Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[NH:23][C:22](=[O:25])[O:21][C:20]([CH3:27])([CH3:26])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:28]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[NH:23][C:22](=[O:25])[O:21][C:20]([CH3:27])([CH3:26])[C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1C
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cccc3c2NC(=O)OC3(C)C)cc1C

Procedure:
Prepared analogously to Example 2 from 8-[4-(3,4-dimethyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(NC(C)C)(C)C>O1CCOCC1.ClCCl>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1
Temperature: 105 °C

Procedure:
A mixture of 7.5 mL of p-fluoronitrobenzene, 10.25 mL 2-morpholin-4-yl-ethylamine and 15 mL N,N-diisopropylamine in 36 mL dioxane is heated at 105° C. for 2 days. The reaction mixture is cooled to room temperature, diluted with dichloromethane (360 mL) and washed with water (3×290 mL). Upon evaporation to dryness, the dichloromethane layer yields the (2-morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine product, which is recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH:3]=1.[CH2:16]([CH:19]([CH2:22]O)[CH2:20][OH:21])[CH2:17][CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[O:21][CH2:20][C@H:19]([CH2:16][CH2:17][CH3:18])[CH2:22][O:15]3)[CH2:10][CH2:9]2)[CH2:4][CH:3]=1
Reactant: CCCC(CO)CO
Reactant: O=C[C@H]1CC[C@H](C2CC=C(F)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CO[C@H]([C@H]2CC[C@H](C3CC=C(F)CC3)CC2)OC1

Procedure:
500 mg of trans-4-(4-fluoro-cyclohex-3-enyl)cyclohexanecarbaldehyde, 310 mg of 2-propyl-propane-l,3-diol and 50 mg of p-toluenesulphonic acid in 8 ml of toluene were boiled at reflux for 1 hour in an apparatus which was gassed with nitrogen and which was fitted with a water separator. After cooling the reaction solution was partitioned in water/ether. The organic phase was washed twice with water. The aqueous phases were extracted twice with ether. The organic phases were combined, dried over magnesium sulphate, filtered and the filtrate was evaporated. The crude product was recrystallized several times from ethanol/1% ethyl acetate and gave 350 mg of trans-2-[trans-4-(4-fluoro-cyclohex-3-enyl)cyclohexyl]-5-propyl-[1,3]-dioxane, m.p. (C-N)<room temperature; S-N 104° C., c1.p. (N-I) 118.3° C.;
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]([NH:10]C(=O)OC(C)(C)C)[CH2:8][CH2:7][C@@H:6]([C:18]2[N:19]([CH3:26])[N:20]=[CH:21][C:22]=2[N+:23]([O-])=O)[O:5][CH2:4]1.C(OC([NH:34][C:35]1[S:39][C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])=[N:37][C:36]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:34][C:35]1[S:39][C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])=[N:37][C:36]=1[C:47]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:26])[C:18]=1[C@@H:6]1[CH2:7][CH2:8][C@@H:9]([NH2:10])[C@@H:3]([O:2][CH3:1])[CH2:4][O:5]1)=[O:48]
Reactant: CO[C@H]1CO[C@H](c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4ccccc4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-methoxy-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 93), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid (Example 7) gave 183 as the hydrochloride salt as a dark salmon pink solid (68 mg, 45%). 1H NMR (400 MHz, d6-DMSO) δ 9.47 (s, 1H), 8.18-8.09 (m, 5H), 7.74 (s, 1H), 7.52-7.36 (m, 4H), 4.96 (dd, J=9.9, 2.8 Hz, 1H), 4.19 (dd, J=13.6, 5.0 Hz, 1H), 4.00 (dd, J=13.6, 5.3 Hz, 1H), 3.86 (d, J=4.5 Hz, 1H), 3.78 (s, 3H), 3.62-3.49 (m, 1H), 3.33 (s, 3H), 2.14-1.97 (m, 2H), 1.98-1.74 (m, 2H). LCMS (ES+) m/z 461 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4](C(CCC)=O)[CH2:5][C@H:6]([C:14]([O:16]C)=[O:15])[N:7]2N.[OH-:23].[Li+]>O1CCCC1.O>[C:14]([C@H:6]1[CH2:5][C@H:4]([NH:7][C:6]([CH2:5][CH2:4][CH3:3])=[O:23])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7]1)([OH:16])=[O:15]
Reactant: [OH-]
Reactant: CCCC(=O)[C@H]1C[C@H](C(=O)OC)N(N)c2cc(Cl)cc(Cl)c21
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-5,7-dichloro-2-methoxycarbonyl-4-n-propylcarbonyl-amino-1,2,3,4-tetrahydroquinoline (0.70 g, 0.493 mmol) in a mixture of tetrahydrofuran (15 ml) and water (5 ml) was added aqueous lithium hydroxide (1.1 ml of a 0.50M solution, 0.55 mmol) and the resulting mixture was stirred at room temperature for 20 h. The organic solvent was then removed under vacuum and the aqueous residue was diluted with dilute sodium bicarbonate solution (50 ml) then washed with ethyl acetate (1×30 ml). The aqueous phase was separated, acidified with dilute hydrochloric acid and extracted with ethylacetate (2×50 ml). The combined extracts were washed with brine (1×50 ml), dried (MgSO4) and evaporated to give a solid which was triturated with diethyl ether to give the title compound as colourless crystals (0.123 g) m.p. 174°-176° C. (dec). δ (DMSO, 360 MHz) δ 0.85 (3H, t, J=7.4 Hz, COCH2CH2CH3), 1.48-1.64 (3H, m, CHACHBHCCHD) and COCH2CH2CH3), 2.04 (2H, t, J=7.2 Hz, COCH2CH2CH3), 2.16 (1H, dm, J=13.1 Hz, CHACHBHCCHD), 3.82 (1H, dd, J=12.6 and 2.8 Hz, CHACHBHCCHD), 5.01 (1H, m, CHACHBHcCHDNHCO) 6.64 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.76 (1H, s, ArNH), 6.87 (1H, d, J=2.1 Hz, 6-H or 8-H), 8.10 (1H, d, J=7.2 Hz, --CHDNHCO--); m/e 330 (M+), 198 (100%, M-NHCOCH2CH2CH3, CO2H and H); Found C, 50.09; H, 4.78; N, 8.41; C14H16Cl2N2 03.0.2H2O requires C, 50.22; H, 4.94; N, 8.37%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][NH:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>O.C(Cl)Cl.O>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][N:14]1[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=C1CNN(C(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Yield: 62 %

