Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:10]O)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.O>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:8]=[C:4]2[CH:3]=1
Reactant: COc1ccc(C(Cc2cc(Cl)ccn2)=NO)cc1
Agent: Cl[Fe]Cl
Solvent: COCCOC
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3cc(Cl)ccn3n2)cc1
Temperature: 15 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (11.8 g, 42.6 mmol) in 1,2-dimethoxyethane (200 mL) at 0° C. was added trifluoroacetic anhydride (6.3 mL, 44.8 mmol), keeping the temperature below 10° C. during the addition. After the addition was complete, the reaction was warmed to 15° C. The solution was then cooled to 4° C. and a solution of triethylamine (12.5 mL, 89.5 mmol) in 1,2-dimethoxyethane (15 mL) was added over a period of 0.5 hours. The mixture was allowed to warm to room temperature and was stirred at room temperature for 5 hours. To this mixture was added iron(II)chloride (0.11 g, 0.85 mmol) and the reaction was heated at 75° C. for 15 hours. The reaction mixture was poured into water (300 mL). The resulting suspension was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was recrystallized from methanol to give 5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine (6.64 g, 60%) as white needles. 1H NMR (CDCl3): δ 8.35 (d, 1H), 7.86 (d, 2H), 7.46 (d, 1H), 6.97 (d, 2H), 6.67 (d, 1H), 6.65 (s, 1H), 3.85 (s, 3H); MS m/z 259 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([CH:30]=1)[O:7][C:8]1[N:9]=[C:10]([NH:21][C:22]2[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=2)[C:11]([C:18]([NH2:20])=[O:19])=[N:12][C:13]=1[C:14](O)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([CH:30]=1)[O:7][C:8]1[N:9]=[C:10]([NH:21][C:22]2[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=2)[C:11]([C:18]([NH2:20])=[O:19])=[N:12][C:13]=1[C:14]([CH3:16])=[CH2:15]
Reactant: CC(C)(O)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Oc1cc(N)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C=C(C)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Oc1cc(N)ccc1F
Yield: 82.7 %

Procedure:
A mixture of 5-(5-amino-2-fluorophenoxy)-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (515 mg), diisopropylethylamine (409 μL), and N-methylpyrrolidone (3 mL) was reacted in a microwave reaction device at 200° C. for 4 hours. The mixture was purified by silica gel column chromatography (eluent; chloroform:methanol=98:2-90:10) to obtain 5-(5-amino-2-fluorophenoxy)-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(prop-1-en-2-yl)pyrazine-2-carboxamide (408 mg) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][CH:15]1[CH2:19][CH2:18][CH:17]([CH3:20])[NH:16]1>>[CH3:14][CH:15]1[CH2:19][CH2:18][CH:17]([CH3:20])[N:16]1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC1CCC(C)N1
Product: CC1CCC(C)N1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (300 mg; 1.62 mmol; 1 eq.) and 2,5-dimethylpyrrolidine (Maybridge AC11676DA; 0.70 mL; 5.72 mmol; 3.53 eq.) was stirred at 100° C. for 5 minutes in the MW. The solution was concentrated in vacuo and the residue taken up in water (100 mL). The aqueous phase was washed with diethyl ether (2×20 mL) then acidified to pH 5 with acetic acid. Extraction with diethyl ether (150 mL), drying over magnesium sulfate and concentration in vacuo afforded the title compound (360 mg, 84%) as an orange solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH2:11])(=[O:10])[CH:8]=[CH2:9]>CCO>[N:1]1([CH2:9][CH2:8][C:7]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: C=CC(N)=O
Solvent: CCO
Product: NC(=O)CCN1CCCCC1
Yield: 75 %

