Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH2:10])=[NH:9].[C:11]([CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OC)=[O:16])(=O)[CH3:12].C[O-].[Na+]>CO>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[NH:10][C:11]([CH3:12])=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15](=[O:16])[N:9]=1
Reactant: N=C(N)Cc1ccco1
Reactant: CCCCCC(C(C)=O)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCc1c(C)[nH]c(Cc2ccco2)nc1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 37.4 %

Procedure:
The mixture of 2-(furan-2-yl)acetamidine hydrochloride (30.0 g), methyl 2-acetylheptanoate (34.8 g) and sodium methoxide (10.1 g) in methanol (300 ml) was stirred for 4.5 hours at ambient temperature, and then the solvent was removed by concentration. To the residue was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 9 with 6N-hydrochloric acid. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-(furan-2-ylmethyl)-6-methyl-5-n-pentyl-4(1H)pyrimidinone (18.18 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:26]([OH:30])=[CH:25][C:23]=1[NH2:24]>C(O)(C)C>[ClH:2].[F:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:26]([OH:30])=[CH:25][C:23]=1[NH:24][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Clc1ncnc2cc(OCc3ccncc3)ccc12
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(F)c(Nc2ncnc3cc(OCc4ccncc4)ccc23)cc1O
Yield: 33.9 %

Procedure:
A mixture of 4-chloro-7-(4-pyridylmethoxy)quinazoline hydrochloride (350 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (155 mg, 1.1 mmol), (prepared as described for the starting material in Example 13), in isopropanol (15 ml) was heated at reflux for 1 hour. The resulting precipitate was collected by filtration and purified by reverse phase HPLC using a gradient (0-75%) of methanol in water. Concentrated hydrochloric acid (0.5 ml) was added to the combined fractions of pure product and the solvent was removed by evaporation to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(4-pyridylmethoxy)quinazoline hydrochloride (140 mg, 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:37])([CH2:35][OH:36])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:31][C:32]([CH2:35][OH:36])([CH3:37])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: CC(N)(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Product: Cc1cc(F)ccc1-c1nc(NC(C)(CO)CO)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 61.7 %

Procedure:
Following the general procedure outlined in Example 60, the product of Example 121 (200 mg, 0.47 mmol) and 2-amino-2-methyl-1,3-propanediol (494 mg, 4.7 mmol) were reacted to give the crude material, which was purified as described in Example 126 to give the desired product 130 mg (62%). LC-MS: 449.0 (MH+, m/z), 1.67 (Rt, min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:17]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([CH2:29][CH2:30]S(C)(=O)=O)[CH2:21]1)(=[O:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CC(CC(C)C)=O>[C:17]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([CH2:29][CH2:30][N:14]2[CH2:13][CH:12]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH2:16][CH2:15]2)[CH2:21]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CC(CCS(C)(=O)=O)c2ccccc21
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(=O)N1CC(CCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Yield: 10.4 %

Procedure:
A mixture of of 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.6 g), 19a (2.0 g), K2CO3 (4.0 g), and methylisobutylketone (20 ml) was refluxed for 16 hours. The mixture was filtered and evaporated in vacuo, and the residue was purified on silica gel eluted with ethyl acetate-methanol-triethylamine (90:5:5). Crystallization from ethanol gave the title product (0.3 g).
Reaction SMILES: CC(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[C:10]([S:33]([CH3:35])=[O:34])[CH:9]=1)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:35][S:33]([C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1)=[O:34]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OC(C)(C)C)cc(S(C)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(S(C)=O)c1

