Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.ClC[CH:15]([O:18]C(CCl)CCl)CCl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:15]=[O:18])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1c(O)ccc2cc(Br)ccc12
Reaction time: 1 h

Procedure:
6-Bromo-2-naphthol (25.33 g) was suspended in dichloromethane (300 ml) and titanium tetrachloride (25.0 ml) was slowly added dropwise under cooling in an ice bath. 1,1-Dichloromethylmethyl ether (10.5 ml) was added dropwise to the reaction mixture and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into iced water and dichloromethane was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed successively with IN hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated to give the title compound (28.17 g) as brown crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.C[Si]([C:30]#[CH:31])(C)C.CCN(CC)CC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1)#[CH:31]
Reactant: C#C[Si](C)(C)C
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (1.0 g, 2.8 mmol) in DMF (10 mL) under nitrogen was added trimethylsilylacetylene (2.0 mL, 14 mmol), cupric iodide (0.11 g, 0.58 mmol) and Et3N (1.2 mL, 8.4 mmol). Upon completion of addition, the mixture was degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium (0.20 g, 0.28 mmol) was then added and the resulting mixture was again degassed with nitrogen for 10 min. After this time, the reaction mixture was heated in a sealed tube to 120° C. where it stirred for 16 h. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water. The resulting reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was dissolved in methanol and saturated with ammonia gas. The saturated solution was stirred for 2 h at 0° C. and then concentrated under reduced pressure to yield a residue. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether to afford 2-ethynyl-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (650 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.15 (d, J=4.0 Hz, 1H), 7.86 (dd, J=8.4, 1.2 Hz, 1H), 7.69 (t, J=8.4 Hz, 1H), 7.56 (dt, J=3.6, 1.6 Hz, 1H), 7.49-7.42 (m, 5H), 7.26-7.23 (m, 1H), 7.13-7.08 (m, 2H), 6.94 (bs, 1H), 4.67 (d, J=10.0 Hz, 2H), 3.02 (s, 1H). LCMS Method O: retention time 1.35 min, [M+1]=337.0.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([Cl:20])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1)([OH:9])=[O:8].[OH-].[Na+]>O>[Cl:20][C:13]1[CH:12]=[CH:11][C:10]([C:7]([OH:9])=[O:8])=[CH:15][C:14]=1[S:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(Cl)c(S(=O)O)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
157.55 g of sodium sulfite (1.25 mol) were dissolved in 725 ml of water and heated to 70° C. At this temperature, 255.08 g of 5-carboxy-2-chlorobenzenesulfonyl chloride were added in portions, the pH (electrode) being kept beween 8 and 10 by continuous addition of 320 ml of half-concentrated sodium hydroxide solution (the reaction is slightly exothermic). After the end of the addition, the mixture was subsequently stirred at 70° C. for 2 hours. As soon as the reaction had ended, 5 g of active carbon were added, and after 30 minutes the mixture was filtered hot through a clarifying layer and diluted with 600 ml of water. The solution was allowed to cool to 15-20° C. and was adjusted to pH 0 using 250 ml of conc. hydrochloric acid, the viscous suspension was stirred in an ice bath for a further 30 minutes and the mixture was then stood well closed in a refrigerator over the weekend. The precipitate was filtered off with suction, washed once with 100 ml of 2N hydrochloric acid and then sucked dry in a stream of air. The substance was sucked dry in vacuo at 50° C.
Reaction SMILES: [NH2:1][C:2](=[N:38][N+]([O-])=O)[NH:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Pd].C(O)(=O)C>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][NH:26][C:24](=[O:25])[C@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2](=[NH:1])[NH2:38])[NH:8][C:9](=[O:23])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(CNC(=O)[C@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CNC(=O)[C@H](CCCNC(=N)N)NC(=O)C(c2ccccc2)c2ccccc2)cc1OC
Yield: 58 %

