Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8](OC(OCC)CBr)[CH3:9].Br>C(O)C>[N:1]1[CH:8]=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:2]=12
Reactant: CCOC(CBr)OCC
Reactant: Nc1ncccn1
Agent: Br
Solvent: CCO
Product: c1cnc2nccn2c1
Yield: 81.4 %

Procedure:
A solution of 2-aminopyrimidine (0.5 g, 5.26 mmol), bromoacetaldehyde diethyl acetal (2.07 g, 10.5 mmol) and 48% aqueous hydrobromic acid (0.5 ml) in ethanol (5 ml) was heated at reflux for 18 h. The reaction was cooled and pre-adsorbed directly onto silica gel. Purification by flash chromatography eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-3%) gave a solid which was triturated with 5% diethyl ether in isohexane to afford imidazo[1,2-α]pyrimidine (0.51 g, 82%) as a tan solid: δH (400 MHz, CDCl3) 6.92 (1H, dd, J 7 and 4), 7.59 (1H, d, J 1), 7.84 (1H, d, J 1), 8.49 (1H, dd, J 7 and 2), 8.58 (1H, dd, J 7 and 2).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].S(Cl)(Cl)=O.C(O)(=O)C(CCC)CCC.[NH2:25][C:26]([NH2:28])=[O:27]>C(#N)C>[CH2:3]([CH:2]([CH2:6][CH2:7][CH3:8])[C:1]([NH:25][C:26]([NH2:28])=[O:27])=[O:9])[CH2:4][CH3:5]
Reactant: NC(N)=O
Reactant: CCCC(CCC)C(=O)Cl
Agent: CCCC(CCC)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCCC(CCC)C(=O)NC(N)=O

Procedure:
Valproyl chloride (0.057 mol), prepared by coupling of thionylchloride and valproic acid according to a published method [24], was dissolved in dry acetonitrile (50 ml), and the resulting solution was slowly added to a boiling solution of urea (0.14 mole) in dry acetonitrile (100 ml) and allowed to reflux for 2 hours. Thereafter the organic solvent was evaporated under reduced pressure and the product was dissolved in ethyl acetate (100 ml) and washed three times with 20 ml of distilled water. The organic fraction was dried over MgSO4, filtered and evaporated under reduced pressure. The products were purified by crystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1C=C[C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.Cl[CH2:30][CH:31]1[O:35][C:34](=[O:36])[CH2:33][CH2:32]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:43][N:44](C=O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:30][CH:31]3[CH2:32][CH2:33][C:34](=[O:36])[O:35]3)[N:9]=2)[C:5]([O:25][CH:26]([F:28])[F:27])=[N:44][CH:43]=1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: O=C1CCC(CCl)O1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1CCC(Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)cnc3OC(F)F)n2)O1
Reaction time: 0.17 h

Procedure:
A 8-mL microwave tube was charged with N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (150 mg, 0.37 mmol), 5-(chloromethyl)oxolan-2-one (74.6 mg, 0.55 mmol), Cs2CO3 (242 mg, 0.74 mmol) in DMF (2 mL). The vessel was evacuated under vacuum and refilled with nitrogen 3 times. The final reaction mixture was irradiated with microwave radiation at 120° C. for 30 min. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with ethyl acetate. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (39.0% up to 53.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 39.0% in 2 min); Detector, UV 254/220 nm. This resulted in 35.8 mg (19%) of N-[3-[5-chloro-2-(difluoromethoxy)pyridin-3-yl]-1-[(5-oxooxolan-2-yl)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=503.1, RT=1.65 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.68-8.66 (m, 2H), 8.38 (s, 1H), 7.63 (dd, 1H, J=2.7, 8.7 Hz), 7.61 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H, J=73.2 Hz), 4.98-4.94 (m, 1H), 4.48 (d, 2H, J=5.1 Hz), 2.46-2.23 (m, 3H), 2.07-1.98 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[C:26](F)[C:25]([F:29])=[CH:24][C:23]=1[C:30](=[O:32])[CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:26]3[CH:27]=[C:22]([F:21])[C:23]([C:30](=[O:32])[CH3:31])=[CH:24][C:25]=3[F:29])[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: CC(=O)c1cc(F)c(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)c1cc(F)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)cc1F
Temperature: 130 °C
Yield: 62 %

