Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]([C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])[C:25](O)=[O:26])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][C:2]=1[NH:1][C:25](=[O:26])[C@H:24]([C:21]1[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=1)[C@@H:28]([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CCOC(=O)[C@H](C)Cc1ccc(Cl)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](C)Cc1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.07 mmol) of ethyl (−)-(2R)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate and 607 mg (2.28 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in a mixture of 2.0 ml of DMF and 1.0 ml of pyridine, and 1022 mg (2.69 mmol) of HATU were added at room temperature. The reaction mixture was stirred at RT overnight. The mixture was diluted with ethyl acetate, and the solution was washed successively with 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 998 mg (98.4% of theory) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[C:8]([CH:9]=[O:10])=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:13](Br)[C:14]#[CH:15]>O1CCCC1>[N+:1]([C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([CH2:15][C:14]#[CH:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: C#CCBr
Reactant: O=Cc1c[nH]cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1cc(C=O)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
826 mg of 3-nitro-1H-pyrrole-4-carboxaldehyde [prepared by the process in Bull. Soc. Chim. p. 283-29 (1972)] were poured into 40 ml of tetrahydrofuran and then, at +5° C., 280 mg of sodium hydride as 50% in oil were added. After leaving the temperature at 20° C. for one hour, 1.19 g of propargyl bromide were added. The mixture was stirred for 18 hours at 20° C. and then was filtered and concentrated. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (1-1) to obtain 800 mg of 3-nitro-1-(2-propynyl) 1H-pyrrol-4-carboxaldehyde melting at 120° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH:13]=[O:14])[NH:10]2)=[CH:6][CH:5]=1.[CH3:15]I>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH:13]=[O:14])[N:10]2[CH3:15])=[CH:6][CH:5]=1
Reactant: O=Cc1cc2ccc(Br)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C=O)cc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.8 %

Procedure:
Sodium hydride (60% weight dispersion in mineral oil, 80.0 mg, 1.98 mmol) was added to a solution of 6-bromo-1H-indole-2-carbaldehyde (371 mg, 1.66 mmol) in DMF (10.0 mL) at 0° C. under N2. Methyl iodide (0.124 mL, 1.98 mmol) was added, and the reaction mixture was allowed to warm slowly to room temperature. After stirring for 4 h, the mixture was quenched with H2O at 0° C., upon which a solid precipitated out of solution. The slurry was extracted with ethyl ether (3×). The combined organic layers was dried over Na2SO4, filtered and concentrated to give the title compound (422 mg, 99%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.28 (dd, J=8.5, 2.0 Hz, 1H), 7.22 (s, 1H), 4.07 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl[CH2:18][CH2:19][S:20][CH3:21].CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH2:18][CH2:19][S:20][CH3:21])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CSCCCl
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CSCCSc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, 2-chloroethyl methylsulfide and sodium ethylate in ethanol. EI-MS m/e (%): 302 (M+, 2), 228 ([M—MeSCH═CH2]+, 100).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH:26]=O)[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH2:26][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3]
Reactant: C1CCNC1
Reactant: COc1cc(-c2cc3c(C=O)cccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3c(CN4CCCC4)cccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 35.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-formylindol-2-yl]isoindolinone (0.299 g, 0.597 mmol) was dissolved in acetonitrile (15.0 mL), and the solution was treated with pyrrolidine (0.997 mL, 11.9 mmol), acetic acid (0.684 mL, 11.9 mmol) and sodium triacetoxyborohydride (0.633 g, 2.99 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=3/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.117 g, yield 35%).
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.N(OCCC(C)C)=O.C(=O)(O)[O-].[Na+].[I:39]CI>ClCCl>[I:39][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: ICI
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(I)nc21
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (34.4 mg, 0.102 mmol) in diiodomethane (102 μL) at 60° C. was slowly added isoamyl nitrite (27.4 μL, 0.203 mmol). The reaction mixture was stirred at 60° C. 5 h. After cooling to rt, the reaction mixture was diluted with dichloromethane. Saturated aqueous sodium bicarbonate was added and the aqueous layer was extracted with dichloromethane (3×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was placed on the pump for 16 h to remove any additional diiodomethane. LCMS was deemed pure enough to be carried forward crude. The product was used immediately in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.Br[C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: COc1cccc(OC)c1B(O)O
Product: CCOC(=O)/C=C(\C)c1ccc(-c2c(OC)cccc2OC)cc1
Yield: 71 %