Procedure:
Sodium hydroxide (0.12 g, 3 mmol) is dissolved in a 1:2 water/methylene chloride solution (30 mL) with rapid stirring followed by the addition of 4-methylene-pyrazolidine-1-carboxylic acid 1-benzyl ester, 9, (0.62 g, 2.8 mmol) at room temperature. (4-Fluorophenyl)acetyl chloride (0.39 mL, 4.2 mmol) is added and the reaction is allowed to stir for 18 hours after which time the reaction mixture is diluted with water (10 mL) and the layers allowed to separate. The aqueous layer is extracted with methylene chloride, the organic layers combined, dried, and filtered. Concentration in vacuo affords the crude product which is purified over silica (1:3 ethyl acetate/hexane) to provide 0.54 g (62% yield) of the desired product.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]([CH3:23])=[CH:8][N:9]=[C:10]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)O1.C([O-])([O-])=O.[K+].[K+].O.O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:38][C:35]1[CH:36]=[CH:37][C:32]([C:2]2[N:6]3[C:7]([CH3:23])=[CH:8][N:9]=[C:10]([NH:11][CH2:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[C:5]3=[N:4][CH:3]=2)=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1cnc(NCc2ccc(S(N)(=O)=O)cc2)c2ncc(Br)n12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(NCc2ccc(S(N)(=O)=O)cc2)c2ncc(-c3ccc(O)cc3)n12
Temperature: 88 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[(3-Bromo-5-methyl-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide (0.1 g, 0.252 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.061 g, 0.277 mmol), K2CO3 1.5M in water (0.34 mL, 0.504 mmol), Pd(OAc)2 (3.0 mg, 0.013 mmol), and (oxidi-2,1-phenylene)bis(diphenylphosphine) (14 mg, 0.026 mmol) in DMF 1 mL is stirred at 88° C. overnight. The reaction mixture is filtered through cotton, diluted with AcOEt, washed with water, the organic layer dried with MgSO4 anh. filtered and evaporated. The crude mixture is purified by prep. HPLC under acid conditions using a gradient of 0.1% formic acid in H2O/0.1% formic acid in Acetonitrile (95/5:5 min, 9/1:13 min, 0/1:4 min) to give 4-{[3-(4-hydroxy-phenyl)-5-methyl-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide as a brown oil, (36.5 mg) LC-MS m/z 410 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]2)[CH2:6][C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:4][NH:3]1>C(#N)C.[Cu](Cl)Cl>[O:1]=[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:4][NH:3]1
Reactant: O=C1NN=C(c2ccccc2)CC1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl[Cu]Cl
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccccc3)n[nH]c2=O)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Copper(II) chloride (anhydrous; 1.27 g, 9.45 mmol) was added to a solution of benzyl 4-(3-oxo-6-phenyl-2,3,4,5-tetrahydropyridazine-4-yl)piperidine-1-carboxylate (1.85 g, 4.73 mmol) in acetonitrile (16 mL). The reaction mixture was heated to 90° C. After 2 h, the mixture was allowed to cool to ambient temperature and concentrated. Dichloromethane was added to the concentrated mixture, followed by hydrochloric acid (1 N in water). The mixture was extracted with dichloromethane (3×) and the combined organic extracts were dried over magnesium sulfate and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (1.1 g). MS 390.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Cl:22])[CH:8]=[C:9]2[C:14]=1[O:13][CH:12]([C:15]([F:18])([F:17])[F:16])[C:11]([C:19]([OH:21])=[O:20])=[CH:10]2)#[C:2][CH2:3][CH3:4].[OH-].[Na+:24]>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([Cl:22])[CH:8]=[C:9]2[C:14]=1[O:13][C@H:12]([C:15]([F:16])([F:17])[F:18])[C:11]([C:19]([O-:21])=[O:20])=[CH:10]2)#[C:2][CH2:3][CH3:4].[Na+:24]
Reactant: CCC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC#Cc1cc(Cl)cc2c1O[C@H](C(F)(F)F)C(C(=O)[O-])=C2

