Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:28]=4)[NH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CCC(=O)Nc1ccc2c(c1)c(-c1cncc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)cn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)Nc1ccc2[nH]cc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-propionamido-1H-indole-1-carboxylate (200 mg, 0.35 mmol) in DCM (2 mL) was treated with TFA (2 mL) and stirred at RT for 12 h. The reaction mixture was quenched with water and neutralized with K2CO3. The resulting precipitate was filtered, washed with water and dried to obtain the crude product. The crude product was purified by prep HPLC (column: Zorbax Eclipse XDBC Prep C18 5 μm 21.2*150 mm; flow rate: 15.0 mL/min; mobile phase: A: 0.1% TFA in water. B: ACN+MeOH (1:1); gradient: % B, 10% to 50%) to N-(3-(6-(4-aminopiperidin-1-yl)pyrazin-2-yl)-1H-indol-5-yl)propionamide (234) (50 mg, 39%). MS (ESI, pos. ion) m/z: 413.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:8](=[CH:9][C:10]=1[O:11]C)[C:7](=[O:13])[O:6][C:5]2=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:13])[O:6][C:5]2=[O:14]
Reactant: COc1cc2c(c([N+](=O)[O-])c1O)C(=O)OC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C1OC(=O)c2c1cc(O)c(O)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Hydroxy-6-methoxy-4-nitro-isobenzofuran-1,3-dione (115 mg), aluminum chloride (80 mg) was mixed with ethyl acetate (3 ml). Pyridine (155 μl) in ethyl acetate (2 ml) was added dropwise. The resulting mixture was stirred at room temperature for 0.5 hours, heated to reflux for 3 hours, and then quenched with water (0.5 ml) and conc. HCl (0.5 ml) at 60° C. Ethyl acetate and water was removed in vacuo. The remainder was mixed with brine (2 ml) and extracted two times with ethyl acetate (15 ml). The combined organic layers were dried over anhydrous Na2SO4, filtrated, evaporated and triturated with diethyl ether.
Reaction SMILES: CO[CH:3]1[CH:7]=[CH:6][CH:5](OC)[O:4]1.[CH2:10]([O:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].O>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:10]([O:12][C:13](=[O:20])[CH:14]([C:5]1[O:4][CH:3]=[CH:7][CH:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: COC1C=CC(OC)O1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
340 g (2.5 mmol) of zinc chloride were added in one portion to a solution of 217 g (1.67 mol) of 2,5-dimethoxy-2,5-dihydrofuran, 1500 ml (10 mol) of malonic acid diethyl ester, 167 ml of Water and 330 ml of glacial acetic acid. The temperature rose to 35°. The dark solution was stirred at room temperature overnight, poured onto ice, extracted three times with diethyl ether, washed in succession with saturated sodium bicarbonate and sodium chloride solutions, and finally dried. After evaporating the excess malonic acid diethyl ester (70°/13 Pa), the remaining oil was distilled over a Vigreux column, to obtain 109.2 g (29%) of 2-furylmalonic acid diethyl ester (purity 94%), boiling point 100°-110°/39 Pa.
Reaction SMILES: Cl.[NH:2]([C:4]([C:6]1([NH:9][C:10]([C:12]2([NH:15][C:16]([C:18]3[N:22]4[C@@:23]([CH2:36][C:37]5[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=5)([CH3:35])[C:24](=[O:34])[N:25]([C:26]5[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=5)[C:21]4=[N:20][CH:19]=3)=[O:17])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7]1)=O)[NH2:3].Cl.C(O[C:49]([CH:51]1[CH2:53][CH2:52]1)=[NH:50])C.CCN(CC)CC>CN(C=O)C>[CH:51]1([C:49]2[NH:50][C:4]([C:6]3([NH:9][C:10]([C:12]4([NH:15][C:16]([C:18]5[N:22]6[C@@:23]([CH2:36][C:37]7[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[CH:41][CH:42]=7)([CH3:35])[C:24](=[O:34])[N:25]([C:26]7[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=7)[C:21]6=[N:20][CH:19]=5)=[O:17])[CH2:13][CH2:14]4)=[O:11])[CH2:7][CH2:8]3)=[N:2][N:3]=2)[CH2:53][CH2:52]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(C(=O)NN)CC4)CC3)n21
Reactant: CCOC(=N)C1CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5nnc(C6CC6)[nH]5)CC4)CC3)n21
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 27.3 %

Procedure:
To a solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [1-(1-hydrazinocarbonyl-cyclopropylcarbamoyl)-cyclopropyl]-amide hydrochloride (0.080 g, 0.12 mmol) and cyclopropanecarboximidic acid ethyl ester hydrochloride (0.018 g, 0.12 mmol) in DMF (1 mL) was added Et3N (0.051 mL, 0.37 mmol). The reaction was heated in a microwave at 140° C. for 45 min and then at 180° C. for 1.5 h. The mixture was cooled to room temperature and purified via reverse-phase HPLC to give (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide (0.022 g, 28%) as a white solid, m/z 670.8 [M+1]+.