Procedure:
A solution of 1.5 g (2.86 mmol) of 3-(methylsulfinyl)-5-(octadecyloxy)phenylcarbamic acid dimethylethyl ester and 1.1 ml (14.3 mmol) of trifluoroacetic acid in 50 ml of methylene chloride was kept at room temperature for 41 hours. The solvent was removed at reduced pressure, the residue was treated with NaHCO3 solution and the product was extracted with methylene chloride. The dried extract was concentrated at reduced pressure to a solid which was recrystallized from methylene chloride-hexane to give 1.13 g (94% yield), mp 104°-106°, of 3-(methylsufinyl)-5-(octadecyloxy)benzenamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:8])[CH:5]=1.COC(=O)C1C=C(OC)C=C(C(O)=O)C=1.C(OC(N1CCC(N)CC1)=O)(C)(C)C.ClC1N=C(OC)N=C(OC)N=1.C(O)(C(F)(F)F)=O.[CH2:69]([O:71][C:72]1[CH:73]=[C:74]([CH:77]=[C:78]([O:81][CH2:82][CH3:83])[C:79]=1[F:80])[CH:75]=O)[CH3:70].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:6]([C:7]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:75][C:74]3[CH:77]=[C:78]([O:81][CH2:82][CH3:83])[C:79]([F:80])=[C:72]([O:71][CH2:69][CH3:70])[CH:73]=3)[CH2:14][CH2:15]2)=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(OC)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: COC(=O)c1cc(OC)cc(C(=O)O)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 5-methoxy-N-piperidin-4-yl-isophthalamic acid methyl ester [prepared from 5-methoxy-isophthalic acid monomethyl ester (Synthetic Communications, 31(12), 1921-1926; 2001) by condensation with 4-amino-piperidine-carboxylic acid tert-butyl ester, using acid activation with 2-chloro-4,6-dimethoxy-1,3,5-triazine in analogy to the procedure described in example 50 h) followed by Boc cleavage with TFA in analogy to the procedure described in example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 489.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:13])[C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.B([O-])[O-:15]>>[CH:10]1([CH2:9][O:8][C:5]2[N:6]=[CH:7][C:2]([OH:15])=[CH:3][C:4]=2[F:13])[CH2:12][CH2:11]1
Reactant: Fc1cc(Br)cnc1OCC1CC1
Reactant: [O-]B[O-]
Product: Oc1cnc(OCC2CC2)c(F)c1

Procedure:
Following Typical Procedures 4 and 5a, conversion of 5-bromo-2-cyclopropylmethoxy-3-fluoro-pyridine to the boronate and oxidation with NaBO3 provided the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH:20]N)=O>>[Cl:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]1[NH:20][N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([CH3:2])=[CH:4][CH:5]=2)[N:8]=1
Reactant: NNC(=O)c1sccc1Cl
Reactant: Cc1ccc(C(=N)N)cc1
Agent: Cl
Product: Cc1ccc(-c2n[nH]c(-c3sccc3Cl)n2)cc1

Procedure:
The title compound was prepared from 4-methyl-benzamidine hydrochloride and 3-chloro-thiophene-2-carboxylic acid hydrazide by a procedure similar to Example 88b as a yellow solid (0.054 g, 17%). 1H NMR (CD3OD): 7.80 (d, J=7.8 Hz, 2H), 7.52 (d, J=6.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 6.97 (d, J=5.10 Hz, 1H), 2.30 (s, 3H).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: NCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)NCCCCCCCCCCC(=O)O

Procedure:
30.65 g (178.8 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 30 g (149 mmol) of 11-aminoundecanoic acid and 45.24 g (447.1 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 800 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 300 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1.[OH-].[K+]>C(O)C>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
A mixture of ethyl 2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (4.6 g), aqueous potassium hydroxide (1.07 g in 200 ml water) and ethanol (92 ml) was refluxed for 6 hours. After allowing to cool to ambient temperature, the reaction mixture was washed with ethyl acetate (150 ml×2). The separated aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid. To this mixture was added acetic acid (40 ml) and stirred for 30 minutes under ice cooling The resulting precipitates were collected by filtration, washed with water and dried in vacuo to give 2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylic acid (1.98 g).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Br:9]Br>C(Cl)Cl>[Br:9][CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8]
Reactant: O=C1CCCC(=O)C1
Reactant: BrBr
Solvent: ClCCl
Product: O=C1CCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A solution of 1,3-cyclohexanedione (50 g, 0.45 mol) in CH2Cl2 (111 mL) was stirred at 5° C. Bromine (18 mL, 56.3 g, 0.35 mol) in CH2Cl2 (17 mL) was added dropwise over a period of 5-10 min. The reaction mixture was stirred at room temperature for 1 h. The brown precipitate that formed was collected by filtration, washed with CH2Cl2/toluene (100 mL), and air dried, before being crystallized from H2O to afford the title compound as pale yellow crystals (42.6 g, 50%): mp 167-168° C. Anal. RP-HPLC: tR 7.9 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 2.49 (t, 4H, J 6.1, 2×CH2), 1.85 (qu, 2H, J 6.1, CH2). MS (ESI−): m/z 190.90/188.90 (M-H)+.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[CH:27][CH:26]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][Br:19])=[CH:27][CH:26]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1ccc(-c2ccccc2C)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2CBr)cc1
Yield: 99 %

Procedure:
2′-Bromomethyl-biphenyl4-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 2′-Methyl-biphenyl-4-carboxylic acid ethyl ester (4.4 g, 18.31 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.58 g, 20.14 mmol, 1.1 eq.), and 2,2′-azobisisobutyronitrile (0.15 g, 0.92 mmol, 5 mol %). When complete, the reaction was worked up as described leaving 2′-bromomethyl-biphenyl-4-carboxylic acid ethyl ester (5.77 g, 99% yield) as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH3:14][S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25]Cl)=[CH:21][CH:20]=1)(=[O:17])=[O:16].C(=O)(O)[O-].[Na+].[I-].[Na+]>C(#N)C>[CH3:14][S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:16]
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Nc1ccc(OCCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc([N+](=O)[O-])cc1
Yield: 38.1 %