Procedure:
A solution of 98.9mg (0.299 mmole) of 8-but-I -ynyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 2.0 mL of ethanol was treated with 2.967 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide a quantitative yield of a yellow solid: 1H NMR (CD3OD/400 MHz) 1.22 (t, 3H, J=7.6 Hz), 2.44 (q, 2H, J=7.6 Hz), 5.88 (q, 1H, J=7.2 Hz), 7.17-7.19 (m, 2H), 7.32 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][NH2:14].CCOC(C)=O>C1COCC1>[CH3:13][NH:14][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
4-Nitrobenzoyl chloride (7.00 g, 38 mmol, 1 eq) was dissolved in 50 ml of THF and added to a 2.0 M solution of methylamine in THF (41.5 ml, 83 mmol, 2.2 eq.) at 0° C. Worked up after 3 hours by adding EtOAc and rinsing 3× with 1N NaOH, 1× with brine. The organic layer was dried over MgSO4, then stripped to obtain 2.25 g of off-white solids as product. NMR (300 MHz, DMSO-d6) δ 8.80 (m, 1H), 8.33 (d, 2H, J=7 Hz), 8.06 (d, 2H, J=7 Hz). 2.86 (d, 3H, J=7 Hz).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][NH:16][C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]1.ClC(Cl)(Cl)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>CN(C)C=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 70.7 mg, 1.06 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (301 mg, 0.884 mmol) in N,N-dimethylformamide (7 mL) at −35° C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.314 mL, 1.91 mmol) was added and the reaction was stirred at −35° C. After 30 min, an additional amount of sodium hydride (27 mg, 0.40 mmol) and 2,2,2-trifluoroethyl trichloromethanesulfonate (0.140 mL, 0.85 mmol) were added. After 2 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (306 mg). MS 423 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[C:11]([CH3:19])=[N:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1)#[CH:2].[C:20]([O:26][CH2:27][N:28]=[N+:29]=[N-:30])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].N1C(C)=CC=CC=1C>C(O)(C)(C)C.CC#N.[Cu]I>[C:20]([O:26][CH2:27][N:28]1[CH:2]=[C:1]([C:3]2[CH:8]=[C:7]([O:9][C:10]3[C:11]([CH3:19])=[N:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[CH:6]=[CH:5][N:4]=2)[N:30]=[N:29]1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Reactant: C#Cc1cc(Oc2ccc([N+](=O)[O-])nc2C)ccn1
Agent: [Cu]I
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cn(COC(=O)C(C)(C)C)nn2)c1
Yield: 83.9 %

