Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:26](=O)([O:37]N1C(=O)CCC1=O)[O:27][CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([Cl:36])[CH:30]=1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:26]([O:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([Cl:36])[CH:30]=3)=[O:37])[CH2:23][CH2:24]2)=[O:25])[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(OCc1cc(F)cc(Cl)c1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCNCC2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1cc(CCCC(=O)NC2CCN(C(=O)OCc3cc(F)cc(Cl)c3)CC2)nn1
Temperature: 25 °C

Procedure:
To a stirred suspension of (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (step 5) (150 mg, 0.387 mmol) and 3-chloro-5-fluorobenzyl 2,5-dioxopyrrolidin-1-yl carbonate (117 mg, 0.387 mmol) in DCM (5 mL) was added NaOH (1.547 mL, 1.547 mmol) with stirring at RT and the mixture was stirred at RT for 18 hrs. A further 5 ml DCM was added followed by 1M NaOH (1 ml). The reaction mixture was diluted with DCM (30 ml) and the organic portion was dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product;
Reaction SMILES: C([NH+](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([O-])=[O:23])=[N:16]2)=[C:11]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:10]=1.O1CCCC1.C(Cl)(=O)OCC.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:23])=[N:16]2)=[C:11]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:10]=1
Reactant: COc1ccc(C(=O)c2cc(Cl)ccc2-n2nc(C(=O)[O-])nc2CCl)cc1
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cc(Cl)ccc2-n2nc(C(=O)N3CCOCC3)nc2CCl)cc1
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 5.07 parts of 1-[4-chloro-2-(4-methoxybenzoyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid triethylammonium salt in 60 volume parts of dry tetrahydrofuran, 1.0 volume part of ethyl chlorocarbonate is added under cooling with ice-salt. After 5 minutes a solution of 2.6 volume parts of morpholine in 3 volume parts of dry tetrahydrofuran is added to the mixture. After stirring for an additional 5 minutes the reaction mixture is diluted with water and concentrated under reduced pressure. The concentrate is extracted with ethyl acetate and the ethyl acetate layer is washed with water. After evaporation of the solvent the residue is treated with ethanol-ether to yield 1-[4-chloro-2-(4-methoxybenzoyl)phenyl]-5-chloromethyl-3-morpholinocarbonyl-1H-1,2,4-triazole as crystals. Recrystallization from aqueous ethanol gives colorless prisms melting at 180°-181°C. The crystals are hemihydrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]>C1COCC1.CN(C1C=CN=CC=1)C>[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 62.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (103 mg, 0.3 mmol), described in the previous step. The crude was purified by silica gel chromatography (DCM/MeOH 0-15%) and triturated in diethyl ether to afford 1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (102 mg, 62%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.99 (t, J=18 Hz, 3H), 3.99 (s, 6H), 6.66 (s, 1H), 6.94 (d, J=9.6 Hz, 1H), 7.18 (d, J=9.6 Hz, 1H), 7.35-7.40 (m, 2H), 7.51-7.60 (m, 7H), 8.55 (s, 1H), 8.66 (s, 1H), 9.26 (s, 1H); LC-MS (ESI) m/z 547 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8](=O)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>C1C=CC=CC=1>[CH2:8]([C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Nc1ncccc1Cc1ccco1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
A mixture of 20 g (0.213 mol) of 2-aminopyridine and 22.5 g (0.234 mol) of furfural in 400 ml of benzene was refluxed for 2 hours. The benzene was then evaporated off and the residue was taken up with 500 ml of methanol. The mixture was stirred in an ice bath whereupon 8.9 g (0.234 mol) of NaBH4 were added in small portions. The mixture was then stirred at ambient temperature for 5 hours. After the methanol had been evaporated off, the residue was extracted with ether to give 24.1 g of furfuryl aminopyridine having a boiling point of b.p. 0.1=98° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10](Cl)(=[O:12])[CH3:11].O>CN(C)C1C=CC=CC=1>[C:10]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1)(=[O:12])[CH3:11]
