Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: OB(O)c1ccc(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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 90 °C
Reaction time: 17 h
Yield: 65.2 %

Procedure:
Step 1 A mixture of 6-bromo-1H-indole (0.25 g, 1.275 mmol), 4-fluorophenylboronic acid (0.178 g, 1.275 mmol), and 2 M aqueous sodium carbonate (2.0 mL, 4.00 mmol) in toluene (10 mL) and ethanol (2.500 mL) was purged with argon and treated with tetrakis(triphenylphosphine)palladium (0.074 g, 0.064 mmol). The mixture was heated at 90° C. After 17 h, the mixture was cooled to rt and partitioned between water and EtOAc. The organic phase was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 60:40 hexane-EtOAc) to provide 6-(4-fluorophenyl)-1H-indole as a white solid (175.5 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 11.17 (1H, br. s.), 7.65-7.71 (2H, m), 7.56-7.62 (2H, m), 7.37 (1H, t, J=2.9 Hz), 7.22-7.31 (3H, m), 6.44 (1H, t, J=2.0 Hz). Mass spectrum m/z 212.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14](N)[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:18]S(O)(=O)=O.N([O-])=O.[Na+].C1COCC1>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)N1CCc2ccc(N)cc2CC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2ccc(O)cc2CC1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
Into a 250 ml flask, the product from step (b) (3 g, 12.82 mmol) dissolved in water (15 ml) and concentrated H2SO4 (1.02 ml, 19.23 mmol) was added The reaction mixture was heated to 70° C. and stirred for 15 minutes. A solution of NaNO2 (1.01 g, 14.74 mmol) in water (30 ml) was quickly added, followed by addition of THF (45 ml). The reaction mixture was stirred at 70° C. for 30 minutes and then allowed to cool to room temperature. The reaction mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-title compound as a yellow solid (2.0 g) that was used without further purification. MS: ESI (positive): 236 (M+H).
Reaction SMILES: [CH3:1][O-:2].[K+].C[O-].[Li+].[Br:7][C:8]1[C:9](Cl)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.Cl>C1(C)C(C)=CC=CC=1.C(O)(C)(C)C>[Br:7][C:8]1[C:9]([O:2][CH3:1])=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: C[O-]
Agent: Cl
Agent: [K+]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1C
Product: COc1c(Br)cnc2[nH]ccc12
Temperature: 117 °C
Yield: 25.2 %

Procedure:
Potassium methoxide (103 mg), lithium methoxide (27 mg) and tert-butanol (40 μl) were added to a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (81 mg) in xylene (3.5 ml), and the mixture was heated under reflux at 117° C. for 16 hours. The reaction solution was brought to pH 4 by adding concentrated hydrochloric acid in small portions and separated by adding ethyl acetate and distilled water. The resulting aqueous layer was brought to pH 8 by adding a 5 N aqueous sodium hydroxide solution and separated by adding ethyl acetate. All the resulting organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by thin-layer chromatography (developed with ethyl acetate-hexane) to give the title compound (20 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.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][O:17][C:11]1[CH:10]=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([C:21]#[N:22])=[CH:8]2)=[CH:13][CH:12]=1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc2ccc(C#N)cc2c1
Temperature: 80 °C
Yield: 80 %

Procedure:
A solution of 7-methoxy-2-naphthyl trifluoromethanesulfonate (4.95 g, 16.1 mmol) in DMF (20 mL) is degassed by repeatedly evacuating the flask then flushing with N2. Zinc cyanide (1.13 g, 9.7 mmol) is added followed by Pd(PPh3)4 (930 mg, 0.81 mmol). The resulting mixture is again degassed and heated to 80° C. for 3 hours. The reaction is allowed to cool, poured into water and washed twice with toluene and once with CH2Cl2. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The resulting material is purified by column chromatography (step gradient, 25–50% CH2Cl2 in hexanes) to give 7-methoxy-2-naphthonitrile as a white solid (2.36 g, 80%). HRMS (EI) calculated for C12H9NO: 183.0684, found 183.0684.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[CH2:14]([O:16][C:17](=[O:28])[C:18](=O)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:15].Cl>C(O)C.[Ni]>[CH2:14]([O:16][C:17]([C@@H:18]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH3:15]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
50 moles (9.3 g) Ala-Pro were suspended in 100 ml ethanol, combined with 75 moles (15.5 g) 2-oxo-4-phenyl-butyric acid ethyl ester and 18 g molecular sieve 3 A and agitated for 2 hours under anhydrous conditions. One teaspoon of dehydrated Raney nickel and 15 g molecular sieve 3 A were now added, briefly reacted and subsequently hydrogenated for 22 hours under an atmosphere of 4 bars of H2. The reaction mixture was filtered and evaporated to concentrate it to a small volume. Conversion (according to HPLC) relative to Ala-Pro used: 76.7%, product yield (according to HPLC): 35%. The residue was taken up is 250 ml ethanol and adjusted to pH 4.25 with conc. HCl (an aliquot was removed for this purpose, diluted with water and the pH was adjusted, then the entire amount was calculated). The solution was evaporated to low bulk under reduced pressure at 40° C. to 50 g, filtered by Celite and diluted to 100 ml total volume with ethyl acetate. 5.2 g maleic acid dissolved in ethyl acetate+ethanol were added and seeded with enalapril maleate. The crystallizate formed was separated off and dried.
Reaction SMILES: C([Li])CCC.Cl[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]#[C:8][CH:9]1[CH2:11][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#CCCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CC1CC1)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.1 %