Procedure:
A solution of 3-((2-ethynylpyridin-4-yl)oxy)-2-methyl-6-nitropyridine (0.2 g, 0.78 mmol) and azidomethyl pivalate (0.209 g, 1.33 mmol; See: Syn Lett. 2005, (18), 2847-2850) were combined in tert-butanol (3 mL) and treated with copper(I) iodide (0.030 g, 0.157 mmol) followed by a solution of 2,6-lutidine (0.091 mL, 0.78 mmol) in MeCN (3 mL) and the resultant mixture was stirred at RT for 3 h. The mixture was partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (EtOAc/Hex) to afford (4-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (0.27 g, 84%) as an orange foam. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.60 (d, J=5.7 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.12 (dd, J=5.6, 2.5 Hz, 1H), 6.37 (s, 2H), 2.50 (s, 3H), 1.11 (s, 9H); MS (ESI) m/z: 413.2 (M+H+).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14].F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[N+:30]([O-:32])=[O:31].C(OCC)(=O)C>C1COCC1.CCCCCC>[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:21]1[C:22]([N+:30]([O-:32])=[O:31])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27]
Reactant: Nc1ccc(I)cc1F
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
1.0M LHMDS in hexane (153 mL, 153 mol) was added drop wise to a solution of 2-fluoro-4-iodoaniline (30.0 g, 128 mol) in dry THF (600 mL) at −78° C. over a period of 30 minutes and the resulting mixture was stirred at −78° C. for 30 minutes. This was followed by the addition of 2,3,4,6-tetrafluoronitrobenzene (25 g, 128 mol) in dry THF (150 mL) and stirring was continued for a further 1 hour at room temperature. The reaction was monitored by TLC (10% ethyl acetate in hexane). The reaction mixture was quenched with 2N HCl (100 mL), concentrated and the concentrate was partitioned between water (500 mL) and ethyl acetate (300 mL). The aqueous layer was washed with ethyl acetate (2×200 mL). The combined organic phase was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated to afford 38 g of the crude product. Purification by column chromatography on silica gel (0-5% ethyl acetate in hexane) afforded 31 g of the product (58.8% yield). LCMS: 95.5%, m/z=410.9 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[O:14])[C:6]([CH:11]1[CH2:13][CH2:12]1)=[CH:7][N:8]([CH3:10])[CH3:9])[CH3:2].[CH2:16](OC(=O)C(=O)CC1CCC1)C>>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[O:14])[C:6]([CH:11]1[CH2:13][CH2:12][CH2:16]1)=[CH:7][N:8]([CH3:9])[CH3:10])[CH3:2]
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C1CC1
Reactant: CCOC(=O)C(=O)CC1CCC1
Product: CCOC(=O)C(=O)C(=CN(C)C)C1CCC1
Yield: 51 %

Procedure:
The title compound (0.663, 51%) is prepared essentially as described in the preparation of 3-cyclopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester using 3-cyclobutyl-2-oxo-propionic acid ethyl ester. LC-ES/MS m/e 226.0 (M+1)
Reaction SMILES: C([C:4]1[C:9]2[N:10]=[N:11][S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=O.B(OCC)(OCC)[O:14][CH2:15]C.CO>O1CCCC1>[OH:14][CH2:15][C:7]1[C:8]2[S:12][N:11]=[N:10][C:9]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc2snnc12
Reactant: CCOB(OCC)OCC
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cccc2nnsc12