Reactant: Cc1cc(Br)cnc1N
Reactant: CC(=O)Cl
Solvent: O
Solvent: CN(C)c1ccccc1
Product: CC(=O)Nc1ncc(Br)cc1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
To a solution of 2-amino-5-bromo-3-methylpyridine (300 mg) in N,N-dimethylaniline (486 mg) was added acetyl chloride (138 mg), and the mixture was stirred for 3 hours at 70° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform) to give 2-acetamido-5-bromo-3-methylpyridine (120 mg).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15]C(Cl)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@H:22]([CH2:23][C@@H:24]([OH:47])[C@@H:25]3[C@@H:40]2[CH2:39][C@H:38]([OH:45])[C@@:37]2([CH3:46])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]1.O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][NH:19][C@H:20]3[CH2:43][CH2:42][C@@:41]4([CH3:44])[C@H:22]([CH2:23][C@@H:24]([OH:47])[C@@H:25]5[C@@H:40]4[CH2:39][C@H:38]([OH:45])[C@@:37]4([CH3:46])[C@H:26]5[CH2:27][CH2:28][C@@H:29]4[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](NOCC5c6ccccc6-c6ccccc65)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of 9-fluorenylmethoxycarbonyl chloride (1.4 g; 5.4 mmol) in 1,4-dioxane (18 mL) was added dropwise to a suspension of (3β,5β,7α,12α)-3-amino-7,12-dihydroxycholan-24-oic acid A (2.0 g; 4.9 mmol) (3) in 10% aq. Na2CO3 (30 mL) and 1,4-dioxane (18 mL) stirred at 0° C. After 6 h stirring at room temperature H2O (100 mL) was added, the aqueous phase washed with Et2O (2×90 mL) and then 2 M HCl (15 mL) was added (final pH: 1.5). The precipitated solid was filtered, washed with H2O (3×100 mL), vacuum dried and then purified by flash chromatography to give B as a white solid (2.2 g; 3.5 mmol). Yield 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1[CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:32][CH2:33][O:34][CH3:35])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Reactant: C1CCOC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
5-Chloro-2-nitro-pyridine-3-ol (86 mmol) is dissolved in THF (300 ml) and triphenylphosphin (2 eq.) and ethyleneglycolmonomethylether (1 eq.) is added at 0° C. After addition of di-tert.-butylazodicarboxylate (2 eq) in THF (100 ml), the reaction is stirred five hours at room temperature. The solvent is removed in vacuo. 5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow solid in a yield of 90%. HPLC (method C): 1.59 min; LC-MS (method A): 1.47 min, 233.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14](OC(=O)C)(=[O:16])[CH3:15].CCCCCC>CO.[Pd]>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:14](=[O:16])[CH3:15])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([N+](=O)[O-])c(C)c1C
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(NC(C)=O)c(C)c1C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2,3-dimethyl-4-nitroanisole (1.04 g, 5.74 mmol) in methanol (20 ml) was added 10%-Pd/C (100 mg) at room temperature, and the resulting solution was stirred under a hydrogen atmosphere. After 1 hour, the reaction solution was filtered by the use of Celite and the filtrate was concentrated under reduced pressure and then dried. The residue was dissolved in ethyl acetate (10 ml), followed by adding thereto acetic anhydride (0.867 ml, 9.18 mmol), and the resulting mixture was refluxed. After 2 hours, hexane (70 ml) was poured into the reaction solution and the crystals formed were filtered under reduced pressure and then dried to obtain N-(4-methoxy-2,3-dimethylphenyl)acetamide (1.02 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:4][C:5]([O:8][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1cc(OC(=O)CCCCCCCCCCCCCCCCC)c(Cl)cn1
Yield: 15 %