Procedure:
Prepared analogously to Example 1c) from N5 -[amino(nitroimino)methyl)-N-[(3,4-dimethoxyphenyl)-methyl]-N2 -(diphenylacetyl)-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% aqueous acetic acid in a yield of 58% of theory. Colourless amorphous substance Rf 0.62.
Reaction SMILES: [C:1]([CH:6]([NH:15][CH2:16][C:17]([N:19]1[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3]CC)=[O:2].[OH-].[Na+]>>[C:1]([CH:6]([NH:15][CH2:16][C:17]([N:19]1[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(CCc1ccccc1)NCC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(CCc1ccccc1)NCC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2

Procedure:
As described in Example 24, hydrolyze 7-[N-(1-carboethoxy-3-phenylpropyl )glycyl]-1,4-dithia-7-azaspiro[4.4 ]nonane-8(S)-carboxylic acid (prepared as described in Example 31) with sodium hydroxide to give the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].N1C=CC=CC=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.C(OCC)(=O)C>[C:21]([O:12][C:6]1[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:13][CH3:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(C=O)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol), pyridine (0.19 mL, 2.3 mmol) in 1.6 mL of dry dichloromethane was added benzoyl chloride (216 μL, 1.84 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The mixture was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a white solid (432 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][NH2:13]>C(Cl)Cl>[CH3:12][NH:13][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:10])=[O:9]
Reactant: CN
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 2-methylbenzenesulfonyl chloride (37.4 g, 0.196 mol) in methylene chloride (300 ml) at -5° to 0° under nitrogen was added liquid methylamine (27.5 ml, 0.588 mol) at a rate to maintain an internal temperature less than 10°. The reaction mixture was stirred at 0° for 1/2 hour and then allowed to warm to room temperature. After 11/4 hours, filtration and concentration of the filtrate gave an oil which solidified upon cooling. Washing the solid with n-butyl chloride gave N,2-dimethylbenzenesulfonamide as a light yellow powder (28.4 g, 78%), mp. 62°-64°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([O:28][C:26]1[CH:27]=[C:22]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:20])[CH2:4]3)[CH:23]=[N:24][CH:25]=1)[CH3:30]
Reactant: CCOc1cncc(Br)c1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cncc(-c2ccc3c(c2)CC(=O)N3C)c1
Temperature: 100 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (137 mg, 0.5 mmol) was added 3-bromo-5-ethoxy-pyridine (CAS#17117-17-8, 112 mg, 0.55 mmol), tripotassium phosphate (266 mg, 1.25 mmol) and DMF (2.5 mL). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (300 mg, 0.027 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 75 minutes. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 5%) to furnish 5-(5-ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 269.1287 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (t, J=6.9 Hz, 3H), 3.27 (s, 3H), 3.62 (s, 2H), 4.18 (q, J=66 Hz, 2H), 6.93 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.46-7.57 (m, 2H), 8.26 (d, J=2.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].O.[NH2:14][NH2:15]>CCO>[CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:14][NH2:15])=[O:5]
Reactant: CCOC(=O)c1cccnc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ncccc1C(=O)NN
Yield: 99.2 %

Procedure:
To a solution of ethyl 2-methylnicotinate (500 mg, 3.0 mmol) in EtOH (2.3 mL) was added hydrazine monohydrate (0.3 mL, 6.1 mmol). The reaction mixture was heated at reflux for 3 days and then concentrated to afford the desired product as a beige solid (450 mg, 98%). MS (ESI): mass calcd. for C7H9N3O, 151.1; m/z found, 152.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.57 (br s, 1H), 8.49 (dd, J=4.9, 1.8 Hz, 1H), 7.66 (dd, J=7.7, 1.7 Hz, 1H), 7.26 (ddd, J=7.7, 4.9, 0.5 Hz, 1H), 4.85-4.05 (bs, 2H), 2.50 (d, J=4.1 Hz, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](Cl)=[O:11].[CH3:13][CH:14]([CH3:37])[CH:15]([NH:20][C:21]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:22])[C:16]([O:18][CH3:19])=[O:17]>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[S:24][C:23]([C:21]([NH:20][CH:15]([CH:14]([CH3:37])[CH3:13])[C:16]([O:18][CH3:19])=[O:17])=[O:22])=[N:27][CH:26]=2)=[CH:29][CH:30]=1)=[O:11]
Reactant: O=C(Cl)C1Cc2ccccc2C1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)C3Cc4ccccc4C3)cc2)s1)C(C)C
Yield: 18 %

