Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.F[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>C1COCC1>[F:17][C:15]1[CH:14]=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[C:11]([NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:16]=1
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Prep 2: Sodium hydride (48.6 g, 60% by wt, 1.22 mol) was added piecewise to a solution of 2-aminopyridine (57.2 g, 0.61 mol) in THF (400 mL) at 0° C. at such a rate that T≦18° C. The reaction mixture was stirred at 0° C. for 10 min. then added via cannula to a solution of 2,4-difluoronitrobenzene in THF (350 mL) at −20° C. at such a rate that T≦10° C. The reaction was stirred at −40° C. for 1 h then allowed to warm to RT. As the reaction reached RT the temperature rose rapidly to 35° C. and effervescence was observed. The reaction mixture was poured onto ice (˜2 L) and the solid which formed collected by filtration. The solid was washed with pentane and dried in vacuo to give the (5-fluoro-2-nitrophenyl)pyridin-2-yl-amine as a bright orange solid (139.3 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]([CH3:15])[C:4]=1[CH:5]=[O:6].P([O-])(O)(O)=[O:17].[Na+].Cl([O-])=O.[Na+].C(=O)([O-])O.[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]([CH3:15])[C:4]=1[C:5]([OH:17])=[O:6]
Reactant: O=P([O-])(O)O
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Product: COc1cc(C)c(C(=O)O)c(OC)c1OC
Reaction time: 2 h
Yield: 458.1 %

Procedure:
45.6 g (217 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde was dissolved in 130 ml of dimethyl sulfoxide, and an aqueous solution (50 ml) of 5.2 g (44 mmol) of sodium dihydrogen phosphate was dropwise added over a period of 20 minutes. Then, an aqueous solution (180 ml) of 28 g (305 mmol) of sodium chlorite was dropwise added over a period of 3 hours, followed by stirring for 2 hours. A saturated sodium hydrogencarbonate aqueous solution was added until no bubbling occurred, followed by stirring for 1 hour. Then, the reaction solution was washed with 50 ml of ethyl acetate twice, and concentrated hydrochloric acid was added to make the aqueous layer acidic, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with hexane to obtain 45.6 g (yield: 93%) of 2,3,4-trimethoxy-6-methylbenzoic acid (melting point 95 to 97° C.).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[CH:8][C:7]=1[CH3:29].[OH-].[Na+].[CH2:33]1COCC1>CO>[CH3:29][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=3)=[CH:17][C:18]=2[CH3:33])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:2])=[O:30]
Reactant: COC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1C
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)cc2C)ccc1CCC(=O)O

Procedure:
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionic acid methyl ester (0.043 g, 0.0959 mmole) is treated with a mixture of NaOH(aq) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight. The organic solvents are removed on rota-vapor. The residue is diluted with water (10 mL), acidified to pH=2 with 6N HCl(aq). The precipitate is collected through filtration, washed with cold water (30 mL) and dried to provide the titled compound as a white solid. MS (ES): 433 (M+H); the structure is also confirmed by proton NMR. A substantially similar process is used to make the following compound and the Compound of Example 45, below.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]=12.[C:13]([C:20]1[NH:21][CH:22]=[CH:23]N=1)([C:15]1NC=CN=1)=O.N1CCCCC1>ClCCl>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([N:21]3[CH2:20][CH2:13][CH2:15][CH2:23][CH2:22]3)=[O:12])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc2nonc2c1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C(c1ccc2nonc2c1)N1CCCCC1
Yield: 72.6 %

