Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:19][C:20]4[CH:25]=[N:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=4)[N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)ncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)ncn12
Temperature: 60 °C
Yield: 16.9 %

Procedure:
To a stirred suspension of 7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (738 mg, 3.0 mmol) in DMF (5 mL) at room temperature under argon was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (647 mg, 3.3 mmol), followed by K2CO3 (828 mg, 6.0 mmol). The resulting mixture was heated at 60° C. for 48 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was triturated with chloroform (3×20 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography eluted with ethyl acetate-dichloromethane to obtain 206 mg of the title compound as a solid. HPLC/MS (methanol-water with 10 mM NH4OAc): retention time=3.58 min, [M+H]30 =406.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=1)=[O:5].[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](Br)[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[CH3:27][O:28][C:29]([C:30]1[CH:31]=[C:32]([C:10]2[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[CH:12][CH:11]=2)[C:33]([CH3:36])=[CH:34][CH:35]=1)=[O:38]
Reactant: CC1(C)OB(c2ccc(NC(=O)c3c(F)cccc3F)cc2)OC1(C)C
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c1
Temperature: 120 °C
Yield: 75 %

Procedure:
A suspension of 2,6-difluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (359 mg, 1 mmol), 3-bromo-4-methyl-benzoic acid methyl ester (228 mg, 1 mmol), benzyl(chloro)bis(triphenylphosphine)palladium (38 mg, 0.05 mmol) and K2CO3 (690 mg, 5 mmol) in 1-methylpyrrolidinone (NMP) (5 ml) was degassed with vacuum and heated at 120° C. for 10 hr. After cooling down to room temperature, ethyl acetate (EtOAc) (200 ml) was added and the mixture was washed with water (60 ml×3). The EtOAc was evaporated and the residue was purified by column chromatography on silica gel (Hexanes:EtOAc) to give Compound 1 (286 mg, yield 75%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[O:11][CH:12]([NH:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:13]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:9])(C)(C)C>N1CCCCC1.Cl.O1CCOCC1>[NH2:7][CH:8]([C:10]1[N:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:12](=[O:11])[C:13]2[C:14](=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[N:15]=1)[CH3:9]
Reactant: CC(NC(=O)OC(C)(C)C)C1=Nc2cccc(Cl)c2C(Nc2cc(F)cc(F)c2)O1
Agent: Cl
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: CC(N)c1nc2cccc(Cl)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
A solution of compound 169 (1.68 mmol) in piperidine (2 mL) was stirred for 3 h at ambient temperature. Evaporation of the reaction mixture to dryness under high vacuum gave a yellow foam. This foam was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred for 17 h at ambient temperature. The reaction mixture was then concentrated to dryness, basified with 10% aqueous potassium carbonate (40 mL) and extracted with MTBE (3×20 mL). Combining the organic extracts, drying over sodium sulfate and concentrating to dryness afforded a solid residue. This residue was dissolved in d-chloroform (5 mL), and warmed for 15 h at 50° C. After cooling to ambient temperature, the reaction mixture was washed with water (3×10 mL), dried over sodium sulfate and evaporated to dryness, affording a 98% yield of compound 170 as a white solid. m.p. 200-202° C.; 1H NMR (CDCl3) δ (ppm) 7.65 (m, 2H), 7.49 (m, 1H), 7.01 (t, 1H, J=6.6 Hz), 6.89 (m, 2H), 3.68 (m, 1H), 1.33 (d, 3H, J=6.6 Hz), 1.25 (s, 2H); m/z=336 (M+H). The reaction described above and compound 170 are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([NH:13][C:14](=[NH:16])[CH3:15])[NH:11][N:12]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].Cl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[N:13]=[C:14]([CH3:15])[NH:16][C:17](=[O:18])[N:11]2[N:12]=1
Reactant: CC(=N)Nc1cc(-c2ccccc2Cl)n[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CS(C)=O
Product: Cc1nc2cc(-c3ccccc3Cl)nn2c(=O)[nH]1
Reaction time: 0.02 h

