Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[CH:12]1([C:15]([CH3:17])=[O:16])[CH2:14][CH2:13]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:12]1([C:15](=[O:16])[CH2:17][C:4]([C:6]2[N:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:14][CH2:13]1
Reactant: CC(=O)C1CC1
Reactant: CCOC(=O)c1cccnn1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1cccnn1

Procedure:
A stirred mixture of 4.0 g. of ethyl-3-pyridazinecarboxylate, 4.4 g. of cyclopropylmethyl ketone and 1.6 g. of sodium methoxide in 100 ml. of benzene is heated under reflux for 5 hours. The mixture is diluted with 300 ml. of water and the benzene phase is separated. The aqueous mixture is made weakly acidic with dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to yield straw-colored crystals which are recrystallized from acetonitrile to give cream-colored crystals, melting point 85°-87°C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:27][C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:29])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: O=C(CBr)c1ccccc1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCC(=O)c4ccccc4)cc3)cc12

Procedure:
2-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)-1-phenylethanone was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 139, but using 2-bromo-1-phenylethanone. 1H NMR (Acetone-d6): δ 8.76 (s, 1H), 8.71 (s, 1H), 8.27 (d, 1H), 8.06 (d, 2H), 7.67 (t, 1H), 7.57 (t, 2H), 7.43 (s, 1H), 7.17 (d, 3H), 6.90 (d, 2H), 5.45 (s, 2H), 3.21 (t, 2H), 3.06 (t, 2H), 2.45 (s, 3H). LRMS [M+H]=448.2
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32]Br)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[CH2:34]([O:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][O:42][CH2:43][CH3:44])[CH3:35].ClCCl>O>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32][N:39]([CH2:40][CH2:41][O:42][CH2:43][CH3:44])[CH2:38][CH2:37][O:36][CH2:34][CH3:35])[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOCCNCCOCC
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C(CBr)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Solvent: ClCCl
Solvent: O
Product: CCOCCN(CCOCC)CC1=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1

Procedure:
A solution of 10 parts of 3β-acetoxy-6-(bromomethyl)cholest-5-ene and 20 parts of bis(ethoxyethyl)amine in 13 parts of dichloromethane is allowed to stand at room temperatures for 24 hours, whereupon 5 volumes of water is introduced and the oil which separates is extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation to give 3β-acetoxy-6-[di(2-ethoxyethyl)aminomethyl]cholest-5-ene as the residue. The product, an oil, has the formula ##SPC9##
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=2)=[CH:6][NH:5][N:4]=1.Br[C:17]1[CH:18]=[C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH:20]=[CH:21][C:22]=1C.[C:37](=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH3:21][C:22]1[CH:17]=[CH:18][C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[CH:20][C:1]=1[NH:2][C:3]1[C:7]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=2)=[CH:6][N:5]([CH3:37])[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: CNc1n[nH]cc1-c1cc(SC)ncn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CSc1cc(-c2cn(C)nc2Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)ncn1
Temperature: 25 °C

Procedure:
Methyl-4-(6-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazol-3-ylamine (61 mg, 0.27 mmol) is mixed with N-(3-Bromo-4-methyl-phenyl)-3-trifluoromethyl-benzamide (161 mg, 0.45 mmol), palladium acetate (20 mg, 0.089 mmol), Xantophos (78 mg, 0.135 mmol) and cesium carbonate (280 mg, 0.86 mmol). 2 mL anhydrous 1,4-dioxane is added under nitrogen environment and the mixture is subjected to microwave irradiation to 150° C. for 45 minutes. The reaction mixture is then cooled to room temperature, treated with 100 mL THF, passed through a celite column and concentrated. The crude product is purified by ISCO chromatography eluting with ethyl acetate in hexanes from 10% to 100% to afford N-{4-Methyl-3-[1-methyl-4-(6-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazol-3-ylamino]-phenyl}-3-trifluoromethyl-benzamide.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[F:13][CH2:14][CH2:15][O:16][NH2:17]>CS(C)=O>[F:13][CH2:14][CH2:15][O:16][N:17]=[C:4]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: NOCCF
Reactant: O=C1Nc2ncccc2C1=O
Agent: Cl
Solvent: CS(C)=O
Product: O=C1Nc2ncccc2C1=NOCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of compound 134a (300 mg, 1.03 mmol) in DMSO (25 mL) was heated at 95° C. at 15 torr for 6.5 hours, The solution containing the corresponding 7-aza isatin was cooled to room temperature, followed by the addition O-(2-Fluoro-ethyl)-hydroxylamine hydrochloride (131 mg, 1.13 mmol). After stirring for 1 hour at room temperature the mixture was quenched with water and extracted with ethyl acetate (6×25 mL). The combined organic phases were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (gradient, 2% MeOH in methylene chloride to 3%) to give 1H-Pyrrolo[2,3-b]pyridine-2,3-dione 3-[O-(2-fluoro-ethyl)-oxime] (200 mg, 93%) as an orange solid that was further purified by trituration from diethyl ether-methylene chloride (1:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](I)[CH3:24]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:23][CH3:24])[CH:12]=1)[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCI
Product: CCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21