Procedure:
A solution of piperidine, 4-(diphenylmethylene) (0.10 mole) and acrylamide (8.95 g, 0.062 mole) in EtOH (50 ml) was refluxed overnight. This reaction mixture was filtered and concentrated. The resulting while solid residue was dissolved in CHCl3, washed with H2O (3×150 ml), dried (Na2SO4) and the solvent removed to give thick yellow oil. Crystallization from CH2Cl2 -i-Pr2O afforded 29.01 g (75%) of 1-piperidinepropanamide, 4-(diphenylmethylene)-; mp 105°-7° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:22])=[C:6]([S:8]([N:11](COCC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.ClC1C(F)=CC(F)=C(S(/N=C2/N=CN(COCC)C=C/2)(=O)=O)C=1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([C:55]2[N:59]([CH3:60])[N:58]=[CH:57][CH:56]=2)[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:54][C:51]2[CH:52]=[CH:53][C:48]([Cl:47])=[CH:49][C:50]=2[C:55]2[N:59]([CH3:60])[N:58]=[CH:57][CH:56]=2)=[CH:4][C:5]([F:22])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: CCOCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: Cn1nccc1-c1cc(Cl)ccc1O
Agent: CCOCn1cc/c(=N\S(=O)(=O)c2cc(Cl)c(F)cc2F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc(Cl)ccc1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 27 %

Procedure:
A suspension of 5-chloro-N-(ethoxymethyl)-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide and 5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide and 5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide (Preparation 719) used as a mixture of three regioisomers, (64 mg, 0.18 mmol), 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol (Preparation 89) (37 mg, 0.18 mmol) and potassium carbonate (37 mg, 0.26 mmol) in dimethyl sulfoxide (1 mL) was stirred at room temperature for 19 hours then diluted with ethyl acetate (30 mL), washed with 1M aqueous sodium hydroxide, water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was taken up in trifluoroacetic acid (1 mL) and stirred for 3 hours then concentrated in vacuo. The residue was purified by reverse phase HPLC to give 29 mg (27%) of the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>CN1C(=O)CCC1.CCOC(C)=O.[Cu](Cl)Cl.CC(C)(C(=O)CC(=O)C(C)(C)C)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: Oc1cccnc1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Oc2cccnc2)cc1
Temperature: 120 °C
Reaction time: 6.5 h
Yield: 77979.8 %

Procedure:
To a solution of 3-hydroxypyridine (2.1 g, 0.02 mmol) in NMP (20 mL) were added cesium carbonate (7.2 g, 0.02 mmol), 4-bromobenzonitrile (2.0 g, 0.01 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.23 mL, 0.001 mmol) and copper chloride (0.54 g, 0.005 mmol) at room temperature. The suspension was stirred at 120° C. for 6.5 hours. The reaction was cooled to room temperature and diluted with EtOAc (75 mL). The suspension was filtered and the filtrate washed with H2O (4×100 mL). Combined aqueous washes were extracted once with EtOAc (100 mL). Combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography (10-20% acetone in hexanes) to provide the title compound as an orange oil (1.53 g, 71%). 1H NMR (300 MHz, CDCl3): δ 8.45-8.60 (m, 2H), 7.67 (d, 2H), 7.28-7.42 (m, 2H), 7.07 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4](/[N:10]=[C:11]2\[N:12]([C:27]#[N:28])[CH2:13][C@@H:14]3[C@H:18]([O:19][Si](C(C)(C)C)(C)C)[CH2:17][CH2:16][N:15]\23)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CC=CC=1.C1C[O:39]CC1>>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4](/[N:10]=[C:11]2\[N:12]([C:27]([NH2:28])=[O:39])[CH2:13][C@@H:14]3[C@H:18]([OH:19])[CH2:17][CH2:16][N:15]\23)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(/N=C2\N(C#N)C[C@@H]3[C@H](O[Si](C)(C)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: Cc1c(/N=C2\N(C(N)=O)C[C@@H]3[C@H](O)CCN23)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 12A (30.0 mg, 0.0699 mmol) was dissolved in THF (1 mL) and HF/pyridine (˜2.3:1, 0.075 mL) was added. After stirring at rt overnight, the reaction was concentrated and purified via preparative HPLC (YMC ODS C-18, 21.2×100 mm, eluting with 50-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm. The peaks were collected, combined and repurified via preparative HPLC (YMC ODS C-18, 21.2×100 mm, eluting with 30-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm to provide compound 12B (8.0 mg) as a clear film. MS: m/z 334 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S-:10][C:11]#[N:12].[K+].BrBr>C(O)(=O)C>[NH2:12][C:11]1[S:10][C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[C:3]=2[N:4]=1
Reactant: Nc1cccc(Cl)c1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2c(Cl)c(Cl)ccc2s1
Temperature: 25 °C