Reaction SMILES: [C:1]([OH:20])(=O)[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][CH3:18].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>>[C:1]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])(=[O:20])[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][CH3:18]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(a-5) was synthesized by a dehydrating esterification reaction between stearic acid and N,N-dimethyl-1,3-propanediamine. Specifically, a four-neck flask equipped with a stirrer, a temperature gage and a dewatering pipe was charged with 120 g of N,N-dimethyl-1,3-propanediamine, 284 of stearic acid and 0.12 g of sodium borohydride and the mixture was raised to 180° C. The mixture was heated under stirring at this temperature for about 5 hours while distilling generated water and a part of N,N-dimethyl-1,3-propanediamine to be distilled together with water. The reaction mixture was then cooled to 120° C. and unreacted amine was distilled under reduced pressure (10 torr) to obtain 368 g of the target N-stearoylaminopropyl-N,N-dimethylamine (a-5).
Reaction SMILES: [N:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[OH:15]O>C(O)(=O)C>[N:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6](=[O:15])[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: c1ccc2c(c1)Nc1nccnc1S2
Solvent: CC(=O)O
Product: O=S1c2ccccc2Nc2nccnc21
Reaction time: 0.5 h

Procedure:
To 1,4-diaza-10H-phenothiazine (1 g, 5 mmoles) in acetic acid (15 ml) was added 50% hydrogen peroxide (1 ml). The mixture was stirred at 55° for 30 minutes. The mixture was evaporated to a small volume and the title compound crystallized out. The crystals were filtered, washed with acetic acid and air dried to yield 983 mg of the title compound, m.p. 261°-263°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[C:10]([Cl:17])=[CH:9][C:4]=1[C:5]([O:7]C)=O.C1(C)C(C)=CC=CC=1.[CH:26]1([CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CO>[CH:26]1([CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:5](=[O:7])[C:4]3[CH:9]=[C:10]([Cl:17])[C:11]([NH:13][C:14](=[O:16])[CH3:15])=[CH:12][C:3]=3[O:2][CH3:1])[CH2:35][CH2:34]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Reactant: NC1CCN(CC2CCCCC2)CC1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Yield: 64 %

Procedure:
A mixture of methyl 2-methoxy-4-acetamido-5-chlorobenzoate (25.7 g; 0.1 moles), xylene (80 ml), 1-cyclohexylmethyl-4-aminopiperidine (21.6 g; 0.11 moles) and aluminium isopropoxide (5 g) was heated to the boiling point whilst methanol was distilled off as it was formed. When the theoretical quantity of methanol was removed, the xylene was distilled off and the residue was dissolved in 2 N hydrochloric acid (200 ml). The aqueous solution was made alkaline with sodium hydroxide solution, extracted with chloroform and the chloroformic layer evaporated to dryness to give N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (27 g). Its hydrochloride monohydrate was prepared by the procedure described in Example 2, m.p. 219°-221° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=[O:24])C>O1CCCC1.O.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([OH:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=C(COC1CCN(C(C)=O)CC1)c1ccccc1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(OCC(C)(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Acetyl-4-(2-phenylallyloxy)piperidine (4.0 g.) in dry tetrahydrofuran (60 ml.) was added dropwise to a stirred solution of mercuric acetate (6.35 g.) in water (60 ml.) and the solution stirred at room temperature for one hour. Sodium hydroxide solution (40 ml., 3 N) and sodium borohydride (0.75 g.) in sodium hydroxide solution (40 ml., 3 N) were then added dropwise to the stirred solution at 0° C. The grey suspension was stirred at 0° C. for one hour, glacial acetic acid was added to pH 6, then the suspension filtered and the filtrate extracted with chloroform (3×150 ml.). The combined chloroform extracts were dried (Na2SO4) and evaporated in vacuo to give N-acetyl-4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (2.1 g.). This product in methanol (30 ml.) and sodium hydroxide solution (20 ml., 5 N) was heated under reflux for 4 hours. The organic solvent was evaporated and the aqueous solution extracted with chloroform (3×20 ml.), dried (Na2SO4) and the solvent evaporated in vacuo to give 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (1.8 g.) as an oil. A sample was characterized as the oxalate salt which recrystallized from ethyl acetate and had an m.p. of 132°-134° C.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:49][N:50]([CH3:59])[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CN(C)C=O>[CH3:49][N:50]([CH3:59])[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:55][CH2:54]1