Procedure:
A 2.00 g quantity of 5-chloro-4-hydroxy-2-pyridone was refluxed in 150 ml of pyridine to obtain a uniform solution. To the solution was added 5.85 g of stearoyl chloride and the mixture was subjected to reaction at room temperature overnight. After completion of the reaction, the pyridine was concentrated and the concentrate was extracted with petroleum ether. The petroleum ether layer was concentrated and subjected to silica gel column chromatography using as an eluent petroleum ether-chloroform (1:9), giving 1.40 g of the title compound in a yield of 15%.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:23]1([C:17]2[CH:16]=[C:15]([C:13]3[C:12]4[C:11]([CH3:28])=[C:10]([CH3:29])[S:9][C:8]=4[CH:1]=[C:2]4[C:7]=3[CH:6]=[CH:5][CH:4]=[CH:3]4)[CH:20]=[CH:19][C:18]=2[OH:21])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 78 %

Procedure:
To (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone (4.8 g, 11.7 mmol) in anhydrous methylene chloride (70 mL) at −78° C. under nitrogen was added dropwise over a period of 20 min boron tribromide (3.6 mL, 37.6 mmol). The reaction mixture was then allowed to stir at room temperature for 22 h. The solution was poured onto a mixture of ice and water (600 mL) and extracted with diethyl ether (800 mL). The diethyl ether layer was washed twice with water (500 mL) and once with brine (500 mL). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (97:3) gave the title compound as a white solid (3.4 g, 78%): mp 156-158° C.; (DMSO-d6): o 9.48 (s, 1H), 8.42 (s, 1H), 7.93 (d, 1H), 7.46-7.41 (m, 2H), 7.35-7.30 (m, 1H), 7.00 (s, 1H), 6.95-6.90 (m, 2H), 3.38-3.28 (m, 1H), 2.39 (s, 3H), 1.99-1.90 (m, 2H), 1.68-1.47 (m, 6H), 1.60 (s, 3H); MS(EI): [M+] 372; Anal. Calc. for C25H24OS: C, 80.60, H, 6.49, N, 0.00. Found: C, 80.39, H, 6.43, N, 0.04.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[NH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: COC(=O)CN
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2g; 3.47 mmol) in THF (100ml) was treated with methyl 2-aminoacetate (540 mg; 4.34 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid (1.05 g, 76%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:14].[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:22]([OH:23])=[C:19]([O:20][CH3:21])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:23][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:14])[CH:16]=[O:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1nc(-c2ccccc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1sc(-c2ccccc2)nc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
A mixture of 5-chloromethyl-4-methyl-2-phenyl-1,3-thiazole (2.30 g), vanillin (1.49 g), potassium carbonate (1.35 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzaldehyde as pale-yellow crystals (3.02 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Cl:10][C:11]1[C:19]([N+:1]([O-:4])=[O:2])=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(F)c(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C

Procedure:
40 ml of concentrated nitric acid are added dropwise to 34 ml of concentrated sulphuric acid with ice cooling and stirring. 20.9 g of 2,4-dichloro-5-fluorobenzoic acid are introduced in portions into this nitration mixture, the temperature rising to 45°-50° C. The mixture is then heated at 90°-100° C. for a further 3 hours, cooled to room temperature and poured into 350 ml of ice water, and the precipitate is filtered off under suction and washed with water. The moist crude product is dissolved in 30 ml of hot methanol, and 150 ml of H2O are added to the solution. The cold precipitate is filtered off under suction, washed with CH3OH/H2O and dried at 80° C. in vacuo. 21.2 g of crude 2,4-dichloro-5-fluoro-3-nitro-benzoic acid are obtained. It is adequately pure for the further reactions. A sample, recrystallized from toluene/petroleum ether, yields crystals of melting point 192° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1([CH3:12])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCOC(C)=O>CCCCCC>[C:1]([NH:5][S:6]([C:9]1([CH2:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)C1(C)CC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)C1(Cc2ccccc2)CC1
Yield: 60 %

Procedure:
Steps 7Ib-7Ic) This compound was obtained in 60% yield using the procedure described for the synthesis of N-tert-Butyl-(1-methyl)cyclopropylsulfonamide except 1.05 equivalents of benzyl bromide were used, followed by trituration with 10% EtOAc in hexane: 1H NMR (CDCl3) δ 0.92 (m, 2H), 1.36 (m, 2H), 1.43 (s, 9H), 3.25 (s, 2H), 4.62 (bs, 1H), 7.29-7.36 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].[CH3:15][N:16]1[CH2:20][CH2:19][CH:18](O)[CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][N:16]1[CH2:20][CH2:19][CH:18]([O:14][C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:17]1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: CN1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)C1
Yield: 67.1 %