Procedure:
To a suspension of 54 g of carboxybenzo-1,2,3-thiadiazole in 420 ml of tetrahydrofuran there are added dropwise under a nitrogen atmosphere with stirring at room temperature 110 ml of triethyl borate, the mixture is stirred for a further hour and subsequently treated dropwise with 45.6 ml of boranedimethyl sulfide complex in 60 ml of tetrahydrofuran, with gentle cooling, during which process gas is evolved vigorously. The mixture is stirred overnight and allowed to stand at room temperature and then cooled down to 5°-10° C. and treated dropwise with 200 ml of methanol with stirring and vigorous cooling, during which process gas is again evolved vigorously. The mixture is subsequently evaporated in vacuo, a further 300 ml of methanol are added, and the mixture is re-evaporated. The residue is purified on silica gel (solvent: ethyl acetate/hexane), and the product obtained is recrystallised from ethyl acetate/hexane. The title compound obtained melts at 79°-81° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:10]([C:12]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:4]1([CH2:3][CH2:2][O:21][C:15]2[CH:14]=[CH:13][C:12]([CH:10]=[O:11])=[CH:20][C:16]=2[C:17]([O:19][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:18])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: BrCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCc2ccccc2)c(C(=O)OCCc2ccccc2)c1
Reaction time: 96 h

Procedure:
(2-Bromoethyl)benzene (41 mL, 0.3 mol, 5 eq) was added to a stirred solution of 5-formylsalicylic acid (10 g, 0.06 mol, 1 eq), tetra-n-butylammonium iodide (44 g, 0.12 mol, 2 eq) and cesium carbonate (39 g, 0.12 mol, 2 eq) in N,N-dimethylformamide (200 mL). The reaction mixture was stirred for 4 days, then concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL) and the organic solution washed with water (200 mL), 1M HCl (2×200 mL), 1M sodium hydroxide (2×200 mL) and then brine (200 mL), dried over sodium sulfate and evaporated in vacuo to give a brown oil. The product was not purified further, but taken immediately onto the next step. RF (petroleum ether:ethyl acetate, 1:1) 0.88. 1H NMR (CDCl3) δ9.88 (s, 1H, O═C—H), 8.23 (d, 1H, J 2.2 Hz, ArH), 7.98 (dd, 1H, J 8.7 and 2.2 Hz, ArH), 7.06 (d, 1H, J 8.7 Hz, ArH), 4.56 (t, 2H, J 7.2 Hz, OCH2CH2Ph), 4.33 (t, 2H, J 7.2 Hz, OCH2CH2Ph), 3.11 (t, 2H, J 7.2 Hz, OCH2CH2Ph), 3.03 (t, 2H, J 7.2 Hz, OCH2CH2Ph).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:24]C)=[C:10]([CH:12]2[CH2:21][C:20]3[N:19]=[CH:18][CH:17]=[C:16]([CH3:22])[C:15]=3[C:14](=[O:23])[CH2:13]2)[CH:11]=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:24])=[C:10]([CH:12]2[CH2:21][C:20]3[N:19]=[CH:18][CH:17]=[C:16]([CH3:22])[C:15]=3[C:14](=[O:23])[CH2:13]2)[CH:11]=1
Reactant: COc1ccc(Cl)cc1C1CC(=O)c2c(C)ccnc2C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1O)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1M boron tribromide in dichloromethane (12.3 ml) was added dropwise a solution of 7-(5-chloro-2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.2 g) in dichloromethane (30 ml) at 0° C. The reaction solution was stirred at room temperature for 1.5 hours, and to the solution were added ice and sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with sodium sulfate. Under reduced pressure, the solvent was evaporated to give 7-(5-chloro-2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH:10]([CH3:13])[C:11]#N>O>[Cl:9][CH:10]([C:13]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1)[CH3:11]
Reactant: Nc1cccnc1N
Reactant: CC(Cl)C#N
Solvent: O
Product: CC(Cl)c1nc2cccnc2[nH]1
Temperature: 80 °C

Procedure:
5.2 g of 2,3-diaminopyridine in 209 g of polyphosphoric acid are heated at 120° C. for 0.5 h. The solution is cooled to 80° C. and 4.6 ml of 2-chloropropionitrile are added. Thereafter, the reaction mixture is heated to 180° C. for 2.5 h. After cooling, the polyphosphoric acid is hydrolyzed with water, the mixture is filtered using charcoal and celite and the pH value of the filtrate is adjusted to pH 4 using 9 M aqueous sodium hydroxide solution. The mixture is extracted twice each with 250 ml of ethyl acetate, the combined organic phases are dried using sodium sulfate, concentrated and lyophilized from ethanol/water to give 3.56 g of the title compound as a light brown, amorpheous solid. M.p. 132° C. TLC: Rf=0.60 (dichloromethane/methanol 8:1).