Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O[I:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)OC(=O)C(F)(F)F)=O.II.C1([C:30]23[CH2:37][CH2:36][C:33]([C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH2:34][CH2:35]2)[CH2:32][CH2:31]3)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[I:6][C:14]1[CH:15]=[CH:16][C:17]([C:30]23[CH2:37][CH2:36][C:33]([C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH2:32][CH2:31]2)[CH2:34][CH2:35]3)=[CH:18][CH:19]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)C12CCC(c3ccccc3)(CC1)CC2
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C12CCC(c3ccc(I)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (3.78 g, 8.78 mmol) and iodine (1.061 g, 4.18 mmol) were added to a stirred solution of ethyl 4-phenylbicyclo[2.2.2]octane-1-carboxylate (prepared according to the procedure described in WO 2007/071966) (2.16 g, 8.36 mmol, CAS 10207-26-8) in CHCl3 (50 mL). The resulting solution was stirred at ambient temperature for 90 minutes. The reaction mixture was poured into sodium thiosulfate (100 mL), extracted with DCM (2×100 mL), the organic layer was washed with aqueous sodium thiosulfate (2×80 mL), separated, dried over MgSO4, filtered and evaporated to afford a yellow oil which solidified on standing. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (2.78 g, 87%) as a white solid.
Reaction SMILES: Cl[CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N+:25]=[N-:26]
Reactant: CCCCCCCCCCCCC(Cl)c1coc([Si](C)(C)C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](C)(C)C)c1
Reaction time: 144 h

Procedure:
A mixture of 3-(1-chlorotridecyl)-5-trimethylsilylfuran (468 mg, 1.31 mmol) and sodium azide (852 mg, 13.1 mmol) in dry dimethylformamide (2 ml) was stirred at 60° for 6 days. Most of the solvent was evaporated under high vacuum and the residue dissolved in water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was flash chromatographed on silica using 5% ethyl ether/hexane. Fractions with Rf of about 0.73 on evaporation gave the title azide as a very pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:10][S-:11].[Na+]>CN(C=O)C.O>[C:1]([C:3]1[C:8]([S:11][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: C[S-]
Reactant: N#Cc1ncccc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cccnc1C#N
Reaction time: 0.08 h

Procedure:
A stirred solution of 1.00 g (8.19 mmol) of 2-cyano-3-fluoropyridine and 0.631g (9.01 mmol) of sodium thiomethoxide in 8 mL of DMF was stirred at room temperature for 1 h. The reaction mixture was diluted with water (80 mL) and stirred for 5 min. The resulting solid was filtered and dried on a high vacuum line to give 3-1 as an off-white solid: 1H NMR (CDCl3) δ 8.46 (d, 1H, 4.6 Hz), 7.66 (d, 1H, 8.3 Hz), 7.44 (dd, 1H, 4.6, 8.3 Hz), 2.58 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O:57][CH2:58][CH3:59])=O.CC(O)=O>C1COCC1>[C:58]([O:23][C@@H:21]1[CH2:20][N:19]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[C@@H:18]([C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:22]1)(=[O:57])[CH3:59]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a mixture of benzyl (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (1.50 g) and triphenylphosphine (1.43 g) in THF (15 mL) was added diethyl azodicarboxylate (0.86 mL) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added AcOH (0.29 mL) at 5° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in EtOAc, washed with saturated sodium hydrogen carbonate solution, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 2:1 elution) to give benzyl (2R, 4S)-4-acetoxy-2-(4,5-diphenyloxazol-2-yl)pyrrolidine-1-carboxylate (1.88 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][N:34]3[CH2:33][CH2:32][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH2:22][CH3:23])[CH2:36][CH2:35]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: COc1ccc(C2=NOC(CCCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1N1CCN(CCCCC2CC(c3ccc(OC)c(OC)c3)=NO2)CC1
Yield: 60.2 %