Procedure:
To a solution of 2,3-dichloroaniline (1.0 g; 6.17 mmol) in glacial acetic acid (30 ml) was added potassium thiocyanate (3.6 g; 37 mmol) and the mixture was stirred at ambient temperature until a clear solution had formed. Bromine (0.48 ml; 9.26 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for five hours. The solvent was removed under reduced pressure and the residue was diluted with water and rendered alkaline by addition of aqueous sodium hydroxide (6M). The product was filtered off, washed with water and dried to yield the desired product quantitatively.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([OH:13])[CH3:12]>>[C:5]1([N:4]2[CH:3]=[CH:2][CH:12]=[CH:11][O:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCO
Reactant: OCCNc1ccccc1
Product: C1=CON(c2ccccc2)C=C1
Temperature: 80 °C

Procedure:
0.271 g of P-(2-phenyl-2-chloro acetyl) dimethylaminobenzene (1 mmole) and 0.274 g of N-(2 hydroxy ethyl) aniline (2.0 mmole) were dissolved in 3 ml of dry ethanol and heated in a sealed tube at 80° C. for 8 hours. On cooling the product crystallized out as pale yellow needles, which was filtered and dried to yield 0.2 g of N-phenyl oxazine Compound 15.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[CH3:32][CH2:33]OCC>O1CCCC1.C(COC)OC>[CH3:3][O:4][C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[CH2:33][CH2:32]1
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1ccccc1C1(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (4.4 g of 60 percent oil dispersion) was placed in a flask with 140 ml of dimethoxyethane. This mixture was cooled with an ice bath and 22.3 g of triethyl phosphonoacetate was added dropwise with stirring over a 30 min period. A murky yellow solution was obtained. 2,2'-Dimethoxybenzophenone (20.2 g) was added and the resulting mixture was heated at reflux with stirring for 20 hours. It was then allowed to cool to ambient temperature and was diluted with 500 ml of ether. The resulting mixture was washed with 3-200 ml portions of 1N hydrochloric acid and with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a turbid, viscous yellow oil. This material was found by gas chromatagraphy to be about 79 percent one compound. It was dissolved in 100 ml of tetrahydrofuran and the solution added dropwise with stirring to a slurry of 4.70 g of lithium aluminum hydride in 100 ml of tetrahydrofuran over a 40 min period. An exothermic reaction ensued. The mixture was heated at reflux for 3 hours and allowed to stand at ambient temperature overnight. About 100 ml of 10 percent sulfuric acid was added carefully with stirring to quench the excess lithium aluminum hydride. About 700 ml of ether was then added and the layers were separated. The ether layer was extracted with water, 10 percent hydrochloric acid, 10 percent potassium hydroxide, and brine. It was then dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was purified by filtration chromatography on silica eluting with a 10:90 mixture of ether and hexane. The solvents were removed by evaporation under reduced pressure to obtain 5.6 g (26 percent of theory) of the title compound as pale yellow crystals melting at 146°-149° C. The carbon-13 and proton nmr spectra were in agreement with the assigned structure.
Reaction SMILES: [ClH:1].Cl.N[C:4]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Br:27])=[CH:21][C:5]=1[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH3:20].N([O-])=O.[Na+]>S(=O)(=O)(O)O.C(O)(=O)C.O.C(Cl)(Cl)Cl.[Cu]>[ClH:1].[Br:27][C:22]1[CH:21]=[C:5]2[C:4](=[CH:24][C:23]=1[O:25][CH3:26])[C:15]1=[C:16]3[CH:7]([N:8]([CH3:20])[CH2:9][CH2:10][C:11]3=[CH:12][C:13]([O:18][CH3:19])=[C:14]1[OH:17])[CH2:6]2
Reactant: COc1cc2c(cc1O)C(Cc1cc(Br)c(OC)cc1N)N(C)CC2
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1Br)CC1c3c(cc(OC)c(O)c3-2)CCN1C
Reaction time: 8 h
Yield: 43 %

