Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:22])=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH:6]([CH3:22])[CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc2c(cc1Br)C(C)CNC(C)C2
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.028 g, 0.069 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3 hours at 20 C. The product mixture was diluted with water (10 mL), extracted twice with EtOAc (10 mL), the combined organic phases were washed with brine (10 mL), dried with Na2SO4 and concentrated to give 0.020 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.30 (s, 1 H), 6.64 (s, 1 H), 6.06 (m, 1 H), 5.47 (d, J=17 Hz, 1 H), 5.30 (d, J=11 Hz, 1 H), 4.56 (s, 2 H), 3.03 (m, 2 H), 2.90 (dd, J=9, 14 Hz, 1 H), 2.80 (m, 1 H), 2.65 (d, J=14 Hz, 1 H), 2.55 (dd, J=10, 14 Hz, 1 H), 1.77 (bs, 1 H), 1.30 (d, J=7 Hz, 3 H), 1.20 (d, J=6 Hz, 3 H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1.O.[NH2:31][NH2:32]>CN(C=O)C>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:32][N:31]=2)=[CH:22][CH:23]=1)#[N:28]
Reactant: NN
Reactant: N#Cc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 73 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-cyanophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (265 mg, 0.69 mmol, prepared in Synthetic Example 25) in DMF (7 ml) was added hydrazine monohydrate (80%, 82 μl, 2.05 mmol, 3.0 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-cyanobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (190 mg, 73%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[N:10]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[C@@H:12]([NH:18][C:19](=[O:36])[O:20][CH:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11]2>C(OCC)(=O)C>[Cl-:1].[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20][C:19]([NH:18][C@@H:12]2[CH:13]3[CH2:14][CH2:15][N+:10]([CH2:2][C:3](=[O:4])[C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)([CH2:17][CH2:16]3)[CH2:11]2)=[O:36])=[CH:33][CH:32]=1
Reactant: COc1ccc(C(OC(=O)N[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Reactant: O=C(CCl)c1cccs1
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC(=O)N[C@H]2C[N+]3(CC(=O)c4cccs4)CCC2CC3)c2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.7 %

Procedure:
2-Chloro-1-(thiophen-2-yl)ethanone (12.0 mg, 0.07 mmol) was added to a solution of (4-methoxyphenyl)(phenyl)methyl(R)-quinuclidin-3-ylcarbamate (22.0 mg, 0.06 mmol, prepared as in example 3) in ethyl acetate (2 ml). The reaction was stirred at room temperature for two days. The reaction was evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain (3R)-3-(((4-methoxyphenyl)(phenyl)methoxy)carbonylamino)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (23 mg, mixture of diastereoisomers).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.NC1C=CC=C2C=1CCC2.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>CCOCC.CCCCCC>[CH2:31]([NH:33][C:34]([NH:1][C:2]1[C:10]([C:11]([OH:20])([C:12]([F:13])([F:14])[F:15])[C:16]([F:17])([F:18])[F:19])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2)=[O:35])[CH3:32]
Reactant: Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2c1CCC2
Reactant: CCN=C=O
Agent: Nc1cccc2c1CCC2
Solvent: CCCCCC
Solvent: CCOCC
Product: CCNC(=O)Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2c1CCC2

Procedure:
To 4-amino-5-(hexafluoro-2-hydroxy-2-propyl)indan (4.2g, 14 mmole, prepared from 4-aminoindan by the procedure of Gilbert, J. Org. Chem., 30, 1001 (1965), m.p. 155°-8°) in 50 ml 4:1 Et2O-hexane add ethyl isocyanate (1.3 g, 18mmole). After 1 hour filter the solid and dry to give 4.4 g N-ethyl-N'-[5-(hexafluoro-2-hydroxy-2-propyl)-4-indanyl]urea; m.p. 142°-143° C.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[C:18]3[NH:25][CH:26]=[CH:27][C:17]=3[C:16]=2[CH:15]=1)=O.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]>C(O)C>[O:24]=[C:19]1[C:18]2[NH:25][CH:26]=[CH:27][C:17]=2[C:16]2[CH:15]=[C:14]([C:12]3[N:9]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[S:8][CH:11]=3)[CH:23]=[CH:22][C:21]=2[NH:20]1.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]
Reactant: NC(=S)c1ccccc1
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=c1[nH]c2ccc(-c3csc(-c4ccccc4)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 6 h
Yield: 21.1 %

Procedure:
54 mg (1.2 mmol) of thiobenzamide is added to a suspension of 124 mg (0.33 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3.5 mL of ethanol. The mixture is stirred at 90° C. for 6 hours then the mixture is cooled to room temperature. The solvent is evaporated, then the product is purified by preparative LCMS. After drying, 29 mg (21%) of 4-oxo-8-(2-phenyl-thiazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [CH:1]([C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=O.[C:17](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[CH:17]
Reactant: O=C([O-])[O-]
Reactant: CC1(C=O)CCCN(C(=O)OC(C)(C)C)C1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a stirred solution of tert-butyl 3-formyl-3-methylpiperidine-1-carboxylate (2.10 g, 9.25 mmol) in methanol (40 mL) was added potassium carbonate (2.76 g, 20.00 mmol). The mixture was treated with dimethyl 1-diazo-2-oxopropylphosphonate (2.11 g, 11.00 mmol), and the resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (6% ethyl acetate/petroleum ether elute) to afford 1.50 g (73%) of tert-butyl 3-ethynyl-3-methylpiperidine-1-carboxylate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].P(Br)(Br)[Br:15]>C(OCC)C.O>[Br:15][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)c1ccc(CO)cc1F
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(CBr)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of (3-fluoro-4-methanesulfonyl-phenyl)-methanol (0.269 g, 1.31 mmol) in diethyl ether (5 ml) under an inert atmosphere of Argon is added dropwise phosphorus tribromide (46 μl, 0.434 mmol). After stirring at room temperature overnight, the reaction mixture is diluted with water (2 ml) and the diethyl ether layer separated. This organic portion is placed over NaOH pellets and after 20 minutes, is used as a reagent in solution in diethyl ether.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([CH2:17][CH2:18][CH3:19])[CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:26][CH2:27][CH2:28][CH2:29]Br.O>CN(C=O)C>[Br:26][CH2:27][CH2:28][CH2:29][C:13]1[CH:14]=[CH:15][C:10]([C:2]2[S:1][C:5]3[CH2:6][CH2:7][CH2:8][O:9][C:4]=3[N:3]=2)=[CH:11][C:12]=1[CH2:17][CH2:18][CH3:19]
Reactant: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1CCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-6,7-dihydro-5H-pyrano[2,3-d][1,3]thiazol-2-yl)-2-propylphenol (560 mg, 2.02 mmol) (Example 505) in DMF (5 mL) were added Cs2CO3 (0.99 g, 3.03 mmol) and 1,3-dibromopropane (0.72 mL, 7.07 mmol). The reaction mixture was stirred at rt for 18 h. Water was added, and the aqueous phase was extracted with Et2O. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (9:1 hexanes/EtOAc) to give the title compound was a white solid (121 mg, 15%). 1H NMR (400 MHz, CDCl3) 7.68 (d, 1H), 7.65 (dd, 1H), 6.82 (d, 1H), 4.30 (t, 2H), 4.12 (t, 2H), 3.62 (t, 2H), 2.78 (t, 2H), 2.61 (t, 2H), 2.34 (quintet, 2H), 2.11-2.03 (m, 2H), 1.63 (hex, 2H), 0.96 (t, 3H); LC-MS: RT=4.05 min, (M+H)+ 396.3.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:33](I)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(OCC)(=O)C>[CH2:33]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCI
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, n-hexyl iodide 0.89 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 40 ml under reduced pressure, and hexane 100 ml was added. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.82 g.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]1[O:22][C:21](=[O:23])[C:20]2([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:19]=1.O>CN(C)C=O>[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]([NH:19][C:20]1([C:21]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]
Reactant: CSCC[C@H](N)CO
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
284 mg (2.1 mmol) of L-methioninol was added to a solution of 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of N,N-dimethylformamide, and the mixture was stirred overnight. Water was slowly added to the mixture and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to give 722 mg (98%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)C>[C:8]([C:7]1[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CCO
Product: N#Cc1cccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
2-Chloro-3-cyanopyridine (5.5 g; 0.04 mole) was dissolved in 80 mL ethanol (warming) and piperazine (17.2 g; 0.2 mole) was combined with this solution and the whole stirred at room temperature for 18 hrs. The reaction mixture was filtered and the filtrate concentrated to a residue which was partitioned between Et2O and H2O. The water layer was made basic and extracted with Et2O. The Et2O extracts were washed with water, dried (MgSO4), concentrated to a solid which was recrystallized from Skellysolve B to yield 3.2 g product, m.p. 102°-104° C.