Procedure:
The procedure of Referential Example 1(a) was repeated, except that N-tert-butoxycarbonyl-D-tryptophan (462 mg) and ethyl iodide (184 μL) were used, whereby the title compound (456 mg) was yielded.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH2:23][CH2:24]Br)=[C:18]3[N:26](C(OC(C)(C)C)=O)[C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:41])[CH:13]=2)(OC(C)(C)C)=O.[OH:42][C:43]1[CH2:47][CH2:46][NH:45][CH:44]=1>>[F:41][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:20]1[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:45]3[CH2:46][CH2:47][CH:43]([OH:42])[CH2:44]3)=[C:18]3[NH:26][C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]2=1
Reactant: OC1=CNCC1
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCBr)c21
Product: OC1CCN(CCCOc2c3[nH]c4ccc(F)cc4c3cc3c2[nH]c2ccc(F)cc23)C1
Reaction time: 8 h
Yield: 90 %

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the staring material is 5,7-diBOC-2,10-difluoro-6-(3-bromopropoxy)indolo[2,3-b]carbazole and the reagent is 3-hydroxypyrroline. The reaction can be completed at room temperature overnight. 1H-NMR (400 MHz, CDCl3) δ ppm 9.57 (br s, 2H), 8.27 (s, 1H), 7.71 (dd, J=9.2, 2.4 Hz, 2H), 7.33 (dd, J=8.8, 4.0 Hz, 2H), 7.03 (td, J=8.8, 2.4 Hz, 2H), 4.67-4.59 (m, 1H), 4.40-4.26 (m, 2H), 3.80 (t, J=5.6 Hz, 1H), 3.15-3.00 (m, 2H), 2.96-2.80 (m, 3H), 2.73-2.61 (m, 1H), 2.38-2.26 (m, 1H), 2.12-1.93 (m, 2H), 1.79-1.70 (m, 1H); MS (ESI) m/z 434.2 (M−H)−; MS (ESI) m/z 436.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.Cl.[CH2:12]=O.[CH3:14][S:15]([NH2:18])(=[O:17])=[O:16]>O1CCOCC1.[Cl-].[Zn+2].[Cl-].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[S:6][C:7]([CH2:12][NH:18][S:15]([CH3:14])(=[O:17])=[O:16])=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1cccs1
Reactant: C=O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(CNS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of thiophen-2-yl-acetic acid methyl ester (2 mL, 12.8 mmol) in 1,4-dioxane (10 mL) was added concentrated HCl (0.4 mL, 4.8 mmol) dropwise over 10 minutes. Zinc chloride (78 mg, 0.57 mmol) was added and the reaction was lowered into a pre-heated water bath at 45° C. and was stirred for 15 minutes. HCl (g) was bubbled into the solution for 2-3 minutes. The temperature of the reaction rose to about 60° C. Upon cooling, 37% aqueous formaldehyde (1.24 mL, 16 mmol) was added dropwise and the temperature rose to 70° C. The reaction was cooled to room temperature and methanesulfonamide (1.25 g, 12.8 mmol) was added in portions. The reaction was stirred for 3 h and was poured into EtOAc (60 mL). The organic solution was washed with water and the aqueous solution was washed with EtOAc (60 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (CHCl3) provided the title compound (69%) as a gold oil. 1H NMR (400 MHz, CDCl3) δ 6.85 (d, 1H), 6.70 (d, 1H), 5.20 (m, 1H), 4.40 (s, 2H), 3.80 (s, 2H), 3.70 (s, 3H), 2.80 (s, 3H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[C:11]2[C:6]=1[N:7]=[C:8](Cl)[C:9](Cl)=[N:10]2.[O:19]1[CH2:23]CCC1>C(OCC)(=O)C>[Cl:15][C:14]1[C:5]([CH3:4])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:16])[N:10]=[C:9]([O:2][CH3:1])[C:8]([O:19][CH3:23])=[N:7]2
Reactant: C[O-]
Reactant: Cc1c(Cl)c(Cl)cc2nc(Cl)c(Cl)nc12
Reactant: C1CCOC1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1nc2cc(Cl)c(Cl)c(C)c2nc1OC
Yield: 100 %