Procedure:
Compound 2d (0.22 g, 0.78 mmol), 1-(2,4,5-trifluoro-phenyl)-ethanone (0.22 mL), DIEA (0.22 mL, 1.33 mmol), and DMSO (2 mL) were combined and heated at 130° C. for 20 h. The mixture was cooled to room temperature and purified by flash chromatography (eluent: 10 to 40% EtOAc+0.1% triethylamine in hexane) to afford 211 mg (62% yield) of 4-[1-(4-acetyl-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 50a: LC-MS 438.0 (MH+).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].C(N(CC)CC)C>C1COCC1.O>[C:27](=[O:28])([O:24][CH2:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH:10]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=4)[N:18]=3)[CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[NH2:29]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CO)cc1OCC2
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(COC(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a solution of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methanol (0.10 g, 0.31 mmol) in THF (1 mL) cooled to −78° C. was added trichloroacetyl isocyanate (40 μL, 0.47 mmol). The resultant mixture was allowed to warm to 0° C. before triethylamine (0.17 mL) and water (0.3 mL) were added and the mixture stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 547 (0.095 g, 83%). LCMS: RT=3.34 min, [M+H]+=369. 1H-NMR 400 MHz (DMSO-d6): δ 8.39 (1 H, d, J=8.24 Hz), 7.92-7.92 (2 H, m), 7.11 (1 H, dd, J=8.30, 1.71 Hz), 7.02 (1 H, d, J=1.63 Hz), 5.88-5.87 (1 H, m), 4.99 (2 H, s), 4.55-4.49 (4 H, m), 3.29 (2 H, s), 1.48 (6 H, d, J=6.60 Hz)
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:18]1([CH2:24][C:25](OCC)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 191.4 %

Procedure:
Alternatively, the product can be prepared as follows: sodium (2.12 g) was dissolved in ethanol (145 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (10 g, 45 mmol), followed by ethyl phenylacetate (2.8 g) were added and the reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, stripped and then water, followed by 2 N HCl were added to the residue. The product was collected by filtration and recrystallized from ethyl acetate to afford 10.52 g (73%) of 1-cyclopentyl-3-ethyl-6-(phenylmethyl)-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:15][CH:14]=1.[N+:27]([O-])([OH:29])=[O:28].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:15][CH:14]=1)[N+:27]([O-:29])=[O:28]
Reactant: CN1CCN(c2ccc(C(=O)NCCCCCCCCCO)cn2)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCO[N+](=O)[O-])cn2)CC1
Reaction time: 6 h
Yield: 69 %

Procedure:
1.67 g of N-(9-hydroxy-1-nonyl)-6-(4-methyl-1-piperazinyl)nicotinamide were suspended in 40 ml of acetonitrile and to the suspension was added dropwise under ice-cooling a mixed solution of 0.8 ml of fuming nitric acid and 1.9 ml of acetic anhydride and stirred for 6 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give 1.30 g (69%) of the title compound. m.p. 90°-92° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=[CH2:12])[C:5](=[O:9])[CH:6](Cl)[Cl:7])[CH:2]=[CH2:3].COCCOCCOC.C(Cl)[Cl:23]>>[CH2:1]([N:4]1[CH2:10][CH:11]([CH2:12][Cl:23])[CH:6]([Cl:7])[C:5]1=[O:9])[CH:2]=[CH2:3]
Reactant: ClCCl
Reactant: C=CCN(CC=C)C(=O)C(Cl)Cl
Solvent: COCCOCCOC
Product: C=CCN1CC(CCl)C(Cl)C1=O
Reaction time: 0.5 h