Procedure:
The title compound was synthesized analogous to Example 27, using 2,3-dihydro-1H-indene-2-carbonyl chloride and intermediate 2. Yield: 18%; 1H NMR (DMSO-d6, 300 MHz): δ 10.28 (s, 1H), 8.75 (d, 1H), 8.37 (s, 1H), 7.75 (s, 4H), 7.25 (m, 2H), 7.16 (m, 2H), 4.35 (t, 1H), 3.68 (s, 3H), 3.43 (m, 1H), 3.19 (d, 4H), 2.28 (m, 1H), 0.96 (t, 6H); MS (ESI) m/z 487.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH4+].[OH-].C([N:30](C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[Li+].[Cl-]>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:30])=[O:8])=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:17]=2)[N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid (6.60 g, 18.24 mmol), NH4OH (40.1 mL, 20.07 mmol), and N-ethyl-N-isopropylpropan-2-amine (3.54 g, 27.4 mmol) in DMF (40 mL) was added HATU (13.87 g, 36.5 mmol) at rt. The solution became cloudy but eventually cleared up as the HATU was added. The reaction was completed after 1 h. The reaction mixture was diluted with 10% LiCl and extracted with ethyl acetate three times. The organic extracts was washed with 10% LiCl, water twice, and then concentrated. The light yellow solid was triturated with CH2Cl2 to give 3.8 g. A second trituration gave 1.95 g, and a third trituration gave 462 mg. A total of 6.2 g of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide was obtained.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[CH3:29][NH:30][CH2:31][CH:32]=[CH2:33]>C1COCC1.O>[CH2:31]([N:30]([CH3:29])[C:3](=[O:13])[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])[CH:32]=[CH2:33]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: C=CCNC
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(C)C(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 2.5 g (13.9 mmol) isophthalic acid mono methyl ester in 25 ml THF, cooled at −30° C. is treated with 2.32 ml (16.9 mmol) Et3N followed by 2.0 ml (15.3 mmol) isobutyl chloroformate. After 30 min at −20° C. are added 1.4 ml (13.9 mmol) methyl allyl amine to the white suspension. After 4 h at −20° C. the mixture is poured into 50 ml water and extracted with EtOAc. The organic phase is washed with water, dried with Na2SO4 and evaporated. The residue is purified via chromatography on silica gel (EtOAc/hexane 1:2), yielding the methyl ester of the title compound. This ester is taken up in 5 ml MeOH and 5 ml 1N NaOH. After stirring for 2 h the mixture is acidified with 6 ml 1N HCl and extracted with EtOAc. The organic layer is dried with Na2SO4 and evaporated to yield the title compound as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH:12]=[C:11]([O:13][CH3:14])[O:10][C:9]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH:12]([C:11]([O:13][CH3:14])=[O:10])[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:29][C:9]2=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cn(C(c2ccccc2)c2ccccc2)c(=O)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1C(c2ccccc2)OC(=O)N1C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Under argon atmosphere, in 3 ml of methylene chloride was dissolved 141 mg (0.5 mmol) of 3-diphenylmethyl-5-methoxy-2(3H)oxazolone, and after cooling the solution to −78° C., 53.1 mg (0.5 mmol) of benzaldehyde and 0.05 ml (0.05 mmol) of a methylene chloride solution containing 1.0 M-TiBr4 were added to the solution and the mixture was reacted under stirring for 2 hours. Then, the temperature of the mixture was raised to room temperature, and after stirring for further 16 hours, 15 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction mixture and the mixture was extracted with 20 ml of methylene chloride. The organic layer was washed with 15 ml of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. When the resulting concentrated residue was quantitated by the HPLC method, yield of 3-diphenylmethyl-4-methoxycarbonyl-5-phenyl-2-oxzolidinone was 26%. A formation ratio of cis/trans-isomers of the formed product was 8/92.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Br:12])=[CH:4][N:3]=1.C1(C)C(C)=CC=CC=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.ClCCl>CN(C)C1C=CN=CC=1.O>[CH:21]1([C:24]([NH:1][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Br:12])=[CH:4][N:3]=2)=[O:25])[CH2:23][CH2:22]1
Reactant: Cc1c(Br)cnc(N)c1[N+](=O)[O-]
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1c(Br)cnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture comprising 10 g (43.1 mmol) of 2-amino-5-bromo-4-methyl-3-nitropyridine, 6.3 g of 4-dimethylaminopyridine and xylene (50 ml) was heated at 110° C. in a nitrogen atmosphere. 5 g (47.4 mmol) of cyclopropanecarbonyl chloride was dropwise added thereto, followed by further stirring at 110° C. for 2 hours. The reaction mixture was brought to room temperature, followed by the addition of dichloromethane (200 ml) and water (50 ml). The organic phase was separated and the aqueous phase was further extracted with dichloromethane (50 ml). The organic phases were combined and washed with water (50 ml). The resulting organic phase was dried over anhydrous magnesium sulfate and concentrated to give a crude crystal. It was recrystallized from chloroform/ethyl acetate to give 11.4 g of the title compound (yield 88%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: CC1Cc2ccccc2C=N1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: CC1Cc2ccc([N+](=O)[O-])cc2C=N1
Reaction time: 8 h

