Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[F-].[Na+]>C(O)C>[CH2:14]([O:13][C:8]1[C:9]([O:3][CH2:1][CH3:2])([O:10][CH2:11][CH3:12])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([O:10][CH2:9][CH3:4])([CH3:16])[CH:7]=1)[CH3:15]
Reactant: CCOc1cc(C)cc(OCC)c1OCC
Agent: [F-]
Agent: [Na+]
Solvent: CCO
Product: CCOC1=CC(C)(OCC)C=C(OCC)C1(OCC)OCC

Procedure:
A 224 mg quantity of 3,4,5-triethoxytoluene and 20 mg of sodium fluoride were dissolved in 10 ml of ethanol. Electrolysis was conducted by immersing a carbon electrode as the anode and a stainless steel electrode as the cathode each having an electrolytic area of 3 cm2, stirring the solution at room temperature and passing through the solution constant current of 30 mA at an electric charge of 3 F/mol. Subsequently the same procedure as in Example 1 was repeated producing 287 mg of 1,3,5,6,6-pentaethoxy-3-methyl-1,4-cyclohexadiene in 91.5% of theoretical yield. The compound thus obtained was identified by NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[OH:11][CH:12](O)[C:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH:12]([OH:11])[C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(c1cccc2ccccc12)C(O)O
Reactant: NC(=O)c1ccc(Br)cn1
Solvent: C1COCCO1
Product: O=C(NC(O)C(=O)c1cccc2ccccc12)c1ccc(Br)cn1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A mixture of 5-bromopicolinamide 111 (0.588 g, 2.92 mmol) and 2,2-dihydroxy-1-(naphthalen-1-yl)ethanone 112 (1.20 g, 5.67 mmol) in dioxane (20 mL) were heated at 100° C. for 18 hours. The dioxane was removed under vacuum and the residue was dissolved in chloroform and methanol and concentrated onto silica gel. The material was purified by auto flash system (CH2Cl2 to 1% MeOH: CH2Cl2) to give 5-bromo-N-(1-hydroxy-2-(naphthalen-1-yl)-2-oxoethyl)picolinamide 113 as a tan solid (0.74 g, 66%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br[CH2:11][CH2:12][CH2:13][CH3:14].[NH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[S:32][CH:33]=[CH:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1>CN(C)C=O>[CH2:11]([NH:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[S:32][CH:33]=[CH:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCBr
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2sccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2ccsc2-3)no1
Reaction time: 1 h
Yield: 24.6 %

Procedure:
1.85 ml (10.9 mmol) of N-ethyldiisopropylamine and 0.7 ml (6.3 mmol) of 1-bromobutane were added to a solution of 1.0 g (3.16 mmol) of 7-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-4-one in 30 ml of dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). There were obtained 290 mg (25%) of 7-(5-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-4-one as a colourless foam, Rf=0.37 (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:19]>O>[N-:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Zn+2:19].[N-:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1c[n-]cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution was prepared by adding 9.5 g of imidazole (0.14 mol) to 200 mL of water while stirring with a stir bar. Then 5.8 g of sodium hydroxide were added to the imidazole solution dropwise while stirring. After complete dissolution of the sodium hydroxide, the solution was added dropwise over a 15 minute period to a stirred aqueous solution of 20 g (0.07 mol) of zinc sulfate-hexahydrate in 1000 mL of water. Immediately a white precipitate formed. Stirring continued for 3 hours with heating to 80° C. Then the solution was cooled to room temperature. The product was collected in a Büchner funnel lined with a paper filter, and washed with 50 mL of water, 50 mL of methanol and finally with 50 mL of diethyl ether. The white solid was dried for 16 hours in an oven heated at 50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[O:4][N:3]=1.[OH-].[Li+]>C(#N)C.O>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[O:4][N:3]=1
Reactant: CCOC(=O)c1cc(N)no1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Nc1cc(C(=O)O)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 3-aminoisoxazole-5-carboxylate (prepared according to Lepage, Francis; Hublot, Bernard; Adolphe, Pierre Sylvie. Preparation of alkyl 3-aminoisoxazole-5-carboxylates. Fr. Demande (1998), FR 2750425) (0.790 g, 5.06 mmol) in acetonitrile (28 mL) and water (9.5 mL) was added lithium hydroxide (0.550 g, 23.0 mmol). The resulting mixture was stirred at rt for 3 h. The reaction was quenched with 1 N HCl. Organic solvent was removed in vacuo. The resulting precipitate was filtered and dried to give the product as white solid (585 mg, 90%). LCMS calculated for C4H5N2O3 (M+H)+: m/z=129.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:3]=1.[Br:13]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:13][C:10]1[S:9][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[CH:12][CH:11]=1
Reactant: BrBr
Reactant: Clc1ccnc(-c2cccs2)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccnc(-c2ccc(Br)s2)c1
Reaction time: 6 h