Procedure:
Add 3-nitro-5-(trifluoromethyl)phenol (1.6 g, 7.7 mmol), 1-methylpyrrolidin-3-ol (940 mg, 9.3 mmol), triphenylphosphine (3.4 g, 11.6 mmol) in THF (20 mL), stir on ice bath, then add diethyl azodicarboxylate (DEAD, 2.0 g, 11.6 mmol). Stir the mixture at ambient temperature for 15 hrs. Add water (100 mL), then extract the mixture with ethyl acetate (100 mL×3), combine the organic layers and dry over anhydrous sodium sulfate. Filter and concentrate the filtrate to get the crude product. Purify by flash chromatography (silica gel, DCM:MeOH=20:1) to afford the target product (1.5 g, 67%). MS: (M+1): 291.1.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[Br:14][CH2:15][C:16](Br)=[O:17]>ClCCl>[Br:14][CH2:15][C:16]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([F:6])[CH:8]=1)=[O:17]
Reactant: O=C(Br)CBr
Reactant: Nc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1cccc(F)c1
Reaction time: 8 h

Procedure:
To a suspension of sodium bicarbonate (1 g) and 3-fluoroaniline (0.46 g) in dichloromethane (100 mL) was added 2-bromoacetyl bromide (0.36 mL) by dropwise addition. After stirring overnight the reaction mixture was washed with water, dried with magnesium sulfate and evaporated to yield the sub-titled compound (1.07 g).
Reaction SMILES: C[O-].[Na+].[N:4](OCCC(C)C)=[O:5].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1>CO.O1CCCC1>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:24])[C:21](=[N:4][OH:5])[CH2:22][CH3:23])=[CH:16][CH:15]=1
Reactant: CCCC(=O)c1ccc(SC)cc1
Reactant: CC(C)CCON=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=NO)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
11.0 g (0.206 mol) of sodium methoxide is suspended in 130 ml of methanol. Then isoamyl nitrite (27 ml, 0.206 mol) and 25 g (0.129 mol) of 1-(4-Methylsulfanyl-phenyl)-butan-1-one dissolved in 70 ml of tetrahydrofuran (THF) are added and the reaction solution is stirred at room temperature for 1.5 days. After concentrating, water and acetic acid are added to neutralise. The crude product is extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (15:85) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 1.14 (t, 3H), 2.52 (s, 3H), 2.72 (q, 2H), 7.25 (d, 2H), 7.89 (d, 2H), 8.01 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]2)=[CH:6][N:7]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCCN(S(C)(=O)=O)C3)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)N1CCCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 4-(3-amino-6-(1-(methylsulfonyl)piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (60 mg, 0.147 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 M LiOH (400 μL, 0.400 mmol). The reaction mixture was stirred at room temperature overnight. The pH of the reaction mixture was adjusted to ˜3 to 4 with 2 N HCl, and the product was extracted with ethyl acetate. The organic layer was separated from water and washed with brine, dried over sodium sulfate, filtered off, and evaporated to provide the crude product, which was taken to the next step without further purification. LCMS (m/z): 395.1 (MH+), 0.573 min.
Reaction SMILES: [CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(O)(=O)C.[C-:20]#[N:21].[K+]>C(OCC)C>[OH:15][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:20]#[N:21]
Reactant: [C-]#N
Reactant: CCCCCCCCCCCCCC=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCCC(O)C#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
To an ice-cooled solution of tetradecanal (18.75 g) in diethyl ether (100 ml) was added acetic acid (5.66 ml) and potassium cyanide (6.64 g). The mixture was warmed to room temperature and stirred for 72 hours. The resulting solution was washed with water, and the aqueous phase was extracted with diethyl ether (50 ml). The combined organic phase was dried, and concentrated to dryness. The residue was purified by silica gel chromatography and triturated in diisopropyl ether (10 ml) to give 2-hydroxypentadecanenitrile (4.66 g).