Procedure:
To a pale yellow solution of N-[5-(2-chlorophenyl)-2H-pyrazol-3-yl]-acetamidine (I-1A-1b; 2.04 g, 8.69 mmol) in DMSO (17 mL) was added 1,1′-carbonyldiimidazole (1.53 g, 9.44 mmol), portionwise over 1 minute at room temperature. After stirring for one hour, the reaction was added to stirred 1 M aqueous HCl (17 ml) over 5 minutes. The colorless precipitate that formed was stirred for 2.5 hours and then collected on a course sintered funnel. The solids were washed with water (50 ml) and then dried on the frit under a stream of air using low vacuum to afford I-1A-1c as a colorless solid (2.29 g, quantitative): +APcI MS (M+1) 261.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:27][CH:26]=2)[CH:10]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: O=C(Nc1cc(F)ccc1C(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
In analogy to example 1,4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid was prepared from 2-amino-4-fluoro-benzoic acid and 4-phenoxy-benzoyl chloride [1623-95-6]. MS (m/e): 350.0 (M−H−, 100%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[C:33](Cl)(=[O:36])[O:34][CH3:35]>ClCCl>[CH3:35][O:34][C:33](=[O:36])[NH:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([C:10]3[C:5]4[O:4][CH2:3][O:2][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:12][CH2:13]2)[CH2:24][CH2:23]1
Reactant: COC(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Temperature: 0 °C

Procedure:
The title compound was prepared from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.068 mmol) and triethylamine (20.6 mg, 28.4 μl, 204 μmol) in dichloromethane (1 mL). Methyl carbonochloridate (7.06 mg, 5.78 μl, 0.075 μmol) was added to the mixture stirring at 0° C. The ice bath was removed and the reaction mixture was stirred for 1 hour at room temp. The reaction was diluted with dichloromethane and quenched with sat NaHCO3 (4 mL). The aqueous layer was extracted with DCM (1×5 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as a white solid (11 mg, 41.6%), MS (ISP) m/z=389.1 [(M+H)+].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[C@@H:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=2)[CH2:27][CH2:26]1)[CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:38][CH:36]([C:33]1[N:32]=[C:31]([N:28]2[CH2:27][CH2:26][CH:25]([C@@H:23]([O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH3:24])[CH2:30][CH2:29]2)[O:35][N:34]=1)[CH3:37]
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Reactant: CC(C)c1noc(N2CCC([C@@H](C)OS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(N2CCC([C@H](C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Step 2, 1.3 g, 5.19 mmol), (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (2.23 g, 7.0 mmol, 70% ee) and K2CO3 (1.45 g, 10.4 mmol) in DMF (35 mL) was stirred at 100° C. in a preheated oil bath overnight. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (75 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown oil, which was by chromatography on a silica gel column eluted with 50% EtOAc/hexanes followed by chromatography on an ISCO silica gel column using 0 to 60% EtOAc/hexanes to give 2-[((1S)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (0.73 g, 70% ee, 30%) as a white solid. The solid was subjected to chiral separation (similar to conditions used above for Example 158) to yield 0.30 g of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H, J=1.3 Hz), 8.25 (d, 1H, J=1.3 Hz), 8.10 (d, 2H, J=8.3 Hz), 8.02 (d, 2H, J=8.5 Hz), 5.20-5.10 (m, 1H), 4.35-4.20 (m, 2H), 3.15-3.00 (m, 5H), 2.90 (septet, 1H, J=7.0 Hz), 2.00-1.80 (m, 3H), 1.60-1.40 (m, 2H), 1.34 (d, 3H, J=6.3 Hz), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 472 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:25][C:26]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH:25]=[CH2:26])=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccc(OC)cc34)ccc12
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (1.00 g, 2.32 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (500 mg, 3.25 mmol) in a 20 mL microwave vial was added PhCH3/EtOH (7 mL/3.5 mL), followed by 1 M Na2CO3 (3 mL, 3 mmol). After stirring for 1 min at rt, Ph(PPh3)4 (50 mg, 0.043 mmol, 1.9 mol %) was added and the resulting mixture was purged with argon, and microwaved 3 h at 120° C. This reaction was repeated twice on the same scale and the resulting mixtures were combined. Aqueous workup gave the crude title compound as a dark orange solid/foam (3.10 g) which was used without further purification. A sample of pure compound can be obtained by flash chromatography (Hex/EtOAc 1:1). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.01 (dd, J=18.2 Hz, J=11.4 Hz, 1H overlapping with d, J=6.8 Hz, 1H; total 2H), 6.83 (d, J=8.4 Hz, 1H), 6.61 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.09 (d, J=18.0 Hz, 1H), 5.56 (d, J=1.6 Hz, 1H), 5.52 (d, J=11.6 Hz, 1H), 3.56 (t, J=7.6 Hz, 1H, partially overlapping with MeOH residue), 3.26 (s, 3H), 2.24 (dd, J=7.8 Hz, J=5.0 Hz, 1H), 2.18 (dd, J=9.2 Hz, J=4.8 Hz, 1H); MS ESI 332.0 [M+H]+, calcd for [C20H17N3O2+H]+ 332.1.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]([CH:16]1[CH2:22][CH2:21][CH2:20][O:19][C:17]1=[O:18])[CH3:15]>C1(C)C(C)=CC=CC=1>[CH2:14]([CH:16]([CH2:22][CH2:21][CH2:20][OH:19])[C:17]([NH:11][CH2:10][CH2:9][C:8]1[C:12]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:13]=2)[NH:6][CH:7]=1)=[O:18])[CH3:15]
Reactant: CCC1CCCOC1=O
Reactant: NCCc1c[nH]c2ccc(Br)cc12
Solvent: Cc1ccccc1C
Product: CCC(CCCO)C(=O)NCCc1c[nH]c2ccc(Br)cc12
Yield: 80 %

