Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)C.[OH-].[Na+:29]>O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+:29]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
8.5 g. of behenic acid were dissolved in 150 ml. of ethanol at 60° C. with stirring, and a solution of 1 g. of sodium hydroxide in 100 ml. of water was dropwise added at 60° C. with stirring to form sodium behenate. 200 ml. of hot water of about 70° C. were then added and sodium behenate was completely dissolved at about 70° C. with continuation of stirring. Subsequently, an about 1/100 N aqueous nitric acid solution containing an equimolar amount, to that of the charged behenic acid, of silver nitrate was dropwise added at 70° C. with stirring. The dissolved sodium behenate was converted to insoluble silver behenate. The obtained silver behenate was recovered by filtration and repeatedly washed with hot water of about 80° C. and hot ethanol of about 70° C., followed by drying.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:11][C@@H:10]2[N:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[C:27]([Cl:39])=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:40])[CH2:13][CH2:14][C@@H:9]2[CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][N:7]1[CH2:11][C@@H:10]2[N:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[C:27]([Cl:39])=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:40][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:13][CH2:14][C@@H:9]2[CH2:8]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
Acryloyl chloride (1M in THF, 0.225 mL, 0.22 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-6-methoxybenzene-1,3-diamine (Intermediate 35, 105 mg, 0.21 mmol) and DIPEA (0.041 mL, 0.24 mmol) in CH2Cl2 (3 mL), which was cooled in an ice/water bath. The mixture was stirred for 0.5 h, washed with brine and then concentrated in vacuo. Purification by FCC, eluting with 0-2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (60 mg, 52%) as a pale yellow solid; 1H NMR: 1.77-1.81 (1H, m), 1.95-2.16 (5H, m), 2.24-2.35 (1H, m), 2.38-2.48 (1H, m), 2.86-2.90 (1H, m), 3.18-3.22 (1H, m), 3.37-3.45 (1H, m), 3.76 (3H, s), 4.33-4.37 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.51 (1H, dd), 6.66 (1H, s), 7.10 (1H, dt), 7.33-7.41 (1H, m), 7.65 (1H, s), 8.3-8.4 (2H, m), 8.56 (1H, s), 8.81 (1H, d), 8.94 (1H, s), 9.38 (1H, s); m/z: ES+, MH+ 545.57.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.Cl[CH2:23]CN1CCCCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:23][CH2:15][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: ClCCN1CCCCC1
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Agent: Cl
Product: CCCC(=O)c1ccc(OCCN2CCCCC2)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step A except that the 2-diethylaminoethyl chloride hydrochloride of Example 1 Step A is replaced by an equimolecular quantity of N-(2-chloroethyl)piperidine hydrochloride. The product is obtained as a pale yellow oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][C:7]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=23)=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=23)[N:6]=1
Reactant: O=[N+]([O-])c1cnc(-c2cnn3ccncc23)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(-c2cnn3ccncc23)nc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A suspension of 5-nitro-2-(pyrazolo[1,5-a]pyrazin-3-yl)pyrimidin-4-ol (Preparation 24d, 1.50 g, 5.8 mmol) in phosphoryl trichloride (12 mL) was stirred and heated to 90° C. in a sealed tube. After 2 hours, the mixture was concentrated in vacuo and the residue was azeotroped with toluene. The resultant solid was treated with saturated aqueous sodium hydrogen carbonate solution and, upon scratching, a solid formed which was filtered, washed with water (40 mL) and dried to give the title compound (1.38 g, 86%) as a yellow solid.
Reaction SMILES: [N:1]([C:4]1[C:5]([F:19])=[C:6]([CH:11]2[CH2:15][N:14]([CH2:16]O)[C:13](=[O:18])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[F:10])=[N+:2]=[N-:3].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(Cl)Cl>[N:1]([C:4]1[C:5]([F:19])=[C:6]([CH:11]2[CH2:15][N:14]([CH2:16][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[C:13](=[O:18])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[F:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)ccc(C2CC(=O)N(CO)C2)c1F
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: [N-]=[N+]=Nc1c(F)ccc(C2CC(=O)N(Cn3ccnc3)C2)c1F
Temperature: 28 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
In a 100 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, distilled tetramethyl-chloro-enamine (1.1 ml, 8.5 mmol) is added to a solution of 4-(3-azido-2,4-difluoro-phenyl)-1-hydroxymethyl-pyrrolidin-2-one a15 (1.9 g, 7.08 mmol) in CH2Cl2 (45 ml) at 0° C. After 3.5 h, the mixture is transferred via a canula into a second three necked flask fitted with a magnetic stirrer, under inert atmosphere, containing a solution of imidazole (2.4 g, 35.4 mmol) in CH2Cl2 (45 ml) at room temperature. The temperature raised up to 28° C. and a precipitate appears. After 1 h, the reaction mixture is filtered, evaporated in vacuo, diluted with CH2Cl2 and the organic layer is washed with water, dried over MgSO4, filtered and evaporated in vacuo. The residue is purified by chromatography on silicagel (CH2Cl2/EtOH/NH4OH: 93.5/06/0.5 (v/v)) to afford 4-(3-azido-2,4-difluoro-phenyl)-1-imidazol-1-ylmethyl-pyrrolidin-2-one 5 (1.66 g, 75%). The racemate is resolved by preparative chiral chromatography (Chiralpak AD, benzine/EtOH) and the enantiomers are recrystallized successively in toluene and AcOEt to afford the two enantiomers 6 (first eluted) and 7 (second eluted) as white solids (0.5 g and 0.45 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1

