Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:11](C)[N:12]=[CH:13][CH:14]=2)[S:7][CH:6]=1)=[O:4].[OH-].[Na+].[CH3:18]O>>[CH3:18][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[S:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:9]=2)=[N:11]1
Reactant: CO
Reactant: COC(=O)c1csc(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc(-c2cc(C(=O)O)cs2)n1
Reaction time: 1.5 h

Procedure:
5-(2-Methyl-2H-pyrazol-3-yl)-thiophene-3-carboxylic acid methyl ester (0.076 g, 0.34 mmol) was suspended in methanol (0.75 mL) then sodium hydroxide (1 M, 0.41 mL) was added and the mixture stirred for 1.5 hours. A further amount of sodium hydroxide (1 M, 0.41 mL) was added and the mixture stirred overnight. The solution was evaporated, the residue was taken up in HCl (1 N, 1.0 mL) and the resultant precipitate was collected by filtration, washed with water and dried to afford 5-(1-methyl-1H-pyrazol-3-yl)-thiophene-3-carboxylic acid as a grey solid (0.042 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(C(=O)OC(C)(C)C)CCO4)c3n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CNCCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-tert-butyl 2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine-4-carboxylate (21.9 g, 54.69 mmol) was dissolved in CH2Cl2 (300 ml), and TFA (5.3 g, 82.04 mmol) was added, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the next reaction was advanced.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([OH:23])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:24])[CH:12]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:24])[CH:12]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c12
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Sodium hydride (54 mg, 1.35 mmol) was added to a solution of 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (380 mg, 1.08 mmol) and DMSO (20 ml) at rt under N2. After 1 h, ethyl 6-bromohexanoate (770 mg, 3.45 mmol) was added, and the mixture was heated at 30° C. for 5 h. The reaction was quenched with drops of water, poured into 0.5 M KH2PO4, and extracted with EtOAc (100 mL×3). The combined extracts were washed with water and then brine, dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate: pet. ether) to give ethyl 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate: MS (ESI): 494.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.Cl.[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39](O)=[O:40].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:40]
Reactant: CN(C)CCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)CCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), 4-(dimethylamino)butanoic acid hydrochloride salt (0.24 g, 1.43 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml), The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then concentrated in vacuo, suspended in ethyl acetate:acetonitrile (1:1) and filtered. The solids were dissolved in a minimum amount of methanol and submitted directly to purification via chromatography (silica gel, 1 to 20% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.195 g), melting point: 148° C.
Reaction SMILES: I[CH3:2].[F:3][C:4]([F:32])([F:31])[C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[N:19][C:18]([N:21]3[CH2:25][CH2:24][NH:23][C:22]3=[O:26])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8]>>[CH3:2][N:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:19]=[N:20][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:7](=[O:8])[C:6]4[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=4[C:4]([F:3])([F:31])[F:32])[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[C:22]1=[O:26]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N3CCNC3=O)nn2)CC1
Reactant: CI
Product: CN1CCN(c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)C1=O
Yield: 39 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 1-iodomethane in place of 1-iodo-3-methylbutane to react with 1-{6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazin-3-yl}imidazolidin-2-one, the title compound was obtained as a white solid in 39% yield (0.020 g). 1H NMR (300 MHz, CDCl3) δ 8.47-8.44 (m, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.62-7.49 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 7.03-6.99 (m, 1H), 4.08 (t, J=7.8 Hz, 2H), 4.02-3.82 (m, 2H), 3.65-3.42 (m, 6H), 3.31-3.28 (m, 2H), 2.89 (m, 3H). 13C NMR (75 MHz, CD3OD) δ 170.4, 135.4, 133.9, 131.0, 128.8, 127.99, 127.91, 127.85, 47.8, 46.7, 46.6, 45.1, 42.5, 42.4, 31.01, 30.8. MS (ES+) m/z 435 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:32]([NH2:35])(=[O:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[C:32]([NH:35][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:34])[CH3:33]
Reactant: O=C(Nc1ccccc1)C1(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)CC1
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccccc4)CC3)cc2F)ccn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide (0.162 g, 0.365 mmol), acetamide (0.108 g, 1.825 mmol), cesium carbonate (0.178 g, 0.548 mmol), and xantphos (0.021 g, 0.036 mmol) were combined in dry dioxane (2.61 mL) and argon was bubbled through the mixture for 5 minutes. Palladium acetate (6.15 mg, 0.027 mmol) was added, and argon was bubbled through the mixture for an additional 5 minutes. The reaction flask was fitted with a reflux condenser and a balloon of argon and the mixture was heated at 100° C. for 20 hours. The reaction mixture was cooled to room temperature and partitioned between a 4:1 mixture of ethyl acetate and THF (50 mL) and water (50 mL). The aqueous layer was removed and the organic layer was washed with additional water (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to yield a light peach-colored film. Dichloromethane (10 mL) was added and after a few minutes solid began to precipitate. Sonication was used to precipitate out more solid. After sitting for 30 minutes the bright white solid was collected by suction filtration and washed with additional dichloromethane to give N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide (0.099 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 10.59 (s, 1H), 9.78 (s, 1H), 8.19 (d, 1H), 8.07 (dd, 1H), 7.65 (d, 1H), 7.55 (m, 3H), 7.32 (m, 2H), 7.09 (t, 1H), 6.71 (dd, 1H), 2.02 (s, 3H), 1.63 (m, 2H), 1.57 (m, 2H); MS (ESI) m/z: 467.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH:11]([CH3:22])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH:11]([CH2:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[O:14])[CH3:22])[C:29](=[O:32])[O:30][CH3:31])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(CC(=O)c1ccc(F)cc1)N[C@@H](C)c1ccc(Br)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N(C(C)CC(=O)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
A solution of 3-((S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)butan-1-one (28.8 g, 79.2 mmol) and K2CO3 (100 g, 0.79 mol) in methylene chloride (1000 mL) was added methyl carbonochloridate (100 g, 0.72 mol) at 0° C. The formed mixture was stirred at rt overnight. The mixture was filtered and concentrated to give the crude product, which was purified by preparative HPLC to give methyl (S)-1-(4-bromophenyl)ethyl(4-(4-fluorophenyl)-4-oxobutan-2-yl)carbamate (7.5 g, 23%). 1H NMR (400 MHz, CDCl3): δ=1.28 (d, 3H), 1.52 (d, 3H), 2.59 (m, 1H), 3.72 (m, 5H), 5.43 (m, 1H), 6.98 (m, 3H), 7.16 (m, 2H), 7.31 (m, 2H), 7.60 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1.[CH:27](OCC)(OCC)OCC>>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][C:3]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:25][CH:26]=3)[CH:27]=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Product: CCOC(=O)C(C)Oc1ccc(-n2cnc3cc(C(F)(F)F)ccc32)cc1