Procedure:
To a solution of n-butyllithium (2.5M in hexanes, 159 mL, 0.398 mol) in THF (800 mL) at −10° C. under nitrogen, add 5-chloropentyne (20 g, 0.195 mol) dropwise, keeping the temperature below 10° C. After the addition is complete, allow the reaction to warm to room temperature and stir for 6 hours, then add tributyltin chloride (70 g, 0.215 mol) and stir overnight. Pour the reaction mixture into hexanes (500 mL), wash with saturated sodium bicarbonate (300 mL) and brine (300 mL), dry with sodium sulfate, filter, and concentrate to afford the title compound (70 g, 100%) which can be used without further purification: mass spectrum (m/e): 357 (M+H+); 1H NMR (CDCl3) δ 1.70-1.49 (m, 6H), 1.49-1.24 (m, 7H), 1.10-0.65 (m, 19H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:16]#[N:17])=[C:4]([I:14])[C:5]=1[O:11][CH2:12][CH3:13])(=[O:10])[CH3:9]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1I
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1I
Yield: 77.9 %

Procedure:
A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (1.0 g, 2.9 mmol, from Example 211, Step 1) and potassium cyanide (0.29 g, 4.4 mmol) in DMF (11 mL) was stirred at 40° C. for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×75 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude orange oil. The crude material was dissolved in 1:1 hexane/dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0%-30% over 30 min) to give the desired product (0.79 g, 77%). LCMS for C11H10ClINO2 (M+H)+: m/z=349.9. Found: 349.9.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].OS(O)(=O)=O.O.[CH3:21]O>>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:21])=[O:7]
Reactant: O=C(O)CCCC(=O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCCC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 50.0 g of 5-oxo-5-phenylpentanoic acid (260 mmol) (origin: Fluka) and 70 ml of conc. H2SO4 in 1400 ml of methanol was heated under reflux for 1 h. The reaction mixture was cooled down to room temperature and added to 2 l of water and extracted with ether (2×). The organic phase was washed with water (1×), an aq. solution of NaHCO3 (10%, 2×), again with water (2×), dried (Na2SO4) and concentrated to give 47.9 g (90%) of a slightly yellow oil, which slowly crystallizes at 4° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl>O>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3ccccc3n2)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: c1ccc(C2CCc3ccccc3N2)cc1

Procedure:
2-Phenylquinoline (65 g) was dissolved in absolute alcohol (200 ml) and heated to reflux when sodium metal (25 g) was added in portions over 1 hr. The resulting mixture was maintained at reflux for a further 3 hr. The mixture was diluted with water (300 ml) and acidified with conc. hydrochloric acid. The alcohol was removed in vacuo and the residue made basic with 10M sodium hydroxide solution. The resulting solution was extracted with ether (4×150 ml) and the ether layer was dried (magnesium sulphate) and evaporated in vacuo to give an oil which was distilled twice to give the product, 1,2,3,4-tetrahydro-2-phenylquinoline (b.pt. 114°/0.1 mm Hg). This was characterised by its nmr spectrum.
Reaction SMILES: S1C=CC2C=CC(C(=O)CC)=CC1=2.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23](F)[CH:22]=1>>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[CH:25]=[C:15]([C:14]([O:18][CH3:19])=[O:17])[S:16][C:27]=2[CH:28]=1
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Agent: CCC(=O)c1ccc2ccsc2c1
Product: COC(=O)c1cc2ccc(Br)cc2s1