Procedure:
(E)-Ethyl 3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-enoate (1.02 g, 73% yield) was prepared from 2,6-dimethoxyphenylboronic acid (1.20 g, 6.60 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by a procedure analogous to that described in example 52a.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:7][CH2:6]1)=[O:4].ClCC(Cl)=O.C(C1C=CC=CC=1N1CCNCC1)#[N:24].C(=O)([O-])[O-].[Ca+2]>C(C(C)=O)C>[Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:24])[CH2:7][CH2:6]1)=[O:4]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: Cc1ccccc1N1CCN(C(=O)CCl)CC1
Agent: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Product: N#Cc1ccccc1N1CCN(C(=O)CCl)CC1

Procedure:
Compound 17A is prepared according to the same procedure as that for 12A, using the following reactants: chloroacetyl chloride (670 μl, 8.4 mmol), 1-(2-cyanophenyl)piperazine (1.32 g, 7 mmol), calcium carbonate (2.1 g, 21 mmol), methyl ethyl ketone (30 ml).
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[C:6]([O:19]C)=[CH:5][CH:4]=1.[N+]([O-])(O)=O>CC(C)=O>[CH:12]1[CH:13]=[C:14]2[C:15]([C:16]3[C:3](=[O:2])[CH:4]=[CH:5][C:6](=[O:19])[C:7]=3[C:8](=[O:18])[C:9]2=[CH:10][CH:11]=1)=[O:17]
Reactant: COc1ccc(OC)c2c1C(=O)c1ccccc1C2=O
Solvent: CC(C)=O
Solvent: O=[N+]([O-])O
Product: O=c1ccc(=O)c2c(=O)c3ccccc3c(=O)c1=2

Procedure:
1,4-Dimethoxyanthraquinone (II) (0.596 g, 2 mmole) is dissolved in hot aceton (60 ml) and argentic oxide (1g, 8mmole) was added to this warm solution. Brief sonication forms a uniform dispersal of oxident. The mixture is heated up to boiling on steam bath again and the mixture stirred vigorously with magnetic stirrer. The oxidation is then initiated by the addition of 6N aqueous nitric acid (2 ml). After addition, the mixture is stirred while cooling for an extra 20 minutes and filtered. The residue is washed thoroughly with water and dried under reduced pressure to give quinizarinquinone (III) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]1[C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]1[C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1
Reactant: COc1ccccc1N1CC(c2ccccc2)N=C1c1nonc1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COc1ccccc1-n1cc(-c2ccccc2)nc1-c1nonc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4,5-dihydro-1-(2-methoxyphenyl)-4-phenyl-1H-imidazol-2-yl)-1,2,5-oxadiazol-3-amine (34 mg, 0.10 mmol) was dissolved in THF with DDQ (23 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, filtered through silica and resubjected to the same reaction conditions overnight. The reaction mixture was absorbed onto a Biotage column and eluted with 5 to 30% EtOAc/hexanes to give a white foam, 28 mg, 0.084 mmol, 84%. HPLC Method B Rt 4.50 min, MH+ 334.10. 1H NMR (500 MHz, CDCl3) δ 7.76 (m, 2H), 7.42 (m, 1H), 7.35 (m, 2H), 7.23 (m, 2H), 7.00 (m, 2H), 5.71 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: COc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 72.7 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 308 mg of 4-methoxyindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 269 mg of 2-[2-(4-methoxy-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a pinkish powder, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:8]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[CH2:9][C:10]([C:13]([F:16])([F:15])[F:14])(O)[N:11]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:8]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:11]=2)=[CH:4][CH:3]=1
Reactant: OC1(C(F)(F)F)CN(c2cc(Cl)ccc2Cl)C(c2ccc(Br)s2)=N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cn(-c2cc(Cl)ccc2Cl)c(-c2ccc(Br)s2)n1
Temperature: 120 °C
Yield: 64.3 %