Reactant: CN(C)CCN1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccn2)CC1
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To [4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was added a solution of 1-[2-(dimethylamino)ethyl]piperazine (48.6 mg) in N,N-dimethylformamide (1.0 ml) at room temperature, followed by stirring for 5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (34.7 mg, 76%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[N:21]1>>[NH:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[N:21]1
Reactant: O=Cc1cc[nH]n1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cc[nH]n4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-pyrazole-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-pyrazol-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:3]=1[C:4]#[N:5].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25]>>[S:24]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[C:4]#[N:5])(=[O:27])(=[O:26])[NH2:25]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: N#Cc1c(NS(N)(=O)=O)cccc1OCCCCCO
Yield: 4 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(5-(tert-butyldimethylsilyloxy)pentyloxy)benzonitrile (Example 241b) and sulfamoyl chloride in 4% yield. MS 300 (MH+).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:34]C(F)(F)S([O-])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F>ClCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[C:23]([F:34])[CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)c1cnc(-c2[nH]c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)cc2F)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (420 mg) in dichloromethane (5 mL) was added 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate (410 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (35.0 mg). The mixture of the obtained positional isomers was dissolved in hexane-ethanol (850:150, volume ratio, 114 mL), and the solution was subjected to HPLC using TSK GEL SHILICA-60 (20 mm ID×250 mL, manufactured by Tosoh Corporation silica). Using hexane-ethanol (850:150, volume ratio) as a mobile phase, the solution was eluted at flow rate 20 mL/min and at room temperature, and the fraction was separated at retention time 39.0 min, and concentrated. The obtained solid was dissolved in ethyl acetate and the insoluble material was filtered off. The filtration was concentrated to give the title compound (26.8 mg, yield 4%) as a colorless amorphous solid. MS: 505 (MH+).
Reaction SMILES: BrC1C=C2C(=CC=1)C=C([OH:12])C=C2.CC(C[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][C:26]=2[CH:27]=1)=O.BrC1C=C2C(=CC=1)C=C(OC)C=C2>CN(C)C=O>[CH3:29][O:28][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[CH:27]=[C:18]([CH:17]=[O:12])[CH:19]=[CH:20]2
Reactant: COc1ccc2cc(CCC(C)=O)ccc2c1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: COc1ccc2cc(Br)ccc2c1
Solvent: CN(C)C=O
Product: COc1ccc2cc(C=O)ccc2c1

Procedure:
When it is wished to convert the 6-bromo-2-naphthol to nabumetone, the 6-bromo-2-naphthol is first converted to a 6-bromo-2-methoxynaphthalene intermediate as described above, and the intermediate is then converted to nabumetone by any of the techniques already known for that conversion. For example, as described in U.S. Pat. No. 5,225,603 (Aslam et al.), the 6-bromo-2-methoxynaphthalene may be (a) reacted with N,N-dimethylformamide to form 6-methoxy-2-naphthaldehyde, which is then condensed with acetone to prepare a 4-(6-methoxy-2-naphthyl)-3-buten-2-one intermediate that is then catalytically hydrogenated to nabumetone or (b) reacted with methyl vinyl ketone to form the 4-(6-methoxy-2-naphthyl)-3-buten-2-one intermediate that is then catalytically hydrogenated to nabumetone.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].C([O-])([O-])=O.[K+].[K+].[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C:20](=[O:23])[CH:21]=[CH2:22])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CC(=O)Cl