Procedure:
Benzofurazan-5-carboxylic acid (1 g, 5.6 mmol) was suspended with stirring in 15 mL dichloromethane to which was added carbonyl diimidazole (0.90 g, 5.6 mmol). Gas evolved and the resulting solution was stirred for 40 minutes at which time piperidine (0.5 g, 5.9 mmol) was added with stirring. The reaction solution was concentrated onto silica and product was eluted with hexanelethyl acetate (3:1). Recrystallization from 2-propanol/hexane (1:10) yielded 1-(benzofurazan-5-ylcarbonyl)piperidine (0.94 g, 69%) as a yellow solid with, m.p. 94.5-96.5° C. IR: 2938, 2855, 1620, 1612, 1528, 1487, 1435, 1257, 1233, 1018, 1000, 852, 811, and 747 cm−1. 1H NMR (500 MHz): δ 7.10-7.80 (3H, br s); 3.72 (2H br s); 3.39 (2H, br s); 1.72 (4H, br s); and 1.54 ppm (2H, br s).
Reaction SMILES: C(N1CCN(C2N=C(Br)C=C3C=CSC=23)CC1)C.[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][O:45]C(=O)C)=[C:38]([Cl:49])[CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20].Cl>C(OCC)(=O)C>[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][OH:45])=[C:38]([Cl:49])[CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCN(c2nc(-c3ccc(OCCOC(C)=O)c(Cl)c3)cc3ccsc23)CC1
Agent: CCN1CCN(c2nc(Br)cc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(OCCO)c(Cl)c3)cc3ccsc23)CC1
Reaction time: 0.75 h

Procedure:
The resulting compound and 7-(1-ethylpiperazin-4-yl)-5-bromothieno[2,3-c]pyridine (0.19 g) were reacted in the same manner as in Example 300-4, to give a reaction solution containing 7-(4-ethylpiperazin-1-yl)-5-[4-(2-acetoxyethoxy)-3-chlorophenyl)thieno[2,3-c)pyridine. Ethyl acetate and 2N hydrochloric acid were added to the reaction solution, and the resulting insoluble matters were filtered off. The aqueous layer was separated, while the organic layer was extracted with 2N hydrochloric acid. The resulting aqueous layers were combined and washed with ethyl acetate twice. The pH of the resulting solution was adjusted to pH 10 by adding a 8N aqueous solution of sodium hydroxide, and then the solution was extracted with ethyl acetate twice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated. Methanol (6 ml) was added to the resulting residue and dissolved, followed by the addition of a 8N aqueous solution of sodium hydroxide (0.75 ml). The resulting mixture was left as it was at room temperature for 45 min, and then the solvent was evaporated. Water was added to the resulting residue, and then the mixture was extracted with ethyl acetate thrice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give the title compound (0.03 g) as a colorless viscous oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(N3CCN(Cc4nc5ccccc5[nH]4)CC3)nc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1

Procedure:
The product from Example 29D (800 mg) in ethyl acetate (35 mL) was treated with 10% palladium on carbon (85 mg) under a blanket of hydrogen gas at 23° C. until TLC indicated consumption of starting material. The mixture was filtered and the filter cake washed with with methanol and CH2Cl2. The filtrates were combined and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 90:10:0.1 CH2Cl2:methanol:NH4OH) to provide the title compound pure as a white solid (566 mg, 92%). mp 144-145° C.; Rf0.08; (95:5 CH2Cl2:methanol:0.1% NH4OH); MS 310 (M+H)+; 1H NMR (300 MHz, MeOD) δ 7.72 (d, 1H, J=2.7 Hz), 7.53 (m, 2H), 7.21 (m, 2H), 7.12 (dd, 1H, J=9, 3 Hz), 6.75 (d, 1H, J=9 Hz), 3.85 (s, 2H), 3.40 (t, 4H, J=5.1 Hz), 2.69 (t, 4H, J=5.1 Hz); Analysis calculated for C17H19N5O (1.0 equivalent methanol, 0.1 equivalent dichloromethane): C, 62.13; H, 6.68; N, 20.01. Found: C, 62.04; H, 6.57; N, 19.67.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:28]1[N:33]=[C:32]([NH:34]C=O)[CH:31]=[CH:30][N:29]=1)[C:6]([NH:8][CH:9]1[C:26](=[O:27])[N:11]2[C:12]([C:23]([OH:25])=[O:24])=[C:13]([CH2:16][S:17][C:18]3[S:19][CH:20]=[N:21][N:22]=3)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].Cl>>[NH2:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([C:5](=[N:4][O:3][CH2:1][CH3:2])[C:6]([NH:8][CH:9]2[C:26](=[O:27])[N:11]3[C:12]([C:23]([OH:25])=[O:24])=[C:13]([CH2:16][S:17][C:18]4[S:19][CH:20]=[N:21][N:22]=4)[CH2:14][S:15][C@H:10]23)=[O:7])[N:33]=1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nccc(NC=O)n1
Agent: Cl
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nccc(N)n1
Yield: 46.4 %