Procedure:
4-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]butanal (25.1 mg, 0.090 mmol), 1-(2-ethoxyphenyl)piperazine hydrochloride (20.0 mg, 0.082 mmol), molecular sieve (5 beads), NaBH(OAc)3 (52.4 mg, 0.247 mmol) and diisopropylethylamine (26.9 L, 0.082 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 23.1 mg (66.7%) of the target compound was obtained.
Reaction SMILES: [O-]Cl.[Na+].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH:8]=[N:9][OH:10].[CH3:15][O:16][C:17]([C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([C:29]([NH:31][CH:32]([CH2:40][C:41]#[CH:42])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:18]>C(Cl)(Cl)Cl.CCN(CC)CC>[CH3:15][O:16][C:17]([C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([C:29]([NH:31][CH:32]([CH2:40][C:41]4[O:10][N:9]=[C:8]([C:7]5[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=5[O:5][CH3:4])[CH:42]=4)[C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:30])([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:18]
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Reactant: COc1ccccc1C=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C12CC3CC(CC(C(=O)NC(Cc4cc(-c5ccccc5OC)no4)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.25% aqueous NaOCl (1.33 g, 0.77 mmol) in CHCl3 at 0° C. was added a solution of 2-methoxybenzaldehyde oxime (0.77 mmol, 0.116 g) dropwise and tert-butyl 2-(3-methoxycarbonyladamant-1-ylcarbonylamino)pent4-ynoate (300 mg, 0.77 mmol) and one drop of Et3N. After addition, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the crude product was purified on a prep plate (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[C:14]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCOCC1>[C:14]([O:18][C:19]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: NCc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 7.76 g (38.5 mmol) of 4-aminomethylphenylacetic acid hydrochloride, 10.42 g (42.3 mmol) of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile and 13.33 ml (96.2 mmol) of triethylamine in 60 ml of 50% aqueous dioxane was stirred for 2.5 hours at ambient temperature. The solvent was removed, 25 ml of water and 50 ml of ethyl acetate were added and the layers were separated. The aqueous phase was extracted with ethyl acetate then stirred with ethyl acetate and acidified to pH 1-1.5 with 3 N hydrochloric acid. The mixture was then extracted three times with ethyl acetate and the combined extracts were washed with water, dried (MgSO4) and evaporated to give 4-(N-t-butoxycarbonylaminomethyl)phenylacetic acid, m.p. 108°-110°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>C(Cl)Cl>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved in 5 mL of THF: water (1:1) and cooled in an ice bath. Triethylamine (1.45 mL, 10.68 mmol), followed by methanesulfonyl chloride (0.50 mL, 6.44 mmol) in 5 mL of ether were added, and stirred at 0° C. for 1 hour and at room temperature for 2 hours. Solvents were removed and 40 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with brine (30 mL×3) and dried over anhydrous sodium sulfate. After filtered, the filtrate was concentrated in vacuo to yield 1.314 g of N-tert-butyloxycarbonyl-N'-methanesulfonyl-piperazine in 93% yield. MS m/z M+NH4 =282. H1 -NMR (in CDCl3) δ=1.48 (s, 9H, Boc), 2.79 (s, 3H, S-CH3), 3.18 (t, 4H, piperazine), 3.55 (t, 4H, piperazine). The obtained N-tert-butyloxycarbonyl-N'-methanesulfonyl-piperazine (1.3 g, 4.97 mmol) was dissolved in 10 mL of 20% trifluoroacetic acid in methylene chloride and stirred at room temperature for 30 minutes. Solvent and trifluoroacetic acid were removed to obtain N-methanesulfonylpiperazine trifluoroacetic acid salt in quantitative yield. MS m/z M+H=165, H1 -NMR (in MeOH-d4) δ=2.95 (s, 3H, S-CH3), 3.35 (m, 4H, piperazine), 3.5 (m, 4H, piperazine). The obtained N-methanesulfonyl trifluoroacetic acid salt (2.2 g) was dissolved in 30 mL of acetonitrile and cooled in an ice bath. Solid sodium bicarbonate was added to the acetonitrile solution and stirred for 2 hours. Solid was filtered off and the filtrate was concentrated in vacuo to yield N-methanesulfonylpiperazine in quantitative yield. MS m/z M+H =165, M+NH4 =182; H1 -NMR (in MeOH-d4) δ=2.85 (s, 3H, S-CH3), 2.95 (t, 4H, piperazine), 3.22 (t, 4H, piperazine).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][CH3:12])=[CH:4][N+:3]=1[O-].P(Br)(Br)Br.O.CO>ClCCl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CNc1c[n+]([O-])c(Br)cc1[N+](=O)[O-]
Agent: BrP(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CNc1cnc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Bromo-5-(methylamino)-4-nitropyridine 1-oxide (10.0 g, 40.4 mmol) in 200 mL dichloromethane was mixed with phosphorous tribromide (10 mL, 106 mmol) in 50 mL dichloromethane at 10° C. and stirred for 10 minutes at ambient temperature. Water and methanol were added and the mixture was extracted with dichloromethane. The organic layers were washed with Na2CO3 (aq.) dried over MgSO4. The residue was triturated with ethanol, filtered and dried at 50° C. i. vac.
Reaction SMILES: [CH3:1][CH:2]([N:11]([C:13]([CH2:15][NH2:16])=[O:14])[CH3:12])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li+].[Cl-].[Li]CCCC.[C:24]1([CH2:30][CH2:31][CH2:32]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C1COCC1.CCOC(C)=O>[OH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@@H:2]([N:11]([CH3:12])[C:13](=[O:14])[C@H:15]([NH2:16])[CH2:32][CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:1]
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)CN
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)[C@H](N)CCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of pseudoephedrine glycinamide (1.5 g, 6.75 mmol), prepared and used by the method of Myers et al. (J. Am. Chem. Soc. 1997, 119, 656), and LiCl (1.71 g, 40.5 mmol) in THF (30 mL) was cooled to −78° C. and n-BuLi was added (13.16 mmol, 5.25 mL of a 2.5 M solution). After stirring for 20 min at −78° C., the reaction was warmed to 0° C. and stirred an additional 20 minutes. 3-Phenyl-1-bromopropane (1.3 mL, 7.42 mmol) was added and the reaction was stirred for 2 h at 0° C. Aqueous 1 N HCl (50 mL) and EtOAc (50 mL) were added, the organic phase was separated and extracted with 1 N HCl (50 mL). The aqueous extracts were combined, cooled in an ice bath and slowly basified to pH 14 with 6 N NaOH. The product was extracted with CH2Cl2 (4×50 mL) and the combined extracts were dried over MgSO4 and concentrated to give a yellow oil. Purification by flash chromatography (SiO2 gel, 92:4:4, CH2Cl2:MeOH:triethylamine) delivered 400 mg (78%) of the Product of Example 199, Step A: +APcl MS (M+1)+ 341; 1H NMR=400 MHz (CDCl3) δ: 7.38 (m, 10H), 5.26 (m, 1H), 4.15 (m, 1H), 3.86 (m, 1H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([S:12](Cl)(=[O:14])=[O:13])=[C:5]2[CH3:16].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>N1C=CC=CC=1>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][S:12]([C:6]2[N:7]([CH3:11])[C:8]3[C:4]([C:5]=2[CH3:16])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)(=[O:14])=[O:13])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:20]=1
Reactant: Cc1c(S(=O)(=O)Cl)n(C)c2ccc(F)cc12
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C)c2ccc(F)cc12
Yield: 65.9 %