Reactant: C=CCCNc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCCN(C(=O)C=C)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a solution of N-but-3-en-1-yl-4-methoxyaniline (340 mg, 1.92 mmol) in methylene chloride (5 mL) was added K2CO3 (530 mg, 3.80 mmol) and acryloyl chloride (234 μL, 2.88 mmol) at 0° C. After 15 min., the reaction was quenched with NaHCO3 (2 mL, sat. aq.) and the organic layer was isolated, concentrated and subjected to flash chromatography (Hexanes:EtOAc 4:1) to yield N-but-3-en-1-yl-N-(4-methoxyphenyl)acrylamide (395 mg, 89%).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2[F:36])[O:23][N:22]=1>>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])[O:23][N:22]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: Fc1ccc(C(F)(F)F)cc1-c1nc(CCl)no1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cc(C(F)(F)F)ccc3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 3-(chloromethyl)-5-[2-fluoro-5-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (Example 366A): 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 7.85 (m, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.49 (s, 1H), 5.68 (s, 2H), 2.14 (m, 1H), 1.15 (m, 2H), 0.92 (m, 2H); MS (ES) m/z 495 (M+1).
Reaction SMILES: C[SH+](C)=O.[CH3:5][O:6][C:7](=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1.[SH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>ClC(Cl)C>[CH3:5][O:6][C:7](=[O:16])[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[S:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: Sc1ccncc1
Agent: C[SH+](C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)C(Sc1ccncc1)c1cccc(Br)c1

Procedure:
To a solution of dimethylsulfoxonium ylide and 3-bromophenylacetic acid methyl ester (example 530E, 3 g) in dichloroethane (50 mL) are added 4-mercaptopyridine (2 equivalents) and [Ir(COD)Cl]2 (20 mg). The reaction mixture is refluxed overnight then concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel (heptane/ethyl acetate 1/1) to give (3-Bromophenyl)(pyridin-4-ylsulfanyl)acetic acid methyl ester. 1H NMR: 8.50-8.35 (m, 2H), 7.68 (s, 1H), 7.55-7.45 (m, 2H), 7.35-7.20 (m, 1H), 7.20-7.05 (m, 2H), 5.08 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](I)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:28]=[CH:29][C:20]=3[CH3:19])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Reactant: Cc1ccc2ccccc2c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2ccccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 150 °C

Procedure:
In a 2-5 mL Smith Process Vial, 6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (100.0 mg 0.282 mmol), (2-methylnaphthalen-1-yl)boronic acid (176.0 mg, 0.946 mmol, 3.36 equiv), PEPPSI-iPr (19.2 mg, 0.028 mmol, 0.1 equiv) and Cs2CO3 (337.0 mg, 1.126 mmol, 4 equiv) were placed. The mixture was suspended in 1,4-dioxane (1.5 mL) and water (0.5 mL) under N2. The mixture was heated at 150° C. for 75 min using microwave reactor (Biotage Optimizer). After an aqueous work up, the crude product was purified by a silica-gel column chromatography (hexane/EtOAc 20:80) to give 6-(3,5-dimethylisoxazol-4-yl)-4-(2-methylnaphthalen-1-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@H:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]2)[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:33][C@H:29]2[CH2:30][CH2:31][CH2:32][C@H:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: N[C@H]1CCC[C@H](c2cccnc2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N[C@H]3CCC[C@H](c4cccnc4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 84 °C
Reaction time: 9 h
Yield: 24.7 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (800 mg, 2.89 mmol), trans-3-(3-pyridyl)cyclohexylamine (612 mg, 3.47 mmol) and diisopropylethylamine (1.11 mL, 6.36 mmol) in anhydrous DMSO (12 mL) was stirred at 84° C. for 9 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[trans-3-(3-pyridyl)cyclohexylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (309 mg, 24%) as a yellow powder.