Procedure:
A suspension of N-methyl-4-nitrophenethylamine (1.1 g), 2-(4-methanesulphonamidophenoxy)ethyl chloride (1.5 g), sodium bicarbonate (0.5 g) and sodium iodide (0.9 g) in acetonitrile (100 ml) was stirred at reflux for 4 days. On evaporation to dryness the resultant oil was partitioned between 2N aqueous sodium bicarbonate solution and methylene chloride. After two further extractions with methylene chloride, the organic portions were combined, washed with saturated brine solution, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The resultant brown oil was chromatographed on silica ("Kieselgel 60"-Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions to give the title compound as a yellow solid, (0.9 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O1CCOCCOCCOCCOCCOCC1.Cl[CH:24]([C:26]1[O:27][C:28]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:29]([CH3:31])[N:30]=1)[CH3:25]>C(#N)C>[N:1]([CH:24]([C:26]1[O:27][C:28]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:29]([CH3:31])[N:30]=1)[CH3:25])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc(C(C)Cl)oc1-c1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc(C(C)N=[N+]=[N-])oc1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Sodium azide (635 mg, 9.760 mmol) and a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane was added to a solution of 2-(1-chloroethyl)-5-(4-chlorophenyl)-4-methyloxazole (250 mg, 0.976 mmol) in acetonitrile (10 ml) and reluxed at 80° C. for 3 hours. The reaction was concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 0-5% EtOAc/DCM provided the title compound (254 mg, clear oil). HRMS(C) tR=1.52 min; MS m/z 262.0621
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:16])C>[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:13])[O:12][C:7](=[O:16])[NH:8][C:9]=2[C:10]=1[Cl:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2c(ccc(Cl)c2Cl)C1=O
Agent: [Cr+6]
Agent: [O-2]
Product: O=c1[nH]c2c(Cl)c(Cl)ccc2c(=O)o1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6,7-dichloro-1H-indole-2,3-dione (4.95 g) in 25 mL glacial acid and 25 mL acetic anhydride was added chromium (VI) oxide (3.9 g, 39 mmol) portionwise at 85° C. After addition, the mixture was stirred at 90° C. for 30 min. and cooled down to room temperature. Filtration provided a small amount of 7,8-dichloro-1H-benzo[d][1,3]oxazine-2,4-dione. Evaporation of the filtrate gave the majority of the product as a green solid containing chromium (III) oxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1O
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1OCC(=O)N(C)C
Temperature: 25 °C

Procedure:
The reaction mixture of 4-bromo-2-methylphenol (Aldrich, Cat. No. 681121) (0.50 g, 2.7 mmol), 2-chloro-N,N-dimethylacetamide (Aldrich, Cat. No. 24350) (0.27 mL, 2.7 mmol) and potassium carbonate (1.1 g, 8.0 mmol) in DMF (4 mL) was stirred at 60° C. overnight. After cooling to r.t., the mixture was adjusted to pH˜2 with aqueous HCl, and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford the product which was directly used in nest step reaction without further purification. LCMS (M+H)+=272.2/274.2.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([N:9]([CH3:15])[CH2:10][CH:11]2[CH2:13][CH:12]2[CH3:14])[N:6]=[C:5]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:4]=1)=[O:2].[I-].[CH3:23][S+](C)C.[OH-].[K+]>C(#N)C.O.CCOC(C)=O>[CH3:21][N:16]([C:5]1[CH:4]=[C:3]([CH:1]2[CH2:23][O:2]2)[CH:8]=[C:7]([N:9]([CH3:15])[CH2:10][CH:11]2[CH2:13][CH:12]2[CH3:14])[N:6]=1)[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: C[S+](C)C
Reactant: CC1CC1CN(C)c1cc(C=O)cc(N(C)S(C)(=O)=O)n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CC1CN(C)c1cc(C2CO2)cc(N(C)S(C)(=O)=O)n1
Temperature: 65 °C