Procedure:
General procedure as described in Example III. 1-(2'-Amino-5'-bromo-4'-methoxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (4c) (448 mg) in 20% sulfuric acid (4 ml) and glacial acetic acid (4 ml) was diazotized using sodium nitrite (77 mg) in water (0.75 ml), and the subsequent Pschorr cyclization used copper powder (450 mg) in the usual manner. The crude product was a brown gum (353 mg) which was dissolved in chloroform and filtered through a short column of silica gel (3 g), eluting with chloroform-methanol (97:3, 200 ml). Removal of solvent left a brown gum which was treated with ethanol (6 ml) saturated with hydrogen chloride gas. Solvents were removed and the residue was stirred overnight with ether (30 ml). Filtration gave the crude aporphine hydrochloride as a pale brown solid (318 mg). Recrystallization from methanol gave 9-bromo-2,10-dimethoxy-1-hydroxyaporphine hydrochloride (5c) as a dull yellow crystalline solid (171 mg, 43%), mp 237°-240° (dec). Three recrystallizations from methanol pale yellow-greenish needles, mp 241°-243° (dec); λmaxKBr 2.75-3.30 μ (broad O--H and N--H); λmaxEtOH (c) 219 (39,415), 269.5 (13,710), 279.5 (16,970), 305 sh (13,195), and 311 nm (13,540); mass spectrum m/e 390, 389 (M+ - HCl), 388 (M+ - HCl-1), 387, 376, 374, 348, and 346.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:11][C:10]([O:14][Si](C)(C)C)([C:12]#[N:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:26].[OH-].[NH4+]>ClCCl>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:11][C:10]([OH:14])([C:12]([NH2:13])=[O:26])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: C[Si](C)(C)OC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
1-(Diphenylmethyl)azetidin-3-one (600 mg, 2.53 mmol), was dissolved in dichloromethane (1 mL) and treated with triethylamine (0.5 mL, 3.59 mmol) and trimethylsilylcyanide (0.8 mL, 6.01 mmol) at ambient for 2 h and then the mixture was concentrated in vacuo to afford 1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (774 mg, 2.30 mmol, 91% yield) as a yellow solid. 1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (250 mg, 0.744 mmol) was dissolved in dichloromethane (2 mL) at 0° C. and concentrated sulfuric acid (0.2 mL) was added dropwise. The mixture was stirred at ambient for 2 h and then was cooled to 0° C. and 25% ammonium hydroxide solution was added carefully dropwise to pH ˜10-11. The mixture was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a residue which was triturated with hexanes/ether to afford 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (160 mg, 0.567 mmol, 76% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3): 7.92 (br s, 1H), 7.39-7.34 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 5.61 (br s, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.50 (dd, 2H), 3.20 (dd, 2H); MS (EI) for C17H18N2O2: 283 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[C:13](Cl)(=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([O:9][CH3:13])=[O:8]
Reactant: O=C(O)C=Cc1cccc(Br)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C=Cc1cccc(Br)c1

Procedure:
To a solution of 50.0 g (220 mmol, Aldrich) of 3-bromocinnamic acid in 1 L sieve-dried methanol (Burdick & Jackson), stirred at 0° C., was added dropwise a solution of acidic methanol (prepared by the addition of 2.5 mL acetyl chloride to 250 mL methanol). The reaction
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[CH3:8][N:9]([CH2:11]N(C)C)[CH3:10]>>[CH3:8][N:9]([CH2:11][C:5]1[O:1][C:2]([CH2:6][OH:7])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CN(C)CN(C)C
Reactant: OCc1ccco1
Product: CN(C)Cc1ccc(CO)o1