Procedure:
0.48 g. (2.0 mmoles) of 5-bromo-tryptamine and 0.30 g. (2.3 mmoles) of 2-ethyl-pentanolide are dissolved in 5 ml. of abs. xylene, and the solution is refluxed for 4 hours. The reaction mixture is evaporated in vacuo, the residue is triturated twice with 3 ml. each of petroleum ether, thereafter it is dried in a desiccator. 0.59 g. (80%) of N-(α-ethyl-δ-hydroxyl-valeroyl)-5-bromo-tryptamine are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C>C1CCCCC1>[C:11]([C:7]1[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Reaction time: 0.25 h

Procedure:
2,6-di-t-butylphenol (8 g, 39 mmoles) is dissolved in 25 ml of cyclohexane at 10° C. A (1/1) mixture of nitric acid/acetic acid (5 ml) is added dropwise to the reaction medium maintained at this temperature. Agitation is then carried out for 15 minutes at ambient temperature. Then the precipitate formed is filtered off, rinsed with water and pentane. The 2,6-di-t-butyl-4-nitrophenol obtained (6.34 g, 65%) is dried in an oven and will be used without further purification in the following stages. Pale yellow powder. Melting point: 167-168° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N+:17]=[N-:18]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Temperature: 57.5 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A mixture of intermediate 46, 2-bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (880 mg, 2.97 mmol) and sodium azide (200 mg, 3 mmol) in dimethylformamide (4 mL) was stirred at 55-60° C. for 30 min after which the solvent was removed in vacuo. The residue was partitioned between CH2Cl2 and water, and the organic phase was washed with water, dried (Na2SO4), filtered and concentrated to provide 670 mg (Yield 87%) of the title compound as a yellow oil; 1H NMR (500 MHz, CDCl3) δ ppm: 2.84 (6H, s) 4.78 (2H, s) 7.29-7.34 (1H, m) 7.59-7.64 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[S:8][C:9]([CH:12]=O)=[CH:10][N:11]=2)[CH:6]=1.[C:14](=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[C:12]([C:9]1[S:8][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[N:11][CH:10]=1)#[CH:14]
Reactant: Cc1cn(-c2ncc(C=O)s2)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cnc(-n2cnc(C)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-bromo-1,3-thiazole-5-carbaldehyde (10 mg, 0.068 mmol), 4-methyl-1H-imidazole (7.23 mg, 0.088 mmol), potassium carbonate (28.1 mg, 0.203 mmol) and DMF (5 ml) were heated at 110° C. for 1 h. The mixture was purified on silica gel (EtOAc/hexane 8:2) to afford 2-(4-methyl-1H-imidazol-1-yl)-1,3-thiazole-5-carbaldehyde (38.4 mg, 0.199 mmol) as a yellow solid. This aldehyde (38.4 mg, 0.199 mmol) and anhydrous potassium carbonate (110 mg, 0.795 mmol) were placed in a 25-ml flask and placed on high vacuum for 10 min. Under N2, anhydrous MeOH (2 ml) was added. To the suspension was added dimethyl (1-diazo-2-oxopropyl) phosphonate (40 μl, 0.256 mmol). The reaction was stirred at rt for 22 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, concentrated to afford crude product, which was used in next step directly.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][N:31]2[CH2:35][CH:34]([CH3:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[CH:34]([CH3:36])[CH2:35][N:31]([CH2:30][C:29]5[CH:38]=[CH:39][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:32]4=[O:37])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Yield: 63.2 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 1, the title compound (130 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19]([NH2:21])=[O:20].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19]([NH2:21])=[O:20])=[O:8]
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
To solution of (2,4,5-trichloro-phenoxyacetic acid (100 mg, 0.39 mmol), 2-amino isonicotinamide (107 mg, 0.78 mmol) and DMAP (96.22 mg, 0.78 mmol) in DMF 12 ml was added PyBOP (409.7 mg, 0.78 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1-2:4:1) to afford 2-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.06 g, 41% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][S:7]([NH:10][C:11]2[C:12](=[O:22])[N:13]([CH2:18][CH2:19][CH2:20]O)[C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][S:7]([NH:10][C:11]2[C:12](=[O:22])[N:13]([CH2:18][CH2:19][CH2:20][Br:45])[C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccc(Cl)cc2)c(=O)n1CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)Cc2ccc(Cl)cc2)c(=O)n1CCCBr
Temperature: 0 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
3-(4-Chlorobenzylsulfonylamino)-6-methyl-1-(3-hydroxypropyl)pyridone (3-8) (292 mg, 0.8 mmol) was dissolved in 8 mL methylene chloride under a nitrogen atmosphere. Triphenylphosphine (250 mg, 0.96 mmol) was added, followed by 370 mg (1.12 mmol) carbon tetrabromide. The reaction mixture was cooled to 0° C. and held at that temperature for 16 hours. The solvent was evaporated in vacuo and the product purified by flash chromatography (50:50 ethyl acetate: hexanes) to afford 227 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.25 (m, 2H), 2.39 (s, 3H), 3.50 (t, 2H), 4.28 (t, 2H), 4.27 (s, 2H), 5.93 (d, 1H), 7.20-7.31 (m, 5H).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:16]1([S:22]([C:14]2[S:15][C:9]3[CH2:8][CH2:7][NH:6][CH2:12][CH2:11][C:10]=3[CH:13]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)c1cc2c(s1)CCNCC2
Temperature: 80 °C