Procedure:
Twenty and eight-tenths grams of N,N-diallyl dichloroacetamide was mixed with 25 g. of diethylene glycol dimethyl ether (diglyme), 1 g. of ferrous chloride (FeCl2.4H2O) added and the mixture was heated at reflux for 30 minutes. The conversion was monitored by the appearance of a new carbonyl peak at ~5.8 microns in the infrared. An additional gram of ferrous chloride (FeCl2.4H2O) was added and heating was continued for an additional 30 minutes. The reaction mixture was diluted with methylene chloride, washed with water and dried and stripped. The dark liquid product was distilled under vacuum to give 8.4 g. of light yellow oil, b.p. 124°-127° C. at 0.25 mm. nD30 1.4850.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.C1COCC1.[CH3:13][O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1>O>[CH3:13][O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH:1]=[O:3])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: O=CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(NC=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Anhydrous acetic acid (268 mL) was added dropwise to formic acid (401 mL) at room temperature, and the reaction solution was agitated for 40 minutes at room temperature. To this reaction solution, a THF (600 mL) solution of 4-amino-3-methoxybenzoic acid methyl ester (134 g) was added dropwise at room temperature, and the reaction solution was agitated for 1 hour. 3.8 L of iced water was added to the reaction solution, and the deposited solids were separated by filtering, and further washed with water (2 L). 111 g of the title compound was obtained by drying the obtained solid at 50° C. overnight. The physical properties was in agreement with the reported values (CAS#700834-18-0).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnn(Cc2ccccc2)c1N
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnn(Cc2ccccc2)c1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
To a solution (50 mL) of 1-benzyl-4-methyl-1H-pyrazol-5-amine (5 g) and tetrahydro-4H-pyran-4-one (3.2 g) in acetic acid was added sodium cyanoborohydride (6.8 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.9 g, 38%).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:71]1([C:77]2[CH:84]=[CH:83][C:80]([CH:81]=O)=[CH:79][CH:78]=2)[CH2:76][CH2:75][O:74][CH2:73][CH2:72]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:81]([C:80]3[CH:79]=[CH:78][C:77]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)=[CH:84][CH:83]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(C(F)(F)F)nc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: FC(F)(F)c1ccc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCOCC6)cc5)nc34)CC2)cn1
Reaction time: 6 h
Yield: 23.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.043 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.13 mmol, 0.13 mL) and 4-morpholin-4-yl-benzaldehyde (1.1 eq, 0.048 mmol, 9 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (6 mg, 23%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.65 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 3.24 (t, J=4.9 Hz, 4H, morpholine N(CH2)2), 3.66 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.73 (s, 2H, CH2), 3.76 (t, J=4.9 Hz, 4H, morpholine O(CH2)2), 7.06 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 7.90 (d, br, J=8.0 Hz, 1H, pyridine H-5), 8.04 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 8.08 (dd, J=8.1, 1.0 Hz, 1H, pyridine H-4), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.77 (s, br, 1H, pyridine H-2), 13.23 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([CH3:19])[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:10]1[C:9]([CH3:19])=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 88 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-toluenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-toluenesulfonyl chloride according to the procedures described in Example 40b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give white crystalline solid, m.p. 93°-96° C., yield 88%.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[H-].[Na+].[CH2:31](Br)[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.C(OCC)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:31][CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: BrCC=Cc1ccccc1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(N(Cc2ccc(OCC=Cc3ccccc3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
The product from Example 33A (0.1 g, 26 mmoles) in DMF (0.65 mL) was treated with sodium hydride (0.011 g, 0.26 mmoles). After 10 minutes, the reaction mixture was treated with cinnamyl bromide (0.10 g, 0.52 mmoles) and shaken overnight. The mixture was diluted with diethyl ether (50 mL), washed with saturated ammonium chloride (50 mL) and water (2×50 mL), brine (50 mL), dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[C:15]1([NH:21]N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.Cl>C(O)C.O>[CH3:14][O:13][C:3]1[C:4]([CH3:12])=[CH:5][C:6]([C:8]2[NH:21][C:15]3[C:20]([C:9]=2[CH3:10])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:2]=1[CH3:1]
Reactant: NNc1ccccc1
Reactant: CCC(=O)c1cc(C)c(OC)c(C)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1c(C)cc(-c2[nH]c3ccccc3c2C)cc1C
Yield: 62.6 %