Procedure:
2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 278.36 (C14H22N4O2); MS (ESI): 279 (M+H+).
Reaction SMILES: CO.C[O-].[Na+].[O:6]1CCC[CH2:7]1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1>O>[CH3:7][O:6][C:15]1[N:14]=[N:13][C:12]([Cl:11])=[CH:17][CH:16]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: C1CCOC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 7.4 mL, 3.69 mmol) was slowly added to an anhydrous tetrahydrofuran (12 mL) solution having 3,6-dichloropyridazine (107, 500 mg, 3.36 mmol) dissolved therein, stirred at room temperature for one hour, followed by adding water. Organic compounds were extracted with ethyl acetate. Then, the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 3-methoxy-6-chloropyridazine (108a, 436 mg, 90%) as a white solid.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[O:16][CH3:17])=[O:7])C.OS(O)(=O)=O.N>>[F:15][C:11]1[C:10]([O:16][CH3:17])=[C:9]2[C:14]([CH:4]=[CH:5][C:6]([OH:7])=[N:8]2)=[CH:13][CH:12]=1
Reactant: CCO/C=C/C(=O)Nc1cccc(F)c1OC
Agent: N
Agent: O=S(=O)(O)O
Product: COc1c(F)ccc2ccc(O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of (E)-N-(3-fluoro-2-methoxyphenyl)-3-ethoxypropenamide (3a) (3.16 g, 13.2 mmol) and 25 mL of concentrated H2SO4 was allowed to stir overnight at room temperature. The solution was poured over ice and concentrated NH3 was added until pH 5 to precipitate out the product. The mixture was filtered, washed and dried to give the product (2.55 g, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 11.35 (bs, 1H), 7.86 (d, J=9.6 Hz, 1H), 7.41 (dd, J=8.8, 5.6 Hz, 1H), 7.08 (dd, J=11.2, 8.8 Hz, 1H), 6.45 (d, J=10 Hz, 1H), 3.87 (s, 3H). 19F NMR (376 MHz, DMSO-d6) −128.88 (dd, J=11.5, 5.5 Hz).
Reaction SMILES: [OH-].[Na+].CC(O)C.[OH:7][C:8]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH:39]([CH3:41])[CH3:40])[CH2:35][CH2:34]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:11].Cl>O>[OH:7][C:8]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:34][CH2:35][N:36]([CH:39]([CH3:41])[CH3:40])[CH2:37][CH2:38]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:11]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C(C)C)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)N1CCC(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.27 mL) was added to a 2-propanol (1.5 mL) suspension of the obtained methyl 2-(2-hydroxy-5-(1-isopropylpiperidin-4-yl)benzamido)-4-phenylbenzoate (0.086 g), followed by stirring at 50° C. for 1 hour. A 2.0 mol/L aqueous solution of sodium hydroxide (0.091 mL) was added to the reaction mixture, followed by stirring at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and water was added thereto. After adjusting the pH to 6.0 with 1.0 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.062 g of 2-(2-hydroxy-5-(1-isopropylpiperidin-4-yl)benzamido)-4-phenylbenzoic acid as a light yellow solid.
Reaction SMILES: ClC1C=CC=CC=1.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[OH:19])([CH3:11])([CH3:10])[CH3:9].[CH3:20][O:21]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.O>[C:8]([C:12]1[C:13]([OH:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH:17]=1)[CH:20]=[O:21])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(Cl)Cl
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1cc(O)c(C(C)(C)C)cc1C=O
Temperature: 5 °C