Procedure:
3-Methyl-3,4-dihydroisoquinoline (7.0 g, 48.2 mmol) was dissolved in concentrated sulfuric acid (150 ml) and to this was added potassium nitrate (4.9 g, 50.0 mmol). The mixture was allowed to stir overnight, dumped onto ice, and neutralized with the addition of concentrated ammonium hydroxide. The precipated solids were collected by filtration, washed, and air-dried: 7.5 g (82%), m.p. 110-2° C.
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: Oc1ccc2cc(Br)ccc2c1
Reactant: COc1ccc2cc(CCC(C)=O)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: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.[OH-].[Na+].CN(C)[CH:35]=[O:36]>C(O)(=O)C>[CH:35]([C:25]1[C:24]2[C:19](=[CH:20][C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:36]
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)OC)cc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCc1[nH]c2cc(C(=O)OC)ccc2c1C=O
Reaction time: 2 h

Procedure:
A solution of phosphorus oxychloride (20 ml) in dimethylformamide (80 ml) was added to a solution of methyl 2-(n-undecyl)indole-6-carboxylate (58.3 g) in dimethylformamide (250 ml) and the mixture was stirred at a temperature of 55°-90° C. for 2 hours. After cooling, the mixture was poured into rapidly stirred water. Aqueous sodium hydroxide (50% w/v) was added until pH 12, the mixture was stirred for 10 minutes, and then glacial acetic acid was added to pH 5. The mixture was stirred until the gummy product solidified. The solid was then collected and recrystallised from ethanol to give methyl 3-formyl-2-(n-undecyl)indole-6-carboxylate (52.5 g), in the form of a buff powder, m.p. 147°-149° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([C:15]([O:17]C(C)C)=[O:16])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.Cl>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CC(C)OC(=O)c1ccc2c(c1)Cc1cccnc1O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)Cc1cccnc1O2
Yield: 87.1 %

Procedure:
A mixture of 3.4 g of isopropyl 5H-[1]benzopyrano[ 2,3-b]pyridine-7-carboxylate, 7 ml of concentrated hydrochloric acid and 17 ml of acetic acid is heated under reflux on an oil bath for 3 hours. The reaction mixture is concentrated, and a small amount of water is added to the residue. The mixture is adjusted to pH 2-3 by addition of 10% sodium hydroxide. The crystalline precipitate is filtered off and recrystallized from acetic acid to give 2.5 g of 5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid melting at 285°-286°C.