Procedure:
The mixture of 2-(5-bromo-thiophen-2-yl)-1-(2,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazol-4-ol (822 mg, 1.8 mmol) and p-toluenesulfonic acid monohydrate (172 mg, 0.9 mmol) in 10 mL toluene was heated at 120° C. for 6 hrs. The solvent was removed, and the residue was redissolved into dichloromethane, then washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (hexane/EtOAc 85/15) to give an off-white solid (512 mg, 64% yield). 1H-NMR (400 MHz, CDCl3): δ 6.68 (d, 1H), 6.89 (d, 1H), 7.31 (dd, 1H), 7.47 (dd, 1H), 7.55 (d, 1H), 7.56 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10]O)=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:13]CCl>S(Cl)(Cl)=O>[Cl:13][CH2:10][C:9]1[C:2]([F:1])=[C:3]([CH:6]=[CH:7][C:8]=1[F:12])[C:4]#[N:5]
Reactant: ClCCl
Reactant: N#Cc1ccc(F)c(CO)c1F
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(F)c(CCl)c1F

Procedure:
A solution of 120 mg (0.710 mmol) of 2,4-difluoro-3-(hydroxymethyl)benzonitrile from Example 134A in 3 ml of dichloromethane and 1 ml of thionyl chloride was stirred at room temperature for 3 h. The solvent was evaporated off under reduced pressure and the residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 60 mg (45% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])C=CN=3)[S:10][C:3]=12.Br[C:18]1[N:19]=[CH:20]N(C)C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:16][N:19]([CH3:20])[CH:18]=3)[S:10][C:3]=12
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: Cn1cnc(Br)c1
Product: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1

Procedure:
Following the procedure described for compound 7 (example 2, step 3) but substituting 2-bromo-1-methyl-1H-imidazole for 4-bromo-1-methyl-1H-imidazole [a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057. b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c) Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.], title compound 10 was obtained as an off-white solid (29% yield). MS (m/z): 250.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:25])[F:26])[CH:17]=2)[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2cccc(OC(F)(F)F)c2)nc(Cl)n1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A 2-dram round-bottom vial was charged with methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 0.483 mmol) and (3-(trifluoromethoxy)phenyl)boronic acid (80 mg, 0.386 mmol, 0.8 equiv) were added in THF (2 mL). Then 2M Na2CO3 (0.362 mL, 0.725 mmol, 1.5 equiv) and Pd(tetrakis)Ph3P (27.9 mg, 0.024 mmol, 0.05 equiv) were added and shaken at 85° C. overnight. The solvent was removed in the Genevac and the residue was washed with saturated NaHCO3 (1 mL). The aqueous layer was extracted with EtOAc (3×1 mL). The combined organic layers were dried on the Genevac and the crude was purified using flash purification with a gradient of 5-40% EtOAc in hexane to provide methyl 2-chloro-6-(3-(trifluoromethoxy)phenyl)pyrimidine-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]3[C:23]([C:14]=2[S:13][C:12]1=S)=[CH:22][CH:21]=[CH:20][CH:19]=3.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[CH2:37]([N:39]1[C:43](=[O:44])[CH2:42][S:41][C:40]1=[S:45])[CH3:38].C(#N)C>C(N(CC)CC)C>[CH2:37]([N:39]1[C:43](=[O:44])[C:42](=[C:12]2[N:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]3[CH:16]=[CH:17][C:18]4[C:23]([C:14]=3[S:13]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:41][C:40]1=[S:45])[CH3:38]
Reactant: COCCOCCOCCn1c(=S)sc2c3ccccc3ccc21
Reactant: CCN1C(=O)CSC1=S
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1C(=O)C(=C2Sc3c(ccc4ccccc34)N2CCOCCOCCOC)SC1=S
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.9 g of 3-methoxyethoxyethoxyethylnaphtho[2,1-d]thiazoline-2-thion and 1.8 g of methyl p-toluenesulfonate were fed into a 50 ml short-neck flask provided with a reflux condenser. The resultant mixture was heated at 120° C. for 4 hours. After cooling the reaction mixture to room temperature followed by addition of 0.8 g of 3-ethylthiazolidine-4-on-2-thion and 24 ml of acetonitrile, the resultant mixture was cooled to 5° C., and 1.0 g of triethylamine was added thereto. After stirring at 10° C. for 24 hours, yellow precipitates thus obtained were suction-filtered, washed with 10 ml of acetonitrile three times, and dried to obtain the intended compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:7]2[CH:19]=[CH:20][C:21](N)=[CH:22][C:6]=2[N:5]=1.COCC1N(S(C2C=CC(C)=CC=2)(=O)=O)C2C=CC([N+]([O-])=O)=CC=2[N:28]=1>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[C:7]2[CH:19]=[C:20]([NH2:28])[CH:21]=[CH:22][C:6]=2[N:5]=1
Reactant: COCc1nc2cc([N+](=O)[O-])ccc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: COCc1nc2cc(N)ccc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: COCc1nc2ccc(N)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h