Procedure:
In a similar manner to Example 9 Method A, 1-(benzo[b]thiophen-6-yl)propan-1-one was prepared starting from methyl thioglycolate (17.8 ml) and 4-bromo-2-fluorobenzaldehyde (40 g) which were reacted together to give methyl 6-bromobenzo[b]thiophene-2-carboxylate (55 g), m.p. 108-110° C. This ester was hydrolysed to give 6-bromobenzo[b]thiophene-2-carboxylic acid (48 g), which was decarboxylated using copper and quinoline at 180-200° C. for 2 hours to give 6-bromobenzo[b]thiophene (20.3 g), m.p. 53-55° C. This compound (7.5 g) was reacted with magnesium (0.9 g) and then with N-methoxy-N-methylpropionamide (6.1 g) to give 1-(benzo[b]thiophen-6-yl)propan-1-one (3.6 g) as a pale yellow solid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][O-].[Na+]>[Br-].C1([N+](C)(C)C)C=CC=CC=1.CN(C)C=O>[CH3:9][O:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1O
Reactant: C[O-]
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccnc1C
Yield: 16.8 %

Procedure:
A stirred solution of 3-hydroxy-2-methylpyridine (1.0 g, 9.2 mmol), phenyltrimethylammonium bromide (2.2 g, 11 mmol) and sodium methoxide (550 mg, 11 mmol) in dimethylformamide (10 ml) was heated under reflux for 3 hours, then the cool reaction mixture washed with water (40 ml) and extracted with ether (3×40 ml). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure, then the residue purified by column chromatography on silica gel, using hexane:ethyl acetate (1:1) as eluant, to give the title compound (190 mg) as a solid. δ (CDCl3): 2.34 (3H, s), 3.68 (3H, s), 6.93 (2H, m), 7.94 (1H, d). LRMS: m/z 124 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][CH2:19]Cl.O>C(#N)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:17][O:18][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COCOc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2,4-dihydroxybenzaldehyde (0.83 g) and cesium carbonate (1.7 g) in acetonitrile (30 mL) was added chloromethyl methyl ether (0.55 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gal (eluent: hexane/ethyl acetate=4/1) to give 2-hydroxy-4-(methoxymethyloxy)benzaldehyde (0.84 g).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6](O)=O)=[CH:4][C:3]=1[CH3:12].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:24][C:25]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>C(Cl)Cl>[Br:34][C:31]1[CH:30]=[C:26]2[C:25](=[CH:33][CH:32]=1)[N:24]=[C:6]([C:5]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH3:12])[CH:4]=1)[NH:29][C:27]2=[O:28]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: NC(=O)c1cc(Br)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccc(Br)cc3c(=O)[nH]2)cc(C)c1O
Reaction time: 1.25 h
Yield: 94.8 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzoic acid (2.00 g, 12.0 mmol) in CH2Cl2 (60.2 mL) cooled to 0-5° C. was added oxalyl chloride (1.47 mL, 16.8 mmol) followed by dropwise addition of DMF (93.3 μL, 1.20 mmol). The mixture was stirred for 1.25 h, the volatiles were removed under vacuum to give crude acid chloride, which was used immediately without further purification. A mixture of 2-amino-5-bromobenzamide (1.99 g, 9.23 mmol) and the acid chloride (crude residue described above) in THE (92.3 mL) was stirred at room temperature for 17 h, then heated at reflux for 4 h. The volatiles were removed under vacuum, the residue was triturated with EtOAc, and filtered to afford the amide (3.02 g, 90%) as a yellow solid. A mixture of the amide (3.01 g, 8.29 mmol), 2 M NaOH (20.0 mL), water (40.0 mL), and MeCN (20.0 mL) was heated at reflux for 15 h, cooled to 5° C., and neutralized with 2 M aqueous HCl. After stirring for 30 min, the white solid was filtered, triturated with acetone, and filtered again to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.28 g, 80%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=2.29 Hz, 1H), 7.93 (dd, J=8.72, 2.42 Hz, 1H), 7.86 (s, 2H), 7.63 (d, J=8.70 Hz, 1H), 5.75 (s, 1H), 2.24 (s, 6H); MS (APCI) m/z 346 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CCN(C(C)C)C(C)C>[Br:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(N2CCOCC2)s1
Temperature: 110 °C

Procedure:
A solution of 2,5-dibromothiazole (0.500 g, 2.06 mmol) in DIPEA (1.50 mL) was charged with morpholine (0.179 mL, 2.06 mmol) and heated to 110° C. for 2 h. The reaction mixture was allowed to cool then partitioned between EtOAc and H2O, and the layers were separated. The aqueous layer was re-extracted with EtOAc (3×), and the combined organic extracts were washed with brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 5% EtOAc in CHCl3] resulting in the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=3.35-3.47 (m, 4H), 3.74-3.86 (m, 4H), 7.09 (s, 1H). MS (ES+): m/z=249.06/251.03 (51/49) [MH+]. HPLC: tR=2.98 min (ZQ2, polar—5 min).
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.N(OC(C)(C)C)=O>O1CCCC1.O>[CH3:11][C:4]1[S:3][CH:2]=[N:6][C:5]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1nc(N)sc1C
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ncsc1C
Temperature: 50 °C
Yield: 59.5 %