Procedure:
In a series of experiments with 2-furanmethanol we have found that the use of bis(dimethylamino)methane gives better yields of 5-(dimethylaminomethyl)-2-furanmethanol than those obtained using dimethylamine and a source of formaldehyde (e.g. aqueous formaldehyde, paraformaldehyde and trioxan). Furthermore the product obtained after distillation was also purer. The yields referred to above were 76-94% and these compare very favourably with the yields reported by R. F. Holdren (12%) (J. Amer. Chem. Soc. 69(464)1947) and Gill and Ing (70%) (J. Chem. Soc. 4728 (1958)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[C:6]([O:8][CH3:9])[CH:7]=1.[N+:22]([O-])([OH:24])=[O:23].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)ccc1OCc1c(OC)ccc(F)c1F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F

Procedure:
To a suspension of 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)anisole (8.6 g) in acetic anhydride (54 mL) was added 60% nitric acid (2.9 mL) in a dropwise manner under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture was added water (54 mL) in a dropwise manner, and the resulting mixture was stirred under ice-cooling for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and a mixed solvent (n-hexane/ethanol=4/1), and dried under reduced pressure to give the title compound (9.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(Cl)cc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-chloro-N2-phenylbenzene-1,2-diamine (975 mg, 4.46 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (928 mg, 4.90 mmol), HOAt (668 mg, 4.90 mmol), 4-methylmorpholine (1.08 mL, 9.81 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (940 mg, 4.90 mmol) in DCM (30 mL) was stirred at RT for 19 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried and concentrated in vacuo to afford [(S)-1-(4-chloro-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester as a purple solid (quantitative). A solution of the compound thus obtained (4.46 mmol) in AcOH (30 mL) was heated at 70° C. for 22 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic layer was washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) to afford the title compound as a yellow solid (1.20 g, 72% over two steps). LCMS (Method C): RT 3.82 min [M+H]+ 372.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[C:14]([OH:18])(=[O:17])[CH:15]=[O:16].C(=O)(O)[O-].[Na+].C(=O)(O)[O-].S(=O)(=O)(O)[O-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:15]([OH:16])[C:14]([OH:18])=[O:17])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=CC(=O)O
Reactant: NC(=O)Cc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Cc1cc(F)cc(F)c1)NC(O)C(=O)O

Procedure:
A mixture of 7.2 g of (3,5-difluorophenyl)acetamide 1 and 4.6 g of glyoxylic acid hydrate in 75 mL of acetone was refluxed 24 hours. The solvent was evaporated and the residue was dissolved in 300 mL of ethyl acetate. This solution washed with 150 mL of distilled water. The aqueous phase was discarded. The organic phase was extracted with a solution prepared by diluting 50 mL of a saturated aqueous solution of sodium bicarbonate with 150 mL of distilled water. The organic phase was discarded and the aqueous bicarbonate solution was acidified with 80 mL of 1 N aqueous sodium bisulfate solution. The acidified solution was extracted with three successive 125 mL portions of ethyl acetate. The combined organic extracts were washed with brine and then dried over magnesium sulfate. The solution was filtered and the solvent was evaporated to yield 2-[(3,5-difluorophenyl)acetylamino]-2-hydroxyacetic acid as 5.2 g of a white solid. 1H-NMR (DMSO-d6): δ 8.95 (d, J=8 Hz, 1H), 7.15-6.90 (m, 3H), 5.37 (d, J=8 Hz, 1H), 3.50 (s, 2H). 13C-NMR (DMSO-d66) δ 171.5, 169.4, 162.4 (dd, JC-F=13, 244 Hz), 140.6 (t, JC-F=10 Hz), 112.6 (dd, JC-F=8, 17 Hz), 71.5, 41.7. MS (CI+): m/z 246. EA Calc'd for C10H9F2NO4: C, 48.98; H, 3.71; N, 5.71. Found: C, 49.02; H, 3.72; N, 5.51.