Procedure:
A solution of 7-[2-ethoxyimino-2-(4-formamidopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (3.97 g) and concentrated hydrochloric acid (0.73 ml) in methenol (80 ml) was stirred for 1.5 hours at ambient temperature. The solvent was evaporated to dryness and the residue was dissolved in water (100 ml). The aqueous solution was washed with ethyl acetate and adjusted to pH 3 with an aqueous solution of sodium bicarbonate and then subjected to column chromatography over nonionic adsorption resin, "Diaion HP 20". The column was washed with water and eluted with 50% aqueous methanol. The eluent containing a desired compound was evaporated to remove the methanol and then lyophilized to give 7-[2-(4-aminopyrimidin-2-yl)-2-ethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.75 g), mp 155°-160° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.O.[NH2:20][NH2:21]>C(O)COCCO>[NH2:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4](=[N:20][NH2:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1N

Procedure:
In the manner given in Preparation 1, 2-amino-5-nitrobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-5-nitrobenzophenone hydrazone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[S:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:23]2[CH2:24][CH2:25][S:21][CH2:22]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: C1CSCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)nc(N2CCSC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
The obtained 2,4-dichloro-6-morpholino-1,3,5-triazine (237 mg, 1.00 mmol) was dissolved in DMF (3 ml), added with anhydrous potassium carbonate (138 mg, 1.00 mmol) and cooled to -5° C.-0° C. This mixture was gradually added dropwise with thiazolidine (103 mg, 1.15 mmol) dissolved in DMF (1 ml). The reaction mixture was stirred at room temperature overnight and was evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography, using n-hexane and ethyl acetate (7:3) as eluant, to obtain 282 mg (yield: 97.2%) of 2-chloro-4-morpholino-6-(3-thiazolidinyl)-1,3,5-triazine having melting point of 137° C.-139.5° C. (3) The obtained 2-chloro-4-morpholino-6-(3-thiazolidinyl)-1,3,5-triazine (85.2 mg, 0.296 mmol) was dissolved in DMF (2 ml), added with sodium hydroxide (23.7 mg, 0.593 mmol) and imidazole (43.4 mg, 0.637 mmol) and stirred at 110° C.-120° C. for 30 minutes. The reaction mixture was evaporated under reduced pressure. The obtained residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using dichloromethane and methanol (98: 2) as eluant, to obtain 83.7 mg (yield: 88.6%) of the titled compound.
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1.N([O-])=O.[Na+].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1
Reactant: COc1cnc(N2CCOCC2)c(N)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cnc(N2CCOCC2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrite as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-morpholino-6-methopxypyrazine with phosphorus oxychloride by Preparation 13, Step B method, gives 2-chloro-3-morpholino-6-methoxypyrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:22][CH2:21][CH2:20][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:33][CH2:32]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2-c2ccccc2)cc1

Procedure:
65 mg (53%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(2-fluorophenyl)piperazine (44 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).
Reaction SMILES: [Cl:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9]C)=[O:8])[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Cl)c1

Procedure:
Methyl 5-chloropyrrole-3-carboxylate (900 g.) was refluxed for 9 hours with 20 ml. of methanol and 10 ml. of 1 N sodium hydroxide. Methanol was removed by evaporation, the aqueous residue was diluted with approximately 10 ml. of water and extracted twice with ether. The aqueous phase was acidified with conc. hydrochloric acid and product extracted into ethyl acetate. The three ethyl acetate extracts were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaported to product (715 mg., m.p. 175°-178° C.). Recrystallization from methylene chloride/hexane afforded purified 5-chloropyrrole-3-carboxylic acid (300 mg., m.p. 178°-180° C.).
Reaction SMILES: [CH:1]([C:3]1[C:19]([O:20]C)=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[O:2].[I-].[Mg+2].[I-].C(C1C(O)=CC=CC=1OCCCC(C)C(OCC)=O)=O.Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)C(C)CCCOc1cccc(OC)c1C=O
Agent: CCOC(=O)C(C)CCCOc1cccc(O)c1C=O
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CCCOc1cccc(O)c1C=O)C(=O)O