Procedure:
5.0 g of 2,6-dimethyl-4-propionylanisole and 2.8 g of phenylhydrazine were dissolved in 30 ml of ethanol. A small amount of acetic acid was added under reflux for 30 minutes. After cooling, 10 ml of a 20% ethanol solution of hydrogen chloride was added to the reaction mixture, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled, poured into water, extracted with benzene, washed with water, and dried. The solvent was evaporated, and the residue was crystallized from benzene-hexane to give 4.3 g of 2-(4-methoxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([CH2:8][C:9](=O)[CH3:10])=O)=[CH:4][CH:3]=1.[NH2:14][C:15]([NH2:17])=[O:16].Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.C(O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]2[CH:8]=[C:9]([CH3:10])[N:17]=[C:15]([OH:16])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)c1ccc(F)cc1
Reactant: NC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2ccc(F)cc2)nc(O)n1
Yield: 46.9 %

Procedure:
A mixture of 5 g of 4-fluorobenzoylacetone, 1.66 g of urea, 25 ml of ethanol, and 3.8 ml of concentrated hydrochloric acid was refluxed for 20 hours. This reaction mixture was cooled, poured into iced water, made basic with aqueous solution of potassium carbonate, and neutralized with acetic acid. The crystals that separated out were collected by filtration, washed with isopropyl ether, and dried to provide 2.65 g of pale yellow crystals. m.p. 265-268° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:14]=1)(=[O:5])=[O:4]
Reactant: Nc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1)C(F)(F)F

Procedure:
2.68 ml of anhydrous trifluoromethanesulfonic acid was slowly dropped into a solution of 2.88 g of 2-amino-4,5-bis(4-fluorophenyl)thiazole and 1.8 ml of triethylamine in chloroform under stirring in a nitrogen atmosphere at -20° to -15° C., and the resulting mixture was stirred as such for 1 hour. Then the reaction mixture was successively washed with diluted hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using isopropyl ether as a developer. The crystals thus obtained were recrystallized from petroleum ether/diethyl ether to give 0.47 g of 2-trifluoromethanesulfonylamino-4,5-bis(4-fluorophenyl)thiazole. The melting point of this product was from 193° to 195° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:7]=O)([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCC1.Cl>C(O)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Agent: Cl
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)c1cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc(C(C)C)c1OCCN1CCOCC1
Reaction time: 12 h
Yield: 10.2 %

Procedure:
A mixture of 3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde (0.4 g, 1.26 mmol), 5-chloro-2-oxindole (0.21 g, 1.26 mmol) and pyrrolidine (0.5 ml, 6.3 mmol) in ethanol (2 ml) was held in sealed tube at 100° C. for 12 hours. The mixture was then poured into 1N hydrochloric acid (100 ml) and the solid which remained were filtered and washed with more water (50 ml). The solid was then dissolved in ethyl acetate (200 ml), the solution dried over magnesium sulfate, filtered and then concentrated. The solid which remained was chromatographed (silica, 4/4/1 dichloromethane/hexanes/methanol) to give 60 mg (10%) of 5-chloro-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one as a brownish-orange solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)=O.[N:11]1[NH:12][C:13](=[O:17])[CH:14]=CC=1>>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[CH:1]=[CH:14][C:13](=[O:17])[NH:12][N:11]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: O=c1cccn[nH]1
Product: O=c1ccc(-c2ccc(I)cc2)n[nH]1

Procedure:
7.8 g of 4-iodoacetophenone are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1.[CH3:16]O>>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[C:8]([CH3:15])[CH:7]=1
Reactant: CO
Reactant: Cc1cc(O)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To methanol (10 ml) was added dropwise thionyl chloride (1.92 ml, 26.3 mmol) at 0° C., 4-hydroxy-2-methylbenzoic acid (2.00 g, 13.1 mmol) was added, and the mixture was stirred at 60° C. overnight. After completion of the reaction, the solvent was evaporated, and the residue was dissolved in ethyl acetate (20 ml). The mixture was washed twice with 5% aqueous sodium hydrogen carbonate solution (10 ml), once with 1N hydrochloric acid (10 ml), and once with water (10 ml), and the solvent was evaporated to give methyl 4-hydroxy-2-methylbenzoate (2.24 g, yield 100%).