Procedure:
The product of Example 1, step (d) (75 mg, 0.33 mmol) was dissolved in 2 mL DCE and treated with phenyl sulfonyl chloride (83 uL, 0.66 mmol) followed by AlCl3 (88 mg, 0.66 mmol). After heating to 80° C. for ½ hour, the reaction was cooled and quenched carefully with 1M NaOH. The product was extracted into DCM (2×). The organic extracts were concentrated and the residue was dissolved in 3 mL each EtOH and 40% aqueous KOH. The reaction was heated to 100° C. for 14 hours, cooled, and diluted with water. The title compound was extracted into DCM (2×5 mL) and purified by preparative HPLC-MS. 1H NMR (CD3OD) δ 7.96 (d, J=8.1 Hz, 2H), 7.67-7.56 (m, 3H), 5.56 (s, 1H), 3.38-3.32 (m, 4H), 3.27-3.23 (m, 2H), 3.09 (t, J=5.4 Hz, 2H); MS: ESI (positive): 294 (M+H).
Reaction SMILES: [IH:1].Cl[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=[CH:11][C:10]=2[F:18])[CH:6]=[C:5]([CH3:19])[N:4]=1>C(Cl)Cl>[CH2:16]([O:15][C:13]1[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:7]2[CH:6]=[C:5]([CH3:19])[N:4]=[C:3]([I:1])[N:8]=2)[CH:14]=1)[CH3:17]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(Cl)n2)c1
Reactant: I
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2cc(C)nc(I)n2)c1
Reaction time: 18 h
Yield: 57.4 %

Procedure:
Hydroiodic acid (57% in water, 8 mL, 106.39 mmol) was added portionwise to 2-chloro-4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidine (which may be prepared as described in Description 16) (2.18 g, 8.17 mmol) in DCM (30 mL) at 20° C. and the dark mixture was stirred for 18 hrs. The mixture was filtered and washed with a little DCM. The yellow solid was suspended in water/DCM and quenched by the addition of satd. aq. K2CO3 (care: gas evolved). After basification, satd. aq. sodium metabisulphite was added and stirring was continued for 5 mins. The mixture was diluted with further DCM and the phases were separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford 4-(5-ethoxy-2-fluoro-phenyl)-2-iodo-6-methyl-pyrimidine (D17) (1.68 g, 4.6908 mmol, 57.4% yield) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1

Procedure:
4-Nitrobenzyl bromide is treated with morpholine and potassium carbonate in acetone to give 4-(4-Nitrobenzyl)morpholine (G-1). The nitro group is reduced with platinum and hydrogen gas to afford the aniline (G-2) which is then treated with [(1-ethoxycyclopropyl)-oxy]trimethylsilane and sodium cyanoborohydride to give the N-cyclopropyl aniline (G-3). Reaction with diethyl ethoxymethylenemalonate in pyridine affords the enamine (G-4) which is cyclized with polyphosphoric acid to the quinoline (G-5). Treatment with p-chlorobenzylamine at elevated temperature converts the ester to the amide (G-6).