Procedure:
2-(Methoxymethyl)-1-tosyl-1H-benzo[d]imidazol-5-amine. 2-(Methoxymethyl)-5-nitro-1-tosyl-1H-benzo[d]imidazole (0.9 g, 2.491 mmol) were dissolved in ethanol and purged with nitrogen. Palladium on activated carbon was added (0.530 g, 0.498 mmol), the nitrogen was evacuated and the reaction was stirred under 1 atmosphere of hydrogen for 16 h. The reaction mixture was filtrated through Celite and washed with ethanol. The organic layer was concentrated on a rotary evaporator to dryness to give desired product as purple solid, which was then crystallized from ethyl acetate in hexane to give the desired compound as a white solid (0.7 g, 85% yield). MS (ESI) m/z 332.2 [M+1]+.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[SH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1>C1C=CC=CC=1>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[S:47][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Sc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CSc2ccccn2)CC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate (Preparation 48, 1.0 g, 5 mmol) in benzene (40 ml) under nitrogen was added triphenyl phosphine (1.44 g, 5.5 mmol). Diethyl azodicarboxylate (0.86 ml, 5.5 mmol) in benzene (4 ml) was added dropwise and the reaction mixture was stirred for 5 min. 2-mercapto pyridine (0.61 g, 5.5 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture washed with sodium hydroxide (1M), water, and saturated brine. The organic extracts were dried (Na2SO4) and concentrated to an oil which was purified by flash chromatography on, silica gel eluting with dichloromethane:ethyl acetate (9:1). The title compound was obtained as an oil (0.7 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:19])[C:14]([O:16]CC)=O.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24]>C(OCC)(=O)C.C(OCC)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:19])[C:14]([NH:24][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])=[O:16]
Reactant: COC(CN)OC
Reactant: CCOC(=O)C(=O)Nc1cc(C(=O)OC)ccc1Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c(NC(=O)C(=O)NCC(OC)OC)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of methyl 4-chloro-3-{[ethoxy(oxo)acetyl]amino}benzoate (Example 330b, 11.2 g) dissolved in ethyl acetate (80 mL) was treated with aminoacetaldehyde dimethyl acetal (5.08 mL) under nitrogen. The resulting mixture was stirred at 20° C. for 3 h. The reaction mixture was diluted with diethyl ether (100 mL) and stirred at room temperature overnight. The solid formed was filtered off and dried under vacuum to afford the subtitle compound (12.64 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+]>>[C:13]1([NH:12][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2ncccc12
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc(Nc2ncnc3ncccc23)cc1
Yield: 26.7 %

Procedure:
4-Chloropyrido [2,3-d]pyrimidine (0.15 g, 0.91 mmol) was carefully added to a solution of aniline (0.15 g, 1.61 mmol) on water (1.5 mL). The solution was heated for 0.5 hour on a steam bath, cooled, and then basified with conc. ammonium hydroxide. The crude precipitate was collected by filtration and recrystallized from 95% ethanol to give the title product as yellow crystals (0.054 g, 27%). MP 258° C.; LC-MS: 223 (MH+).