Procedure:
This compound was prepared in analogy to Example 1 starting from 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonyl chloride (0.25 g) and 2-amino-5-bromobenzotrifluoride (2.3 g) in pyridine (5 ml) for 18 h at 35° C. to obtain the title compound (0.293 g) as a yellow solid. MS (ISN): 551.4, 549.3 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:24]([NH2:25])=[C:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1>O1CCOCC1.C(OCC)(=O)C.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:4]([C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][C:23]=3[N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:16][CH:17]=1
Reactant: Nc1c(Nc2ccc(Cl)cc2)ncnc1N1CCCC1
Reactant: O=C(O)c1ccccc1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccccc1-c1nc2c(N3CCCC3)ncnc2n1-c1ccc(Cl)cc1
Temperature: 95 °C
Reaction time: 48 h

Procedure:
2-Fluorobenzoic acid (22 mg, 0.15 mmol) and N4-(4-chlorophenyl)-6-pyrrolidin-1-yl-pyrimidine-4,5-diamine I-(17A-1)a (30 mg, 0.10 mmol) were dissolved in dioxane (0.7 ml) and 50% propanephosphoric acid cyclic anhydride in ethyl acetate (0.3 ml). The resulting mixture was shaken at 95° C. for 48 h. The reaction was cooled and diluted up to a volume of 1.8 ml with water for purification. The purification of the crude mixture was accomplished by reverse phase preparative Gilson 215 HPLC with the Hewlett Packard Series 1100MSD, and G1315A DAD using a Luna 5 micron C8(2) 250*21.2 mm Phenomenex column. The gradient eluant used was 0.1% formic acid in water (A) and acetonitrile (B) with trifluoroacetic acid as a buffer: 0.04 min.—80% A, 20% B; 20 min.—20% A, 80% B; 25 min.—100% B. The fractions with the desired compound were combined and evaporated to dryness to give title compound 18A-1. The residue was dissolved in methanol (1.5 ml) and treated with 4M HCl/dioxane (0.2 ml). The resulting mixture was shaken at 40° C. for 1 h then dried in a flow of nitrogen at 30° C. over 18 hours to obtain the hydrochloride salt of compound as a solid 18A-1 (4.2 mg, 10%): +ESI MS (M+1) 394.3; 1H NMR (500 MHz, CD3OD) δ 8.36 (s, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.59 (m, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.40–7.33 (m, 3H), 7.14 (t, J=9.3 Hz, 1H), 4.49 (br s, 2H), 3.84 (br s, 2H), 2.24 (br s, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:23])[CH:3]=1.O.C(O)C.[N:28]([O-])=[O:29].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:4](=[O:23])[C:3]=1[N:28]=[O:29]
Reactant: Nc1cc(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Temperature: 25 °C