Procedure:
To a solution of 4-chloro-2-thiophen-2-yl-pyridine (195 mg, 0.55 mmol) in CH2Cl2 (2 mL) was added Br2 (1 M in CH2Cl2, 0.6 mL). After 6 h, the resulting mixture was treated with Na2S2O3 (1 M in water, 1 mL), stirred for 10 min, and extracted with CH2Cl2. The organic layer was dried and concentrated, and the resulting crude product was recrystallized from EtOH to yield 2-(5-bromo-thiophen-2-yl)-4-chloro-pyridine as a solid.
Reaction SMILES: O.[C:2]([N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[P:14]([OH:17])([OH:16])[OH:15].CS(O)(=O)=O.C=O>O>[P:14]([CH2:2][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])([OH:17])([OH:16])=[O:15]
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Reactant: OP(O)O
Agent: C=O
Agent: CS(=O)(=O)O
Solvent: O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Yield: 77.6 %

Procedure:
Cycle 1: A pressure reactor was charged with N-acetyliminodiacetic acid monohydrate (19.3 g), water (16.6 g), phosphorous acid (9.8 g) and methanesulfonic acid (15 g). The mixture was heated to 120° C. and 42% formaldehyde (6.9 mL) was added drop wise over a ¾ hour period. After another ¾ hour at 120° C. the mixture was cooled. The mixture was filtered and the solid was washed with water to give 17.6 g of N-(phosphonomethyl)iminodiacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:45][C@@H:46]1[CH2:51][CH2:50][C@H:49]([OH:52])[CH2:48][CH2:47]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:17]([NH:45][C@H:46]2[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48][CH2:47]2)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](O)CC1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85 mg, 0.22 mmol), followed by cis-4-aminocyclohexanol hydrochloride (26 mg, 0.17 mmol). Triethylamine (52 mg, 0.51 mmol) was added before heating in the microwave at 150° C. for 10 minutes. After 10 minutes, the solvent was removed in vacuo, and the residue was partitioned between water and dichloromethane. The aqueous layer was separated and extracted with dichloromethane (3×10 mL), the combined organic extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford the title compound: (26 mg, 0.067 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[C:18](O)([CH3:21])([CH3:20])[CH3:19].[N+](C)([O-])=O.[F:27][B-:28]([F:31])([F:30])[F:29].[H+]>C(OCC)C>[F:27][B-:28]([F:31])([F:30])[F:29].[C:18]([N+:9]1[O:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]2[CH:16]=[C:2]([Cl:1])[C:3]([CH3:17])=[CH:4][C:5]=12)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)O
Reactant: Cc1cc2noc(-c3ccccc3)c2cc1Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: Cc1cc2c(cc1Cl)c(-c1ccccc1)o[n+]2C(C)(C)C
Temperature: 25 °C
Reaction time: 85 h

Procedure:
To a suspension of 59 g. of 5-chloro-6-methyl-3-phenyl-2,1-benzisoxazole, 26.6 ml. of tert.-butanol and 740 ml. of nitromethane, is added dropwise 45.7 g. of a 50% aqueous solution of tetrafluoroboric acid. The resulting suspension is stirred at room temperature for 85 hours. The reaction mixture is diluted with approximately 10 liters of diethyl ether and the crystalline precipitate formed is isolated by filtration to yield 1-tert.-butyl-5-chloro-6-methyl-3-phenyl-2,1-benzisoxazolium tetrafluoroborate, m.p. 164°-166°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[CH:5][CH:4]=1.C[N:23](C=O)C.S(Cl)(Cl)=O.N>C(Cl)Cl.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([C:13]([NH2:23])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Cn2nc(C(F)(F)F)cc2C(=O)O)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: COc1ccc(Cn2nc(C(F)(F)F)cc2C(N)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (50 g, 0.16 mol) in DCM (750 mL), a catalytic amount of DMF was added and the mixture was cooled to 0° C. Thionyl chloride (61 mL, 0.83 mol) was added drop wise for 30 min at 0° C. The overall reaction mixture was heated to reflux and maintained for 2 h. Progress of the reaction was monitored by TLC (10% ethyl acetate/hexane, Rf˜0.4). On disappearance of the starting material, DCM was distilled off completely. Above prepared acid chloride was dissolved in DCM (500 mL) and added drop wise to aqueous ammonia solution (700 mL) at 0° C. The overall reaction mixture was allowed to stir for 1 h and the progress of the reaction was monitored by TLC (10% ethyl acetate/hexane, Rf˜0.7). On completion of the reaction, ice cold water (200 mL) was added and the product was extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide as an off white solid (37 g, crude). Crude product obtained was directly used for the next step.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].C([Sn](CCCC)(CCCC)[C:23]1[N:24]=[CH:25][S:26][CH:27]=1)CCC>O1CCOCC1.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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[N:24]=[CH:25][S:26][CH:27]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cscn3)c(=O)n12
Temperature: 120 °C
Yield: 80.5 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.32 mmol) and 4-(tributylstannyl)-1,3-thiazole (143 mg, 0.382 mmol) in 1,4-dioxane (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (18.4 mg, 0.0159 mmol). The reaction mixture was heated at 120° C. overnight. After cooling to room temperature, the mixture concentrated under reduced pressure. The crude mixture was purified on silica gel, eluting with 0 to 60% EtOAc in hexane, to give the desired product (82 mg, 81%). LCMS calculated for C12H11N6OS2 (M+H)+: m/z=319.0. Found: 319.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])(C1C=CC(C)=CC=1)(=O)=O>CC(CC)=O>[OH:37][CH:35]([CH3:36])[CH2:34][CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Reactant: O=C1OC(CO)CN1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(O)CCOc1ccc(N2CC(CO)OC2=O)cc1
Yield: 52 %

Procedure:
To a solution of 7.8 g of 3-[(4-hydroxy)phenyl]-5-hydroxymethyl-2-oxazolidinone (MD 760172) in 75 ml of methylethylketone, are added 10.2 g (0.074 mol) of K2CO3, 0.1 g of KI and 10.84 g (0.044 mol) of 3-hydroxy-1-butanol tosylate, the mixture is heated under reflux for 12 hours. After filtration, the reaction medium is concentrated and the product is obtained after chromatography (silica, eluent: CH2Cl2 : 92; CH3OH: 8) with a 52% yield,
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.CS(C)=O>C(#N)C>[CH3:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:36][CH2:37][C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])=[CH:26][CH:25]=1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Reactant: NCc1cccnc1
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}ethanone (1.72 mmol), and 3-aminomethylpyridine (3.44 mmol) in dimethylsulfoxide (8.6 mmol) and acetonitrile (15 mL) was stirred at 80° C. for 18 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. The material was purified by HPLC (Normal phase, Luna CN bonded packing) and crystallized from ethyl acetate/hexane. (0.68 g; 77%), m.p. 176-177° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[O:23][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 80.6 %

Procedure:
2,4-Dibenzyloxyphenol (3.1 g) is added to a stirred suspension of sodium hydride (0.44 g, 60% dispersion in mineral oil) and the mixture is heated at reflux for 30 minutes. Refluxing is allowed to abate when ethyl bromoacetate (1.8 g) is added and the mixture heated at reflux for 1 hour. The reaction mixture is evaporated and the residue partitioned between ethyl acetate and water. The organic phase is washed with water, dried over magnesium sulphate and evaporated to give a light brown oil which is purified by column chromatography on silica eluting with dichloromethane. Fractions homogeneous in the required product are combined and evaporated. The residue is triturated with pentane to give ethyl (2,4-dibenzyloxyphenoxy)acetate (3.2 g) as a white powder, m.p. 62-64° C. [Elemental analysis:- C,73.3; H,6.13%. Calculated:- C,73.5; H,6.13%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([O:37][CH3:38])[C:27]=1[C:28](Cl)=[O:29]>C1COCC1>[F:25][C:26]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([O:37][CH3:38])[C:27]=1[C:28](=[O:29])[CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1ccc(OC)c(C(=O)Cl)c1F
Reactant: CCOC(=O)Cc1cccc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1c(OC)ccc(OC)c1F)c1cccc(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a mixture of 2-fluoro-3,6-dimethoxybenzoic acid (4.8 g, 24 mmol) in anhydrous dichloromethane (75 mL) at 0° C., SOCl2 (14.2 g, 120 mmol) was slowly added followed by DMF (0.1 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated in vacuo to give 2-fluoro-3,6-dimethoxybenzoyl chloride (5.2 g). To a solution of ethyl 2-(3-methoxyphenyl)acetate (4.7 g, 24 mmol) in anhydrous THF (40 mL) at −78° C., LiHMDS (1.0 M in THF, 36 mL) was added dropwise. The resulting solution was stirred at −78° C. for 30 min and a solution of 2-fluoro-3,6-dimethoxybenzoyl chloride (5.2 g, 24 mmol) in anhydrous THF (60 ml) was added dropwise. The reaction mixture was stirred for additional 2 h at −78° C. and quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (7.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=O)[CH3:9])=[C:4]([CH2:13][CH3:14])[CH:3]=1.[OH-].[Na+]>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[O:6][CH:7]=[C:8]([CH3:9])[C:11]=2[CH:12]=1
Reactant: CCc1cc(Br)ccc1OCC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCc1cc(Br)cc2c(C)coc12
Reaction time: 1 h
Yield: 78.1 %

Procedure:
A stirred solution of polyphosphoric acid (461 ml) was heated to 95° C., and 1-(4-bromo-2-ethylphenoxy)propan-2-one 30 (93 gm) was added portionwise. The reaction was stirred 1 hour. The reaction was determined to be complete and the contents poured onto 1:1 hexane; 10% aqeous sodium hydroxide (2 liters). A strong exotherm was noted. The organic layer was separated and washed twice with 1 N Na2S2O3. The organic layer was then stirred with charcoal and anhydrous magnesium sulfate for 30 minutes. The reaction was filtered through celite and the solvent removed in vacuo. The crude product was run through a plug of silica gel (375 g) and eluted with hexanes. The solvent was removed in vacuo to yield 67.58 g of 5-bromo-7-ethyl-3-methylbenzofuran 31.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=O)C.O.[OH-].[Li+]>C1COCC1>[CH:11]1[C:10]2[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)OCCCCn1c2ccccc2c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCCCCn1c2ccccc2c2ccccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.9 %

Procedure:
Compound 9 (35.1 g, 0.125 mol) and lithium hydroxide monohydrate (13.0 g, 0.31 mol) were dissolved in 200 mL THF. The reaction mixture was stirred at 80° C. for 12 hours. The mixture was filtered and the homogeneous solution was evaporated to give the crude product. The resulting product was purified by silica gel column chromatography (eluent: ethyl acetate:methylene chloride=1:10 v/v) to yield 26 g (86%) of 4-(9H-carbazol-9-yl)butan-1-ol (Compound 10).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@@:17]2([CH3:23])[O:21][C:20](=[O:22])[NH:19][CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C@@:17]2([CH3:23])[O:21][C:20](=[O:22])[NH:19][CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc([C@]2(C)CNC(=O)O2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc([C@]2(C)CNC(=O)O2)cc1O

Procedure:
1.1 g of (R)-(-)-5-(3-benzyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone is dissolved in 40 ml of ethyl acetate and mixed with 100 mg of palladium/10% carbon. It is hydrogenated until hydrogen absorption is completed. After filtration on silica gel and concentration by evaporation in a vacuum, 750 mg of (R)-(-)-5-(3-hydroxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone, melting point 141.6° C., is obtained. [α]D =-28.2° (CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[O-]CC.[Na+].[CH2:14]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[OH:29])[C:25](=[O:30])[CH2:24][CH2:23]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>C(O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][O:29][C:28]1[CH:27]=[C:26]2[C:22](=[CH:21][C:20]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:23][CH2:24][C:25]2=[O:30])[CH3:2]
Reactant: CCCCCCc1cc2c(cc1O)C(=O)CC2
Reactant: CCOC(=O)CCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCc1cc2c(cc1OCCCC(=O)OCC)C(=O)CC2

Procedure:
3.6 ml of ethyl4-bromobutyrate dissolved in 15 ml of ethanol are added to a mixture of sodium ethoxide (1.6 g, 0.0233 mol) and 5-hexyl-6-hydroxyindan-1-one (4.5 g, 0.0194 mol) in 45 ml of ethanol. The reaction medium is heated for 5 hours at reflux. The mixture is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and the solvents are evaporated off (5.9 g; 60%).
Reaction SMILES: [C:1](OC(=NC(C)C)NC(C)C)([CH3:4])([CH3:3])[CH3:2].Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=[C:26]([Cl:33])[CH:25]=2)=[C:19]([Cl:34])[CH:18]=1>C1COCC1.CCOC(C)=O>[C:1]([O:31][C:30](=[O:32])[C:29]1[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][C:19]=2[Cl:34])=[CH:25][C:26]([Cl:33])=[N:27][CH:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
2-tert-Butyl-1,3-diisopropylisourea (8.04 g, 40.1 mmol) was added to a mixture of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid hydrochloride salt (24) (2.91 g, 7.31 mmol) in THF (165 mL). After stirring for 2 hours at room temperature and 30 minutes at reflux, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with 10% K2CO3 and brine, dried (Na2SO4) and concentrated. The resulting residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated and purified by flash column chromatography using the Biotage system (CH2Cl2) to give the desired product (40) (3.28 g, 78%).