Procedure:
A solution of sodium methoxide (38 ml, 25% solution in methanol, 175 mmol) was added over 10 minutes to a solution of 5-methyl-2,3,6,7-tetrachloroquinoxaline (from step (e), 21 g, 74 mmol) in dry tetrahydrofuran (200 ml) at 20° C. There was a mildly exothermic reaction followed by formation of a precipitate. After 1 h the mixture was diluted with ethyl acetate (3 L), washed with water (1 L), dried (MgSO4) and concentrated under reduced pressure to give 6,7-dichloro-2,3-dimethoxy-5-methylquinoxaline (20.3 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[OH:18])/[C:8]([O:10]CCS(C)(=O)=O)=[O:9])[N:6]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[O:18][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CS(=O)(=O)CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
In 200 ml of acetone was suspended 10 g (0.0341 mole) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 3. After a serial addition of 9.98 g (0.0512 mole) of t-butyl bromoacetate, 0.6 ml of water and 18.85 g of anhydrous potassium carbonate, the mixture was stirred at 40° C. for 2 hours followed by addition of 200 ml of water. The mixture was stirred at 30°-35° C. for about an hour, whereby the methylsulfonylethyl group was hydrolytically eliminated. Then, the ethyl acetate was added to the hydrolysis reaction mixture. The organic layer was extracted with water and the aqueous layers were combined and adjusted to pH 2 with 2N HCl. The resulting white crystalline precipitate was collected by filtration and dried to give 9.0 g of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetic acid. (Yiled, 87.6%)
Reaction SMILES: Cl.[N:2]1([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[N:21]([CH2:29][CH2:30][NH:31][CH3:32])[CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:33](N(CC)CC)C.C=O.[C:42]([BH3-])#N.[Na+]>CO>[N:2]1([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[N:21]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[N:2]1([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[C:27]4[CH:26]=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=4[N:21]4[CH2:29][CH2:30][N:31]([CH3:42])[CH2:32][C:20]=34)=[O:18])[CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: [BH3-]C#N
Reactant: CCN(CC)CC
Reactant: CNCCn1cc(C(=O)N2CCC(n3nnc4ccccc43)CC2)c2ccc(Cl)cc21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)CCn1cc(C(=O)N2CCC(n3nnc4ccccc43)CC2)c2ccc(Cl)cc21
Product: CN1CCn2c(c(C(=O)N3CCC(n4nnc5ccccc54)CC3)c3ccc(Cl)cc32)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 60 %
Yield: 22 %

Procedure:
A mixture of 0.20 g (0.41 mmol) (4-benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-methanone hydrochloride, 0.057 ml (0.41 mmol) triethylamine and 0.10 g (3.3 mmol) paraformaldehyde in 4 ml methanol was heated at reflux for 7 h. After cooling to 0° C. 0. were added 052 g (0.82 mmol) sodium cyanoborohydride. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. Quenching with 1 M aqueous sodium hydroxide solution was followed by extraction with two portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash chromatography gave 0.040 g (22%) (4-benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-methanone as a white solid (ES-MS m/e (%): 451 (M+H+, 100)) and 0.11 g (60%) (4-benzotriazol-1-yl-piperidin-1-yl)-(7-chloro-2-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanone as a white solid (ES-MS m/e (%): 449 (M+H+, 100)).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-:20].[Na+]>C(O)C>[C:13]1(=[C:5]2[CH2:6][CH2:7][CH2:8][C:11](=[C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH2:2]3)[C:4]2=[O:20])[C:18]2[C:17](=[CH:10][CH:1]=[CH:2][CH:3]=2)[CH:16]=[CH:15][CH2:14]1
Reactant: O=C1CCCCC1
Reactant: O=Cc1cccc2ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C1C(=C2CC=Cc3ccccc32)CCCC1=C1CC=Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(77) To a solution of the 1-naphthaldehyde (1.56 g, 10.0 mmol) and cyclohexanone (491 mg, 5.0 mmol) in 2.5 ml of ethanol was added 1.0 ml 10% sodium hydroxide at 0° C. After stirring for 12 hr at room temperature, the solution was filtered. The precipitate was recrystallized from ethyl acetate to afford 1.35 g (72.2%) of bright-yellow flakes: mp 211.8-213.1° C. (lit. mp 212° C., Aizenshtat, et al., J. Org. Chem., 1977, 42, 2386-2394). 1H NMR (250 MHz) δ 8.46 (s, 2 H), 8.09 (m, 2 H), 7.89 (t, 4 H), 7.61-7.46 (m 6 H), 2.82 (t, 4 H), 1.71 (p, 2 H); 13C NMR (62.7 MHz) 190.3, 138.5, 135.5, 133.7, 133.3, 132.2, 129.1, 128.7, 127.2, 126.6, 126.4, 125.2, 125.0, 29.0, 23.8 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1F.[NH2:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1
Reactant: Fc1cccc(F)c1F
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(F)cccc4F)cc23)n1