Procedure:
To a solution of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (2.15 g, 12.5 mmol) in tetrahydrofuran (60 mL) was slowly added tert-butyl nitrite (2.23 mL, 18.7 mmol) with stirring at 50° C., and the mixture was stirred at 60° C. for 2 hr. The mixture was diluted with water (100 mL), and extracted with ethyl acetate (100 mL×2). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100) to give the title compound (1.17 g, yield 60%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:21][NH:22][C:23]1[CH:24]=[N:25][C:26]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35].C(N(C(C)C)C(C)C)C.O>ClCCl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14]([N:22]([CH3:21])[C:23]2[CH:24]=[N:25][C:26]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNc1cnc(N2CCOCC2)cc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
A solution of 11.8 g (36.9 mMol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride and 50 ml dichloromethane was added dropwise over 15 minutes at 0° C. to a solution of 10.0 g (34.5 mMol) methyl-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine and 8.30 ml (48 mMol) N-ethyl-di-isopropylamine in 70 ml dichloromethane. The reaction mixture was stirred 3.0 hours at 0° C., poured onto 80 ml deionized water and stirred further 30 minutes at room temperature. The phases were separated and the aqueous phase extracted with dichloromethane. The organic extracts were washed with deionized water, aqueous sodium hydroxide 2% and aqueous sodium bicarbonate 5%, dried (Na2SO4) and concentrated under reduced pressure. The residue was crystallized from ethanol at −20° C. to yield 16.25 g (81%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide as a white powder. m.p.=128.8-129.9° C. Concentration of the mother-liquors gave 4.4 g of a slowly crystallizing orange oil which can be further purified.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1[CH2:11][CH2:10][O:9][CH:8]=1)=[O:6])[CH3:2].[CH2:13]([OH:15])[CH3:14].BrN1C(=O)CCC1=O>ClCCl>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:15][CH2:13][CH3:14])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)C1=COCC1
Reactant: CCO
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C(=O)C1CCOC1OCC
Temperature: 7.5 °C

Procedure:
Ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (100 g) was dissolved in dichloromethane (500 ml). Ethanol (150 ml) was added to reaction mass and then reaction mass was cooled to 5 to 10° C. N-bromosuccinimide (115 g) was added lot wise by maintaining temp below 10° C. Reaction mass was then stirred at 20-30° C. till completion of reaction. Reaction mass was washed with sodium bicarbonate solution (8%, 3×400 ml). Sodium sulphite solution (15%, 1700 ml) was charged to dichloromethane layer. Reaction mass was stirred for 8 hrs at 25-35° C. Organic and aqueous layer separated. Dichloromethane layer was washed with water (2×340 ml). Dichloromethane layer was then concentrated to residue to get Ethyl-2-(2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (Yield 114 g)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1[CH2:11][CH2:10][O:9][CH:8]=1)=[O:6])[CH3:2].[CH2:13]([OH:15])[CH3:14]>ClCCl>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:15][CH2:13][CH3:14])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)C1=COCC1
Reactant: CCO
Solvent: ClCCl
Product: CCOC(=O)C(=O)C1CCOC1OCC
Temperature: 45 °C
Reaction time: 12 h

Procedure:
Ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (10 g) was dissolved in Ethanol (50 ml) and Dichloromethane (50 ml). The reaction mass was stirred at 40-50° C. for 12 hrs. Reaction mass was concentrated to residue under vacuum at 40° C. Residue was dissolved in dichloromethane (50 ml) and washed with water (50 ml). Reaction mass was concentrated to residue to get ethyl-2-(2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (Yield 9.9 g).
Reaction SMILES: S([O-])([O-])=O.[NH4+:5].[NH4+].[B:7]([OH:10])([OH:9])[OH:8]>>[B:7]([O-:10])([O-:9])[O-:8].[B:7]([O-:10])([O-:9])[O-:8].[B:7]([O-:10])([O-:9])[O-:8].[B:7]([O-:10])([O-:9])[O-:8].[B:7]([O-:10])([O-:9])[O-:8].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5].[NH4+:5]
Reactant: OB(O)O
Agent: O=S([O-])[O-]
Agent: [NH4+]
Product: [O-]B([O-])[O-]

Procedure:
In addition, as may be seen from Equation 1, ammoniumsulfite and tetraborate ores produce ammoniumpentaborate (NH4.B5O8.4H2O), in quantitative yield contrary to the assertion in British Pat. No. 10,361 which teaches that as a sole product, ammoniumtetraborate (biborate of ammonia, (NH4)2B4O7.4H2O), was obtained from alkali metal and alkaline earth metal borates upon the treatment of their suspensions with ammoniumsulfite.