Procedure:
To a stirred solution of (±)-ethyl 5-(2-formyl-3-methoxyphenoxy)-2-methylpentanoate (5.3 g, 0.018 M) in dry tetrahydrofuran (50 ml) was added dropwise a solution of magnesium iodide (7.44 g, 0.027 M) in dry ether (100 ml). The mixture was then stirred under reflux (51/2 hr). The cooled mixture, containing (±)-ethyl 5-(2-formyl-3-hydroxyphenoxy)-2-methylpentanoate, was poured into 10% hydrochloric acid (50 ml), the organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solutions were washed with water and extracted with 2 N sodium hydroxide solution. The combined extracts were acidified with concentrated hydrochloric acid with cooling and the solid produced filtered off and washed with water to give (±)-5-(2-formyl-3-hydroxyphenoxy)-2-methylpentanoic acid, m.p. 70°-70.5° C. from benzene/petrol.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N:10]([O-])=O.[Na+].[ClH:14]>O>[ClH:14].[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)ccc1NN
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
To a solution of 4-bromo-2-methylaniline (2.50 g, 13.44 mmol) in concentrated HCl (5.4 mL) at 0° C. was added a cold solution of sodium nitrite (1.02 g, 14.78 mmol) in water (5.1 mL). Stirring was continued at 0° C. for 45 min then the mixture was filtered. To the filtrate at 0° C. was added a solution of tin(II) chloride in concentrated HCl (9.5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was made basic at 0° C. with 40% NaOH solution and extracted three times with diethyl ether. The combined organic extracts was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was treated with 1.25 M HCl in methanol (30 mL), stirred for 10 min at 0° C. then concentrated in vacuo to give a pale yellow solid. The solid was triturated with diethyl ether and dried in vacuo to give (4-bromo-2-methylphenyl)hydrazine hydrochloride (2.26 g, 71%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz): δ 10.27 (br s, 3H), 7.97 (br s, 1H), 7.35 (m, 2H), 6.89 (d, J=8.2 Hz, 1H), 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][C:10]([C:21]#[N:22])=[C:9]2Cl)[CH2:2][CH2:3][CH3:4].[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:26]=1[NH2:27].Cl.N1C=CC=CC=1>C(OCCO)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][C:10]([C:21]#[N:22])=[C:9]2[NH:27][C:26]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:25]=1[Cl:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(Cl)c(C#N)cnc2cc1OCCOC
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: CCCCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1OCCOC
Temperature: 120 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
A mixture of 6-butoxy-4-chloro-7-(2-methoxyethoxy)-3-quinolinecarbonitrile (184 mg, 0.55 mmol), 2,4-dichloro-5-methoxyaniline (127 mg, 0.66 mmol) and pyridine hydrochloride (76 mg, 0.66 mmol) in 5 mL of 2-ethoxyethanol is heated at 120° C. for 7 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. Diethyl ether is added to the residue and the solids are collected and suspended in saturated aqueous sodium bicarbonate. After stirring for 1 hour the solids are collected by filtration and washed with water. Purification by preparatory thin layer chromatography, eluting with 7% methanol in dichloromethane provides 93 mg of 6-butoxy-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 166-167° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 44 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (300 mg, 0.61 mmol), a different batch of 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (180 mg, 0.55 mmol), and p-toluenesulfonic acid (278 mg, 1.46 mmol) were weighed into a 40 mL vial. 25 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 30 mL of DCM. 3 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (190 mg, 0.242 mmol, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.20 Hz, 1H), 7.76 (dd, J=8.61, 2.20 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.35-7.46 (m, 3H), 7.26 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.92 (t, J=6.68 Hz, 1H), 6.66 (d, J=2.38 Hz, 1H), 6.53 (d, J=5.13 Hz, 1H), 6.47 (dd, J=8.61, 2.38 Hz, 1H), 4.05 (q, J=7.08 Hz, 2H), 3.97 (s, 3H), 3.31-3.34 (m, 2H), 3.08-3.15 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.78 Hz, 2H), 2.51-2.60 (m, 4H), 1.22 (t, J=6.96 Hz, 3H). MS (ESI): 783 [M+H]+.