Procedure:
Chlorobenzene (100 mL) and 2-tert-butyl-5-methylphenol (20.6 gm, 125 mmol) were combined and the mixture stirred and cooled to 5° C. Titanium tetrachloride (27.5 mL) and dichloromethyl methyl ether (19 mL, 210 mmol) were added separately and simultaneously over 45 minutes while holding the reaction temperature between 4 and 7° C. The resulting mixture was stirred at 0-5° C. for 3 hours. Water (100 mL) was cautiously added over 18 minutes to the reaction mixture while holding the temperature below 14° C. The mixture was extracted with ethyl acetate (200 mL) and the resulting organic layer was extracted with 12% hydrochloric acid (2×75 mL). The combined aqueous acid layers were diluted with water (50 mL) and back extracted with ethyl acetate (100 mL). This extract was combined with the first ethyl acetate extract and the whole extracted with 15% KOH (3×100 mL). The KOH extracts were combined and the pH adjusted to 3 with 37% hydrochloric acid (62.8 gm). The resulting mixture was extracted with 1:1 ethyl acetate/toluene (2×150 mL). These organic extracts were combined and back extracted with water (2×50 mL) and the organic solution concentrated to approximately 75 mL. 5-tert-Butyl-4-hydroxy-2-methylbenzaldehyde seed crystals were added and the mixture stirred and cooled to 25° C. The mixture was filtered and the product washed with toluene (30 mL) and vacuum dried at 40° C. to give 5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (1): 15 g (78 mmol, 62%): mp: 168-170° C.
Reaction SMILES: Br[C:2]1[N:3]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:10]=[C:9]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:8]=2)=[CH:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:42]1[O:43][CH:44]=[CH:45][N:46]=1)CCC.O>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:28][O:27][CH2:26][C@H:25]([CH3:29])[O:24][C:9]1[CH:8]=[C:7]([C:4]2[N:3]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:2]([C:42]3[O:43][CH:44]=[CH:45][N:46]=3)=[CH:6][CH:5]=2)[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(Br)n2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncco3)n2C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
t-Butyl 2-bromo-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (102.9 mg, 0.177 mmol) synthesized in Example (13c) was dissolved in toluene (5 mL), and 2-(tri-n-butylstannyl)oxazole (133.7 mg, 0.373 mmol) and tetrakis(triphenylphosphine) palladium (20.5 mg, 0.0177 mmol) was added, followed by heating to reflux for 18 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added thereto, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=35%-55%) to afford t-butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-5-(1,3-oxazol-2-yl)-1H-pyrrole-1-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1.[CH:15]([NH:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:15]([N:18]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1)[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)c1ccc(CBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CN(C(C)C)C(C)C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-bromomethyl-2-methoxybenzoate (2.59 g), diisopropylamine (3.92 ml), potassium carbonate (1.38 g) and dimethylformamide (30 ml) was stirred at 80° C. for 2 hours, to which was added water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was dissolved in THF-EtOH (1:1, 30 ml), to which was added 1 N sodium hydroxide solution (15 ml) and the solution was stirred at 80° C. for 20 minutes. To the solution was added water and the solution was washed with ether, made acidic with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was dissolved in THF and insoluble materials were filtered off. The filtrate was concentrated and crystallized with isopropylether to give the title compound (0.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[C:13]([Cl:17])[CH:14]=[N:15][CH:16]=1)[NH2:6])#[N:2].[Br:18]Br>C(O)(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[C:13]([Cl:17])[CH:14]=[N:15][CH:16]=2)=[C:3]([C:1]#[N:2])[C:4]=1[Br:18]
Reactant: N#Cc1cc(N)ccc1Oc1cncc(Cl)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: N#Cc1c(Oc2cncc(Cl)c2)ccc(N)c1Br
Yield: 37 %

Procedure:
3-Cyano-4-(3-chloro-5-pyridyloxy)aniline (see Example 2) was combined with bromine in acetic acid in a manner similar to that described in Example 40 to produce 5-(4-amino-2-cyano-3-bromophenoxy)-3-chloropyridine (37%) after chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:11]([C:14]1[N:15]=[C:16]([C:19](O)=[O:20])[S:17][CH:18]=1)([CH3:13])[CH3:12]>>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:19]([C:16]1[S:17][CH:18]=[C:14]([CH:11]([CH3:13])[CH3:12])[N:15]=1)=[O:20])(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccccc1N
Reactant: CC(C)c1csc(C(=O)O)n1
Product: CC(C)c1csc(C(=O)Nc2ccccc2C(N)=O)n1
Yield: 56.8 %