Procedure:
5.3 g of 1C was dissolved in 50 ml of triethyl orthoformate, the solution was refluxed for 1 hour, then concentrated under reduced pressure. The residue, an oil, was chromatographed over silica gel, using as eluent a 2:15:33 v/v/v mixture of tetrahydrofuran, ethyl acetate and hexane (hereinafter, Solvent A), to give 1, as a viscous liquid.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:4]/[CH:3]=[CH:2]/[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C/C(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)/C=C/CBr
Temperature: 25 °C

Procedure:
To the mixture of (E)-tert-butyl but-2-enoate (10.0 g, 70.4 mmol) and NBS (12.5 g, 70.4 mmol) in CCl4 (150 mL) was added benzoyl peroxide (510 mg, 2.11 mmol), and the reaction was refluxed for 12 h. The mixture was cooled to room temperature, and the solid was filtered off. The filtrate was concentrated in vacuo, and purified by column chromatography to afford (E)-tert-butyl 4-bromobut-2-enoate (I-2a). 1H-NMR (400 MHz, CDCl3) δ 7.02-6.76 (m, 1H), 6.05-5.89 (m, 1H), 4.06-3.95 (m, 2H), 1.56-1.40 (m, 9H). MS calculated for C8H14BrO2 (M+H+) 221.01. found: 221.0.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][C:13]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[N:20]2)=[CH:15][CH:14]=1)C(OC(C)(C)C)=O.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][NH:2][CH2:10][CH2:11][O:12][C:13]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([NH:23][C:24](=[O:33])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[N:20]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)Nc2ccc3ccc(OCCN(C)C(=O)OC(C)(C)C)nc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNCCOc1ccc2ccc(NC(=O)c3ccc(OC)cc3)nc2n1
Temperature: 4 °C
Yield: 55.9 %

Procedure:
A solution of N-{7-[2-(N-Methyl-N-tert-butoxycarbonylamino)ethoxy]-1,8-naphthyridin-2-yl}-4-methoxybenzamide (20 g) in trifluoroacetic acid (60 cc) is stirred for 1 hour at a temperature in the region of 20° C. The reaction mixture is poured into water (100 cc) and neutralized with 4N sodium hydroxide (180 cc). The insoluble product obtained is separated by filtration, washed with water and dried in the air, and is then dissolved in boiling acetonitrile (250 cc). After 2 hours' cooling at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 50° C. under reduced pressure (0.07 kPa). N-[7-(2-Methylaminoethoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (8.7 g), m.p. 146° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH:20]=[C:19]([CH3:21])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:20]=[C:19]([CH3:21])[S:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:31]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][S:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)(=[O:25])=[O:24])=[CH:35][CH:34]=4)=[O:32])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2nc(N3CCNCC3)oc2c1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2ccccn2)cc1
Product: O=C(c1ccc(NS(=O)(=O)c2ccccn2)cc1)N1CCN(c2nc3ccc(Cl)cc3o2)CC1

Procedure:
Compound 14 is prepared using synthesis method 2 using intermediates 3b and 5c (yield: 56%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CNCCc1ccc(C(=O)OC)cc1
Product: COC(=O)c1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1f with 2b produced 3g. MS found M+H=453. The oxalate salt of 3g was recrystallized from ethyl acetate; mp 130-131° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:15])([F:16])[F:17])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 94.8 %