Procedure:
To a solution of N-(4-formyl-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide (435 mg, 1.40 mmol) in acetonitrile (5 mL) was added 5 drops water, trimethylsulfonium iodide (342 mg, 1.68 mmol) and potassium hydroxide (188 mg, 3.35 mmol). The reaction was stirred at 65° C., sealed, for 3 h, diluted with EtOAc, washed with sat'd aq NaHCO3, brine, dried over sodium sulfate, and concentrated in vacuo to provide N-methyl-N-(6-{methyl[(2-methylcyclopropyl)methyl]amino}-4-oxiran-2-ylpyridin-2-yl)methanesulfonamide, used as is in the next step. A solution of N-methyl-N-(6-{methyl[(2-methylcyclopropyl)methyl]amino}-4-oxiran-2-ylpyridin-2-yl)methanesulfonamide (440 mg, 1.35 mmol) in EtOH (10 mL) and NH4OH (15 mL) was stirred at 60° C., sealed, for 16 h, concentrated in vacuo and purified by flash chromatography (silica, 5-15% (10% NOH/MeOH)/CH2Cl2) to provide N-(4-(2-amino-1-hydroxyethyl)-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide as a thick oil. 1H NMR (400 MHz, CD3OD) δ 6.52 (s, 1H), 6.47 (s, 1H), 4.58 (X′ of A′B′X′, dd, J=7.6, 4.0 Hz, 2H), 3.54 (A of ABX, dd, J=14.4, 6.4 Hz, 1H), 3.35 (B of ABX, dd, J=14.4, 6.8 Hz, 1H), 3.30 (s, 3H), 3.13 (s, 3H), 3.08 (s, 3H), 3.86 (A′ of A′B′X′, dd, J=13.2, 4.0 Hz, 1H), 2.76 (B′ of A′B′X′, dd, J=13.2, 7.6 Hz, 1H), 1.02 (d, J=6.0 Hz, 3H), 0.80-0.65 (m, 2H), 0.46-0.39 (m, 1H), 0.25-0.18 (m, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:12][N:11]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.CCN(CC)CC.[N+:50]([C:53]1[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1)([O-:52])=[O:51]>C1COCC1.CCOCC.CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:50]([C:53]1[CH:54]=[CH:55][C:56]([S:59]([O:8][CH2:9][C@H:10]2[CH2:12][N:11]2[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])(=[O:61])=[O:60])=[CH:57][CH:58]=1)([O-:52])=[O:51]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]1COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of tert-butyl (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)aziridine-1-carboxylate (prepared following literature procedures: Travins, J. M.; Etzkorn, F. A. Tetrahedron Lett. 1998, 39, 9389-9392) in THF/Et2O (1/1) (0.17 M) was cooled in an ice bath and treated dropwise over 20 min with 1 M TBAF in THF (1.05 eq). The resulting solution was stirred in the ice bath for 30 min, before being quenched by the addition of sat. aq. NaHCO3 and extracted into Et2O/PE (4/1). The organic layers were collected, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was taken up in dry DCM (0.17 M) and Et3N (1.3 eq) introduced prior to cooling to 0° C. DMAP (0.1 eq) and 4-nitrobenzenesulfonyl chloride (1.1 eq) were added and the resulting mixture left to stir at RT overnight. The reaction mixture was diluted with DCM and washed with sat. aq. NaHCO3, water and brine before drying over Na2SO4, filtering and concentrating in vacuo. The crude was purified by FC (PE/EtOAc 8:2) to afford the title compound as an off-white solid (57%). (ES+) m/z 359 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([CH3:18])[CH:4]=1)=[O:2].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.[Li+].[Cl-].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=[C:7]([CH3:9])[C:6]=1[C:24]1[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=1
Reactant: Cc1cc(C=O)cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: Cc1cc(C=O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Yield: 96.2 %

Procedure:
Trifluoro-methanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester (4 g, 14.2 mmol), 4-trifluoromethyl-phenylboronic acid (5.4 g, 28.4 mmol), tetrakis(triphenylphosphine)palladium (1.64 g, 1.42 mmol), LiCl (1.8 g, 42.6 mmol), and K2CO3 (5.9 g, 42.6 mmol) are placed in a flask. The system is purged with nitrogen, followed by the addition of toluene (20 ml) and water (5 ml). The resulting mixture is refluxed overnight, loaded on silica gel directly, and purified by silica gel column chromatography, eluting with EtOAc/hexanes to afford 3.8 g (96%) of the titled compound as a white solid. 1H-NMR.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12](#[N:15])[CH:13]=C.CN1CCOCC1>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]#[N:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: C=CC#N
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CN1CCOCC1
Product: N#CC=Cc1ccc(C=O)cc1
Yield: 8.4 %

Procedure:
3.91 mg (1.6×10-5 mols) of palladium acetate, 6.74 g (40 millimols) of 4-formylbenzoyl chloride, 2.63 ml (40 millimols) of acrylonitrile and 4.41 ml (40 millimols) of N-methylmorpholine, in 80 ml of p-xylene, are stirred for 5 hours. Working up as described in the preceding examples affords 0.53 g (8% of theory) of 4-formylcinnamonitrile.