Procedure:
6-Amino-1,3-bis(cyclohexylmethyl)uracil (from step (b), 25.0 g) was dissolved in glacial acetic acid (440 ml), water (440 ml) and ethanol (440 ml) at reflux. To this solution was added sodium nitrite (5.65 g). The resulting mixture was stirred as it cooled slowly to ambient temperature. The lavender precipitate was filtered off, washed with 1:1 water-ethanol and dried to give 6-amino-1,3-bis(cyclohexylmethyl)-5-nitrosouracil as light purple crystals (23.46 g, 86%), m.p. 240-243° C. dec with effervescence; 1H-NMR (DMSO-d6) δ: 13.23 (br s, 1, ═NOH), 9.00 (br s, 1, ═NH), 3.73 (br t, J=6.86, 4, 2 NCH2), 2.0-1.6 and 1.7-1.1 (both m, total 22, 2 cyclohexyl).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1.[CH3:24]I.[Cl-].[NH4+]>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
15.1 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 102.0 mg of N-(benzothiazol-2-ylmethoxy)acetamide (prepared as described in Example 1) in 2 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred for 5 minutes, after which 0.023 ml of methyl iodide were added, the temperature of the resulting mixture was elevated to room temperature and the mixture was then stirred for 1.5 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate to give 106.8 mg (yield 100%) of the title compound as a solid having a melting point of 119° to 120° C.
Reaction SMILES: [Se]=[O:2].[C:3]([C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:5])[CH3:4]>O1CCOCC1.O>[Cl:11][C:8]1[S:7][C:6]([C:3](=[O:5])[CH:4]=[O:2])=[CH:10][CH:9]=1
Reactant: O=[Se]
Reactant: CC(=O)c1ccc(Cl)s1
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1ccc(Cl)s1
Temperature: 25 °C

Procedure:
Selenium oxide (6.88%) is heated to dissolve in 100 ml aqueous dioxane (95:5 dioxane: H2O). The 2-acetyl-5-chlorothiophene (5.00 g) is added to the mixture. The resulting mixture is refluxed overnight, then cooled. The precipitated selenium metal is filtered after solvent removal a brown thick oil results which solidifies on standing. The solid is heated to dissolve in 400 ml hot water, filtered and allowed to cool to room temperature. The precipitate is collected by filtration, washed with fresh H2O and dried to obtain a light brown flake. The second crop is obtained by extracting the mother liquid with ethylacetate, separated, dried (MgSO4) and concentrated in vacuo to give a light yellow solid which upon treatment with HPLC gives 2-chloro-5-glyoxyloylthiophene, which is used directly in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([NH:16][CH3:17])[N:8]=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:35])[C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=1.[CH3:36][O:37][CH2:38][CH2:39]O.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.C(OCC)(=O)C.CCCCCCC.O.C(N(CC)CC)C>[CH3:36][O:37][CH2:38][CH2:39][O:31][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:26]([C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:7]3[C:6]4[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH3:2])[CH:5]=4)[N:10]=[C:9]([NH:16][CH3:17])[N:8]=3)[CH:19]=2)=[O:35])=[CH:27][CH:28]=1
Reactant: COCCO
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)cc3)c2)c2cc(OC)c(OC)cc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)OCCOC)cc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A mixture consisting of 55 mg (0.11 mmol) of N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid hydrochloride, 40 μL (0.51 mmol) of 2-methoxyethanol, 47 μL of triethylamine, 17 mg of 1-hydroxybenzotriazole hydrate, and 35 mg of WSC hydrochloride, was suspended in 2 mL of dimethylformamide, followed by stirring at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over magnesium sulfate. The residue obtained by filtration and solvent distillation under reduced pressure was subjected to silica gel column chromatography (ethyl acetate-heptane). Thereafter, a solid precipitated with ethyl acetate-hexane was collected by filtration, and was dried under aeration to give 40 mg of the titled compound (yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.CN1C(N)=CC(C2C=CC=CC=2)=N1.[F:38]C1C=CC(C#C)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:38])=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C#Cc1ccc(F)cc1
Agent: Cn1nc(-c2ccccc2)cc1N
Product: Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccc(F)cc3)nnc21

Procedure:
Compound 4 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 1-methyl-3-phenyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine and 4-fluorophenylacetylene instead of phenyl acetylene in Step 4.