Procedure:
To stirred solution of 2-methyl-3-nitro-5-(trifluoromethyl)benzoic acid (1 g, 4.01 mmol) in DMF (3 mL) was added sodium carbonate (0.63 g, 6.02 mmol) and methyl iodide (1.14 g, 8.03 mmol). The resulting mixture was heated at 60° C. for 4 h. On completion, water was added to the reaction, and the product extracted using DCM. Combined organic layers were dried, concentrated under reduced pressure and purified by column chromatography over silica to give methyl 2-methyl-3-nitro-5-(trifluoromethyl)benzoate (1 g, 95.2%).
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1ccco1
Agent: OBO
Product: O=Cc1cccc(-c2ccco2)n1

Procedure:
6-(furan-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and furan-2-ylboronic acid (60 mg, 93.2 mg theoretical, 64.4%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21]CC2C=CC=CC=2)[CH2:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2OCc2ccccc2)CC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2O)CC1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
A suspension of 3.42 g of 4-(2-benzyloxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10c) (8.94 mmol) and 342 mg of 10% palladium-carbon (50% wet) in methanol (90 ml) was stirred under a hydrogen atmosphere at room temperature for six hours. Hydrogen in the reaction vessel was replaced by nitrogen. Then, palladium-carbon was separated by filtration and washed with methanol. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=1/1) to obtain 2.6 g of the title compound (yield: quant.).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:49]([O:56][C:57]1[CH:62]=[C:61]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:60]=[C:59](Cl)[N:58]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.COC1C=C(OC)C=CC=1C[NH2:75].FC(F)(F)C(O)=O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:49]([O:56][C:57]1[N:58]=[C:59]([NH2:75])[CH:60]=[C:61]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:62]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Clc1cc(-c2ccccc2)cc(OCc2ccccc2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(-c2ccccc2)cc(OCc2ccccc2)n1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Cesium carbonate (806 mg, 2.48 mmol), Xantphos (95.0 mg, 0.165 mmol), and tris(dibenzylideneacetone)dipalladium (0) (76.0 mg, 0.082 mmol) were combined into vial fitted with a Teflon septum. The vial was flushed with argon and a solution of 2-(benzyloxy)-6-chloro-4-phenylpyridine (244 mg, 0.825 mmol) in 1,4-dioxane (2 ml) was added, followed by 2,4-dimethoxybenzylamine (0.249 ml 1.65 mmol). The solution was sparged with argon for 10 mins, then heated to 90° C. and stirred for 24 hours. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer was back extracted two times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (2.5 mL, 32.4 mmol) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. The residue was dissolved with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer was back extracted one time with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/ioshexane gradient) to give 6-(benzyloxy)-4-phenylpyridin-2-amine. LRMS (ESI) calculated for C18H17N2O [M+H]+, 277.1; found 277.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:11][C:4]1[C:5]([F:10])=[C:6]([CH:9]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1)[C:7]#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc(Br)cc(Cl)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: N#Cc1cc(N2CCOCC2)cc(Cl)c1F
Temperature: 140 °C

Procedure:
A suspension of 5-Bromo-3-chloro-2-fluoro-benzonitrile (200 mg, 0.85 mmol), morpholine (74 mg, 0.85 mmol), caesium carbonate (389 mg, 1.2 mmol), palladium(II) acetate (10 mg, 0.04 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.06 mmol) in toluene (5 mL) was sealed in a microwave vial and heated for 30 min at 140° C. (Emrys Optimizer; personal chemistry). The reaction mixture was quenched by addition of saturated aqueous NaHCO3, extracted with EtOAc, dried (Na2SO4) and the solvent was removed in vacuo to give the title compound which was used without further purification in the next step. TLC Rf (hexane/EtOAc 1:1)=0.60; tR (HPLC conditions c): 5.28 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12](=[O:20])[CH2:13][C:14](=NN(C)C)[CH3:15])[CH3:2].CC1(C)[O:27][C:26](=O)[CH:25]=[C:24]([CH3:29])[O:23]1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:13]1[C:26](=[O:27])[CH:25]=[C:24]([CH3:29])[O:23][C:14]=1[CH3:15])=[O:20])[CH3:2]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CCc1cccc(CC)c1NC(=O)CC(C)=NN(C)C
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1NC(=O)c1c(C)oc(C)cc1=O
Yield: 74.3 %

Procedure:
A mixture of 25.0 g (90.8 m mol) of N-(2,6-diethylphenyl)-3-(N,N-dimethylhydrazono)butyramide and 130 ml of toluene was refluxed, to which a solution of 28.4 g (200 m mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one was dropwise added over a period of 30 minutes. The mixture was further refluxed for 2 hours. After distilling off the solvent, 200 ml of ethyl ether was added to the residue. The mixture was well stirred and filtered to remove insoluble material. The filtrate was concentrated and subjected to chromatography to remove high polar impurities. The resultant product was recrystallized from hexane to obtain 20.2 g (Yield 74%) of the title compound.