:25])[F:24])=[N:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:7]=2[C:6]1=[O:26]
Reactant: CNC
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCO)CC3)cc1
Agent: BrP(Br)Br
Agent: [Br-]
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCN(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
Part B: 6-(3-Hydroxy-propyl)-1-(4-methoxy-phenyl)-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (0.200 g, 0.542 mmol) and phosphorus tribromide (0.077 mL, 0.812 mmol) were dissolved in methylene chloride (20 mL) and stirred at rt for 2 hr. The reaction was quenched with water (100 mL), extracted with methylene chloride (3×100 mL), washed with saturated NaHCO3 (1×100 mL), washed with brine (1×100 mL), dried over Na2So4, and concentrated to afford 0.096 g (41%). The bromide intermediate (0.048 g, 0.111 mmol) was redissolved in methylene chloride (6 mL), and 2M dimethylamine (0.389 mL, 0.777) was added. The reaction was stirred at rt overnight. The reaction was evaporated, redissolved in toluene (15 mL), and re-concentrated. Purification was performed by reverse phase HPLC and freeze-dried to afford the title compound (0.014 g, 32%): 1H NMR (CDCl3) δ 7.43 (d, j=8.8 Hz, 2H), 6.96 (d, j=9.1 Hz, 2H), 3.85 (s, 3H), 3.71 (t, j=7.0 Hz, 2H), 3.56 (t, j=6.6 Hz, 2H), 3.08–2.98 (m, 4H), 2.80(s, 6H), 2.15–2.02 (m, 2H) ppm; Mass Spec 397.4(M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([NH2:19])[N:14]=[C:13]([S:20][CH2:21][C:22]3[N:27]=[C:26]([CH2:28][NH:29]C(=O)OC(C)(C)C)[CH:25]=[CH:24][CH:23]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.N>>[NH2:19][C:15]1[N:14]=[C:13]([S:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:28][NH2:29])[N:27]=2)[N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[C:16]=1[C:17]#[N:18]
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CNC(=O)OC(C)(C)C)n3)nc(N)c2C#N)cc1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN)n3)nc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To 0.3 g of the compound of Example 30 was added 2 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hour. Then the trifluoroacetic acid was removed under reduced pressure from the reaction mixture, the residue was dissolved in 2 mL of acetonitrile. To resulting solution was added 4 mL of 28% aqueous ammonia, and the resulting crystal was filtrated to give 0.2 g of N-{4-[6-amino-2-(6-aminomethylpyridin-2-ylmethylsulfanyl)-5-cyano-pyrimidin-4-yl]phenyl}acetamide as a white powder.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:18][C:19]([C:21]1[S:25][CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[I:1][C:2]1[C:3]([O:16][CH2:18][C:19]([C:21]2[S:25][CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=2)=[O:20])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Reactant: CC1(C)CCC(C)(C)c2cc(I)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1csc(C(=O)COc2cc3c(cc2I)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of 3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ol (4 g, 12.1 mmol), methyl 5-bromoacetyl-3-thiophenecarboxylate (3.18 g, 12.1 mmol) and potassium carbonate (1.84 g, 13.3 mmol) in methyl ethyl ketone (100 ml), was heated under reflux for 4 h. The reaction medium was filtered and then concentrated in a rotary evaporator. The mixture was extracted with ethyl ether. The organic phase was washed with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[Br:20][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)C(Br)c1ccc([N+](=O)[O-])cc1

Procedure:
To a mixture of 4-nitrophenylacetic acid (2.0 g), benzene (40 ml) and N-bromosuccinimide (3.3 g), 2,2′-azobis(2-methylpropionitrile)(0.16 g) was added and heated under reflux for 22 h. The reaction mixture was diluted with ethyl acetate and washed successively with 2 N HCl and water; the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate:acetic acid=75:25:1) to give 2-bromo-2-(4-nitrophenyl)acetic acid. The resulting bromo compound was mixed with 28% aqueous ammonia solution (5 ml) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure; to the resulting residue, 1 N aqueous sodium hydroxide solution (20 ml), 1,4-dioxane (10 ml) and di-t-butyl dicarbonate (7.2 g) were added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in a mixture of methanol (20 ml) and diethyl ether (10 ml); a solution of trimethylsilyldiazomethane (2.0 M) in n-hexane was added until the reaction mixture no longer foamed; the reaction mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 2-t-butoxycarbonylamino-2-(4-nitrophenyl)acetic acid methyl ester. The resulting methyl ester compound was worked up as in Example 2 to give 0.77 g of the titled compound (yield, 25%).