Procedure:
2-Aminobenzamide (2.04 g, 15 mmol) was reacted with 4-isopropylthiazole-2-carboxylic acid (2.5 g, 14.6 mmol) as described in example 47 which gave the title compound (2.4 g, 56%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:9][NH:8][N:7]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][NH:8][CH:9]=1
Reactant: CCOC(=O)c1n[nH]cc1-c1ccc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1n[nH]cc1-c1ccc(Cl)cc1Cl
Yield: 108.1 %

Procedure:
A solution of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (205 mg; 0.72 mmol) and lithium hydroxide monohydrate (125 mg; 2.9 mmol) in 1:1 THF/water (10 ml) was heated at 60° C. overnight. The THF was removed by evaporation, the aqueous phase acidified with 1M hydrochloric acid then extracted with ethyl acetate (20 ml). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to give 200 mg of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid. (LC/MS: [M+H]+ 256.85).
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.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]2)[CH:42]=[CH:41][C:39]=1[NH2:40].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:40][C:39]3[CH:41]=[CH:42][C:43]([CH2:45][CH2:46][N:47]4[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]4)=[CH:44][C:38]=3[O:37][CH3:36])[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: COc1cc(CCN2CCN(C)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 76.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and neutralized with 1 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 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 (97 mg, 0.138 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ ppm 9.52 (d, J=6.97 Hz, 1H), 9.29 (s, 1H), 8.63 (d, J=2.20 Hz, 1H), 8.30 (d, J=8.80 Hz, 1H), 8.23 (d, J=5.13 Hz, 1H), 7.87 (dd, J=8.43, 2.57 Hz, 1H), 7.66-7.75 (m, 2H), 7.30-7.38 (m, 1H), 7.15-7.23 (m, 1H), 7.13 (d, J=8.80 Hz, 1H), 6.94-7.01 (m, 2H), 6.84-6.90 (m, 1H), 6.78-6.82 (m, 2H), 6.64 (d, J=5.13 Hz, 1H), 4.11 (s, 3H), 3.92 (s, 3H), 2.75-2.86 (m, 2H), 2.43-2.74 (m, 10H), 2.32 (s, 3H). MS (ESI): 705 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)c2cccnc12
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(Cl)c2cccnc2c1O
Temperature: 170 °C
Yield: 23.8 %

Procedure:
5Chloro-8-hydroxyquinoline (5.00 g) and potassium carbonate (11.54 g) are mixed together in a stainless steel bomb and heated to 170° C. under 800 p.s.i. CO2 for 7 days. The reaction is cooled and the resulting solid is dissolved in 800 mL water. The insoluble material is filtered and partitioned between 800 mL water and 400 mL EtOAc in a separatory funnel. The aqueous layer is washed with EtOAc (3×400 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, washed with water and dried. The crude product is triturated with i-PrOH and dried to yield 1.481 g of the title product as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[Cl-].O>[Fe].CO>[S:11]1[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=[C:10]1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3cnccc3s2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cccc(-c2nc3cnccc3s2)c1
Yield: 62.7 %

Procedure:
A mixture of 2-(3-nitrophenyl)thiazolo[4,5-c]pyridine (1.53 g, 5.9 mmol), NH4Cl (2.76 g, 51.6 mmol), iron powder (1.80 g, 32.2 mmol), H2O (30 mL) and methanol (120 mL) was heated to reflux for 5.5 h under N2. The mixture was filtered and the filtrate was diluted with H2O (400 mL). The precipitate was collected by filtration and dried in vacuo to afford 3-(thiazolo[4,5-c]pyridin-2-yl)benzenamine as a brown solid (841 mg, 63%). 1HNMR (400 MHz, DMSO-d6) δ: 9.28 (1H, s); 8.52 (1H, s); 8.21 (1H, s); 7.23-7.38 (3H, d), 6.79 (1H, s), 5.51 (2H, s); MS (ESI) calcd. for C12H9N3S (m/z): 227, found: 228 [M+H]P
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:12][C:10]1([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=[C:2]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=[C:4]2[NH:11]1
Reactant: CC1(C)Cn2c(nc(Cl)cc2=O)N1
Reactant: C1COCCN1
Product: CC1(C)Cn2c(nc(N3CCOCC3)cc2=O)N1
Temperature: 120 °C

Procedure:
A mixture of 1 g of 7-chloro-2,2-dimethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one and 10 ml of morpholine is heated at 120° C. for 1 hour. After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by silica chromatography (eluent: CH2Cl2/MeOH 97/03) so as to give 650 mg of 2,2-dimethyl-7-morpholin-4-yl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, the characteristics of which are the following: