Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][C:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][CH3:17])[N:5]=2.[CH3:26][O-:27].[Na+]>CO.[Cl-].[NH4+]>[CH3:18][C:14]([CH3:19])([CH2:15][CH2:16][CH3:17])[CH2:13][O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:27][CH3:26])[N:3]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:8]([NH2:11])[N:7]=1
Reactant: C[O-]
Reactant: CCCC(C)(C)COc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC(C)(C)COc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1

Procedure:
To a solution of 8-bromo-2-[(2,2-dimethylpentyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (475 mg) in dry MeOH (3.92 mL) was added sodium methoxide solution (0.649 mL, 30% wt. in MeOH). The reaction mixture was stirred at reflux for 5 h. The reaction was cooled and concentrated in vacuo to give an orange residue. The residue was taken up in saturated ammonium chloride solution (25 mL) and was extracted with EtOAc (25 mL). The organic layer was separated and washed with water (15 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange solid (323 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7]([CH2:9][OH:10])=[N:8][C:4]=2[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7]([CH:9]=[O:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cn1c(CO)nc2cc(Cl)ccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1c(C=O)nc2cc(Cl)ccc21
Reaction time: 15 h
Yield: 66.7 %

Procedure:
A solution of (5-chloro-1-methyl-1H-benzimidazol-2-yl)methanol (1.5 g, 7.7 mmol) dissolved in CH2Cl2 at room temperature was treated with Dess-Martin periodinane (4.9 g, 11.5 mmol). The reaction was stirred for 15 hours before the solvent was removed. The residue was purified by flash column chromatography (0-3% MeOH in CH2Cl2) to give the product (1.0 g, 66% yield). 1H NMR (300 MHz, CDCl3) δ: 4.16 (s, 3H), 7.40-7.47 (m, 2H), 7.90-7.93 (m, 1H), 10.11 (s, 1H).
Reaction SMILES: C([CH2:3][NH:4][N:5]1[C:14]2[CH:13]=[C:12]3[O:15][CH2:16][O:17][C:11]3=[CH:10][C:9]=2[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1)=O.[OH-].[K+]>C(O)C.O>[CH3:3][NH:4][N:5]1[C:14]2[CH:13]=[C:12]3[O:15][CH2:16][O:17][C:11]3=[CH:10][C:9]=2[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1
Reactant: CCOC(=O)c1cn(NCC=O)c2cc3c(cc2c1=O)OCO3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(NC)c2cc3c(cc2c1=O)OCO3
Yield: 82.2 %

Procedure:
To a suspension of 4.1 g (0.013 mole) of ethyl 5,8-dihydro-5-[(formyl)methylamino]-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate (Example 6) in 40 ml of hot absolute ethanol was added a solution of 0.8 g (0.013 mole) of potassium hydroxide (85%) in 2.6 ml of water. The mixture was heated at near the boiling point of the ethanol for about 10 minutes and then chilled in an ice bath. The solid product was collected by filtration and washed with absolute ethanol and ether. After a further washing with water, tetrahydrofuran and ether and drying at 0.1 mm overnight there was obtained 3.1 g of ethyl 5,8-dihydro-5-(methylamino)-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate, colorless crystals, m.p. 211°-218° C.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ncccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1ncccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
To a solution of potassium ethoxide (2.44 g, 27.7 mmol) in diethyl ether (90 mL) and ethanol (8 mL) was added diethyl oxalate (3.79 mL, 27.7 mmol) resulting in a yellow suspension. The reaction mixture was stirred for 5 min prior to the addition of 2-methyl-3-nitropyridine (Preparation 29, 3.40 g, 24.6 mmol) in one portion. The resulting red suspension was stirred at rt, under argon, for 20 h. The mixture was filtered, washed thoroughly with diethyl ether and dried. The red solid was dissolved in water and the mixture adjusted to pH 4 by addition of glacial acetic acid. The resulting precipitate was collected by filtration, dissolved in dichloromethane, washed with brine, dried (MgSO4), and then filtered and concentrated in vacuo to give the title compound as an orange solid. δH (CDCl3): 1.40 (3H, t), 4.39 (2H, q), 7.34 (1H, s), 7.36 (1H, dd), 8.43 (1H, dd), 8.66 (1H, dd).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:14][CH:13]=[CH2:12])[CH:7]=1
Reactant: C=CCBr
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C)ccc1[N+](=O)[O-]
Yield: 94.4 %

Procedure:
A solution of 5-methyl-2-nitrophenol (2.00 g, 13.1 mmol), allyl bromide (1.30 mL, 15.0 mmol), and cesium carbonate (5.5 g, 17 mmol) in DMF (100 mL) was stirred at ambient temperature. After 20 hrs the reaction was filtered, frit washed with methanol, and the filtrate evaporated in vacuo at 50° C. The residue was purified by flash column chromatography (4:1 then 2:1 hexane:ethyl acetate eluant) giving the title compound as a yellow oil (2.39 g, 95%) that crystallized after sitting 3 days at ambient temperature. 1H NMR (300 MHz, CDCl3) δ 7.79 (d, 1H, J=8.2 Hz), 6.86 (s, 1H), 6.82 (m, 1H), 6.05 (ddt, 1H, J=17.3 Hz, 10.6 Hz, 5.0 Hz), 5.50 (ddd, 1H, J=17.3 Hz, 3.3 Hz, 1.7 Hz), 5.33 (ddd, 1H, J=10.6 Hz, 2.9 Hz, 1.5 Hz), 4.67 (dt, 2H, J=4.9 Hz, 1.6 Hz), 2.40 (s, 3H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](O)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][S:14][C:13]2=[S:24])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].O>Cl.CO>[C:1]([NH:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][S:14][C:13]2=[S:24])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc(N2C(=S)SCC2(O)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)NNc1ccc(-n2c(-c3ccccc3)csc2=S)cc1
Temperature: 80 °C

Procedure:
3-[4-(2-Acetylhydrazino)phenyl]-4-hydroxy-4-phenyl-thiazolidine-2-thione (1.0 g, 0.0028 mole) was added to water (25 ml) and methanol (5 ml). Concentrated hydrochloric acid (2 drops) was added; and the resulting mixture was stirred and heated at 80° C for 3 hours. The reaction mixture was chilled in ice, and the solid was filtered off. The product was washed with water, then ether, and allowed to dry. Yield 0.80 g (84%), m.p. 230°-232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:5]([CH:4]=1)[NH2:6]
Reactant: COc1cccc(N)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])c(N)c1
Temperature: 5 °C

Procedure:
A solution of 3-methoxyaniline (2.21 g) in acetic acid (3 ml) and acetic anhydride (10 ml) was stirred at room temperature for 1 hour. The solution was cooled to 5° C. and 60% nitric acid (1 ml) was added dropwise with stirring. When the cooling bath was removed, whereupon the solution temperature rose to 60° C. The solution was allowed to cool down to room temperature, poured into ice-water (100 ml) and neutralized with sodium hydroxide. The separated crystals were collected by suction and washed with water. To the crystals was added 4N hydrochloric acid (45 ml) and the mixture was refluxed for 2 hours. The reaction mixture was alkalized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform) to give 0.67 g of 5-methoxy-2-nitroaniline.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[N:21]=[C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]4[CH:29]=3)=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=O.[H-].[Na+].CN(C)C=O.[C:37]([O:40][CH2:41][CH3:42])(=[O:39])[CH3:38]>>[CH3:28][C:26]1[CH:25]=[CH:24][N:23]2[CH:29]=[C:20]([C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:5]4[CH:4]=[C:3]([CH:1]=[CH:38][C:37]([O:40][CH2:41][CH3:42])=[O:39])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=4)[CH2:13][CH2:14]3)=[O:19])[N:21]=[C:22]2[CH:27]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccn2cc(C(=O)N3CCN(c4ccc([N+](=O)[O-])c(C=O)c4)CC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cc(N2CCN(C(=O)c3cn4ccc(C)cc4n3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(3-formyl-4-nitrophenyl)-4-(7methylimidazo[1,2-a]pyridine-2-carbonyl)piperazine (22.8 g), triethyl phosphonoacetate (15.6 g), sodium hydride (60% dispersion in mineral oil) (2.92 g) and N,N-dimethylformamide (250 ml) were stirred for 5 hours at ambient temperature. Ethyl acetate (250 ml) was added thereto and the resulting precipitates were collected and washed with ethyl acetate (100 ml) to give ethyl 3-[3-[4-(7-methylimidazo[1,2-a]pyridine-2-carbonyl)-1-piperazinyl]-6-nitrophenyl]acrylate (18.70 g).
Reaction SMILES: [OH:1][CH:2]([C:14]1(O)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]1=2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([C:11]([OH:13])=[O:12])[CH2:6]1.CS(O)(=O)=O>ClCCl>[CH:25]1[C:16]2[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]([C:2](=[O:1])[CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH2:8][C@@H:7]([C:11]([OH:13])=[O:12])[CH2:6]3)[C:15]=2[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)[C@@H]1CCCN(CCC(O)C2(O)c3ccccc3CCc3ccccc32)C1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: O=C(CCN1CCC[C@@H](C(=O)O)C1)C1c2ccccc2CCc2ccccc21

Procedure:
The above 3-piperidinecarboxylic acid (2.84 g, 5.3 mmol) was dissolved in dichloromethane (200 ml), methanesulfonic acid (0.5 ml) was added and the resulting mixture was heated at reflux temperature for 2 days. The mixture was allowed to cool and was then concentrated in vacuo. The residue was dissolved in water (50 ml) and extracted with dichloromethane (4×50 ml). The combined organic extracts were concentrated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (9:1) as eluent. This afforded after evaporation of the solvent 0.74 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18](O)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:43]([NH:50][CH:51]([CH3:53])[CH3:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH2:43]([N:50]([CH:51]([CH3:53])[CH3:52])[C:18](=[O:19])[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:12][CH2:13]1)=[O:21])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Reactant: CC(C)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)N(Cc1ccccc1)C(=O)C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1

Procedure:
To a stirred solution of 2-(4-(2-tert-butylphenyl)piperazin-1-yl)-2-oxo-acetic acid (0.091 g, 0.31 mmol) in methylene chloride (5.0 mL) was added EDCI (0.078 g, 0.41 mmol) and HOBt (0.055 g, 0.41 mmol) at room temperature. After 40 min N-benzylpropan-2-amine (0.054 g, 0.36 mmol) was added at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 80:20 to 70:30 heptane/ethyl acetate, gradient elution) to provide N-benzyl-2-(4-(2-tert-butylphenyl)-piperazin-1-yl)-N-isopropyl-2-oxoacetamide as a mixture of cis and trans isomers (0.041 g, 32%) as a white solid, mp 65-68° C.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23]Br)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: BrCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc(Cn2c3ccccc3c3c(OCCNCc4ccccn4)cccc32)cc1
Yield: 80.9 %

Procedure:
A mixture of 9-benzyl-4-(2-bromoethoxy)-9H-carbazole (0.0622 g, 0.1635 mmol), diisopropylethylamine (0.0211 g, 0.1635 mmol), 2-(2-aminomethylpyridine (0.0531 g, 0.4907 mmol), and DMF (0.5 mL) is stirred at 100° C. for 30 min. After cooling, the solvent is removed and the residue partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate; chromatography on silica gel (40 mL) using CH3OH—CH2Cl2 (2/98) gave 0.0539 g (81%) of the title compound; IR (drift) 1586, 1457, 1342, 1269, 1237, 1153, 1145, 1118, 1047, 782, 776, 753, 745, 718, 710 cm−1; 1H NMR (CDClCH3) δ3.32, 4.13, 4.44, 5.51, 6.70, 6.99, 7.12, 7.2-7.4, 7.66, 8.39, 8.60. Anal. Calcd for C27H25N3O: C, 79.58; H, 6.18; N, 10.31. Found: C, 79.66; H, 6.41; N, 10.28.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[C:17]([Cl:20])([Cl:19])=[CH2:18]>C(Cl)Cl>[Cl:19][C:17]([Cl:20])=[CH:18][C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[C:8]([F:12])[CH:7]=1)=[O:5]
Reactant: O=C(Cl)c1cc(F)c(Cl)nc1Cl
Reactant: C=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1cc(F)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the 2,6-dichloro-5-fluoronicotinoyl chloride from the previous reaction in CH2Cl2 (25 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (7.9 g, 59.5 mmol) in CH2Cl2 (25 mL). After 15 min, vinylidene chloride (4.75 mL, 59.5 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2Cl2. The organic layer was collected and cooled to 0° C. before TEA (8.3 mL, 59.5 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HCl, NaHCO3, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one: (6.1 g, 90%) as a brown oil: 1H-NMR (d6-DMSO, 300 MHz) δ 8.43 (d, 1H, J=8.4 Hz), 7.56 (s, 1H), Rf=0.76(3:1 Hex:EtOAc).
Reaction SMILES: Cl.N[C:3]1[O:4][C:5]2[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][C:15]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([OH:29])(C)C>>[C:22]([C:15]1[CH:16]=[C:17]([C:18]([CH3:21])([CH3:19])[CH3:20])[C:5]2[O:4][C:3](=[O:29])[CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:6]=2[CH:14]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2oc(N)c(-c3ccccc3)c2c1
Reactant: CC(C)O
Agent: Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
4.8 ml (9.58 mmol) of 2N HCl is added at room temperature to a solution of 3.08 g (9.58 mmol) of 2-amino-3-phenyl-5,7-di-tert-butyl-benzofurane [compound (301), Table 3, prepared according to Example 1a] in 10 ml iso-propanol and stirred at room temperature for 90 minutes. The precipitate is filtered and washed with isopropanol. Crystallization of the residue from isopropanol yields 2.62 g (85%) of 5,7-di-tert-butyl-3-phenyl-3H-benzofuran-2-one (compound (101), Table 1), m.p. 116-119° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([O:21]CC)=O)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:24][NH2:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([NH:25][CH3:24])=[O:21])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)COC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Reactant: CN
Product: CNC(=O)COC(=O)N1CCC(Oc2ccc(Br)cc2)CC1

Procedure:
2.9 g (7.5 mmol) of 2-(ethyloxy)-2-oxoethyl 4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate, prepared in Step 4.3., in solution in 10 ml of a 33% ethanolic solution of methylamine are stirred at ambient temperature for 20 hours. Following evaporation, the product is purified by chromatography on silica gel, eluting with ethyl acetate, to give 0.8 g of product in gum form, which is used as it is in the following step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:27])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C=Cc1ccc(Oc2ccc(C)c(F)c2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(CCO)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To the solution of 4-ethenylphenyl 3-fluoro-4-methylphenyl ether (900 mg, 3.94 mmol) in dry THF (30 mL), was added 9-BBN (9.46 mL, 4.73 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (1.2 mL), followed by aq. NaOH (5.26 mL, 15.77 mmol), and 30% H2O2 (4.03 mL, 39.4 mmol). The reaction mixture was heated at 50° C. for 2 h. Then THF was removed under reduced pressure, and the residue was diluted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.02 g, 4.14 mmol, 105% yield) as a yellow oil. LCMS: rt=3.29 min, [M+H]=229
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[C:13]([C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[OH:2])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: COc1ccc(NC(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(O)c(C(C)=O)c1
Yield: 86.3 %

Procedure:
To a stirring suspension of N-(4-methoxy-phenyl)-acetamide (5.253 g, 32 mmol) and acetyl chloride (6.6 ml, 93 mmol, 2.9 equ) in dichloromethane (55 ml) was added aluminium trichloride (14.55 g, 109 mmol, 3.4 equ) in portions over 90 minutes. The reaction was then heated to reflux for 4.5 hours and cooled overnight. The mixture was poured onto ice then extracted into dichloromethane (5×), dried (MgSO4) and concentrated in vacuo to give N-(3-acetyl-4-hydroxy-phenyl)-acetamide (5.336 g, 87%) as a pale green solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)([CH2:16][CH2:17][OH:18])[O:12][C:11]3=[O:26])[CH3:9])=[CH:4][CH:3]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one by application of procedures analogous to those described in Example 75 Step 1 using 4-fluorophenylboronic acid. The isomers were separated by chromatography on silica gel.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:25]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]=2[OH:25])[N:14]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2-c2ccc(F)cc2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(-c3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(4-fluoro-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 389 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1)[CH3:14]
Reactant: CNC
Reactant: ClCc1ccc2[nH]nnc2c1
Product: CN(C)Cc1ccc2[nH]nnc2c1
Temperature: 100 °C
Yield: 63 %

Procedure:
A mixture of 5-chloromethyl-1H-1,2,3-benzotriazole (Synth. Commun., (1993), 23, 2019) (1.34 g, 8.0 mmol) and dimethylamine (33% solution in ethanol, 10 mL) was heated in an autoclave at 100° C. for 12 hours. The solvent was removed under reduced pressure, and the residue was dissolved in saturated aqueous sodium bicarbonate. A continuous extraction using ethyl acetate was performed, and the resulting solution of the product was dried (MgSO4) and concentrated under reduced pressure to give 5-(N,N-dimethylaminomethyl)-1H-1,2,3-benzotriazole (890 mg, 63%) as a brown hygroscopic gum.
Reaction SMILES: [OH:1][C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].[O:23]1CCC[CH2:24]1>>[CH:24]([N:7]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:6][C:5]1[CH:13]=[C:14]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:2]([OH:1])=[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:4]=1)=[O:23]
Reactant: CC(C)(C)c1cc(CNn2ccnc2)cc(C(C)(C)C)c1O
Reactant: C1CCOC1
Product: CC(C)(C)c1cc(CN(C=O)n2ccnc2)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
15 ml of acetic anhydride and 7.5 ml of formic acid (98-100%) are mixed carefully at 0° and subsequently heated to 50° on a water-bath for 1 hour. The mixed anhydride formed is diluted with 25 ml of abs. tetrahydrofuran and 4.52 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)imidazole are introduced in small portions into the solution obtained. The reaction mixture is left to stand at room temperature for 1 hour and evaporated under reduced pressure on a rotary evaporator. The residue is treated with a small amount of ice-cold water and saturated sodium bicarbonate is added up to a weakly alkaline reaction. After three-fold extraction with methylene chloride, the combined organic extracts are washed once with water and once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is recrystallized from ethyl acetate/n-hexane and there is obtained 1-[N-formyl-N-(4-hydroxy-3,5-di-tert.-butylbenzyl)amino]imidazole of m.p. 167°.