Procedure:
The compound of Example 148 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2,3-trifluorobenzene, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: C[NH:2][S:3](Cl)(=[O:5])=[O:4].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[S:3]([O:15][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:5])(=[O:4])[NH2:2]
Reactant: OCCOc1ccc(Cl)cc1
Reactant: CNS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: NS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.3 %

Procedure:
To a stirred solution of 45.0 g (0.347 mole) of methylsulfamoyl chloride prepared above in 100 ml of methylene chloride was added in a thin stream a solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis, Inc., Windham, N.H. 03087) in 30 ml (0.369 mole) of pyridine and 100 ml of methylene chloride and the reaction mixture was stirred at ambient temperature for 3 days. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a brown viscous residue. The residue was partitioned between water and ethyl ether (400 ml each). The organic layer was washed twice with 300 ml portions of water, dried over magnesium sulfate (MgSO4) and the solvent evaporated under reduced pressure to yield a solid residue. The solid was triturated with 100 ml of isopropyl ether and the solid was recollected by filtration. The solid was recrystallized from isopropyl ether to give 12.9 g (34%) of title compound as a white solid, m.p. 101°-104° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN=C=N[CH2:30][CH2:31][CH2:32][N:33](C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:10]([NH:33][CH:32]2[CH2:30][CH2:31]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2ccccc2)c1N
Reactant: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2)c1N
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid 5 (Example 3, 700 mg, 2.18 mmol, 1.0 eq) in 30 mL of DMF was added EDCI (855 mg 4.35 mmol, 2.0 eq), HOBt (589 mg, 4.35 mmol, 2.0 eq), and diisopropylethylamine (1.59 mL, 8.71 mmol, 4.0 eq) and the solution was stirred for 15 minutes at room temperature when cyclopropylamine (302 μL, 4.35 mmol, 2.0 eq) was added and the reaction stirred for 1 hour. The mixture was diluted with EtOAc (300 mL) and washed with water (2×25 mL) and brine (25 mL), dried (Na2SO4) and concentrated. The product was purified by flash chromatography on silica gel eluted with 8/2 EtOAc/MeOH to provide the product as a brown oil. The product was further purified by trituration with 1/1/1 EtOAc/hexanes/CH2Cl2 and dried under vacuum to provide 3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide 6 (387 mg, 50%) as a white powder: HPLC (4 minute gradient) tR 2.11 min; MS m/z 361 [M+H]+; 1H NMR (CD3OD, 300 MHz) δ 7.92 (d, J=7.6, 1 H), 7.81 (m, 4 H), 7.54 (m, 4 H), 2.85 (m, 1 H), 2.22 (s, 3 H), 0.80 (d, J=5.7, 2 H), 0.63 (s, 2 H) ppm; 13C NMR (CD3OD, 75 MHz) δ 191.2, 170.1, 153.8, 143.3, 142.0, 141.1, 136.9, 134.8, 132.9, 132.7, 130.1, 129.7, 129.2, 128.1, 104.8, 24.1, 17.7, 6.6 ppm.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a dimethylformamide (30 mL) solution of (4-bromophenyl)methanol (3.00 g), imidazole (2.18 g) and tert-butyldimethylsilyl chloride (2.89 g) were added in this order. The reaction solution was stirred at room temperature for one hour. To the reaction solution, water (10 mL) was added and the aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was washed in turn with 1N hydrochloric acid (10 mL) and saturated sodium chloride solution (10 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→9:1) to obtain the title compound (3.77 g) having the following physical properties.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH2:12][N:13](CC)[CH2:14][CH3:15].N(CC)CC>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH2:14][CH3:15])[CH2:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-iodo-benzoyl chloride (75 g) in 500 mL CH2Cl2 was added a mixture of Et3N (50 mL) and Et2NH (100 mL) at 0° C. After the addition, the resulting reaction mixture was warmed up to room temperature in 1 hr and was then washed with saturated ammonium chloride. The organic extract was dried (Na2SO4), filtered and concentrated. Residue was recrystallized from hot hexanes to give 80 g of INTERMEDIATE 5.