Reaction SMILES: Cl.[CH3:2][Si:3]1([CH3:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([F:27])[C:19]=1F.O>CCOC(C)=O>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([F:27])[C:19]=1[N:6]1[CH2:7][CH2:8][Si:3]([CH3:9])([CH3:2])[CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C[Si]1(C)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si]1(C)CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
To a solution of 4,4-dimethyl-1,4-azasilinane hydrochloride 4 (950 mg, 7.35 mmol) in EtOAc (15 mL), triethylamine (2.5 mL, 18.37 mmol) is added and stirred at 25° C. for 10 min. The reaction mixture is cooled to 0° C. and 1,2,3-trifluoro-5-nitrobenzene (1.29 g, 7.35 mmol) is added drop wise and allowed to stir at 25° C. for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc (2×10 mL) and the solvent is removed under reduced pressure. The product obtained is purified by column chromatography using hexane-EtOAc mixtures to give the product as a crystalline yellow solid 9a (1.32 g) in 63% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1.CCCCCC>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Cc1ccc(F)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(F)cc1C=O
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A solution of 2-bromo-4-fluorotoluene (16.0 g) in anhydrous tetrahydrofuran was treated dropwise at −78° C. with a 1.6 M solution of butyllithium in hexane (55.5 ml). At the same temperature, the mixture was stirred and treated dropwise with a solution of dimethylformamide (6.8 g) in tetrahydrofuran (20 ml). After being allowed to warm to 0° C., the reaction mixture was combined with ice-water. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5-fluoro-2-methylbenzaldehyde (11.5 g) as an oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=CC([CH:4]2[CH:3]=[CH:2]1)C3.[CH2:11]=[O:12].[NH2:13]C1C=CC=CC=1>O1CCOCC1.C(OCC)C>[O:12]1[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:10][NH:13]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=O
Reactant: Nc1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCNO2
Temperature: 25 °C

Procedure:
33.2 g (0.2 mole) of dicyclopentadiene novolac (hereinafter abbreviated as DCPDNO) and 32.4 g of aqueous formaldehyde (37%, 0.4 mole) were added into a 4-neck reactor equipped with a stirrer, temperature controller, and condenser, and then 100 ml of 1,4-dioxane was added as a solvent. The mixture was stirred at room temperature, and to the resulting solution 18.6 g (0.2 mole) aniline in 30 ml 1,4-dioxane was dripped at a rate of one drop per second while stirring. Upon completion of the dripping the solution was heated and reacted under refluxing for five hours. The reaction mixture was dried in a rotary evaporator under vacuum to obtain a dark brown solid. The dark brown solid was dissolved in ethyl ether and washed with 3N aqueous NaOH three times, followed by 1 N aqueous HCl solution several times and pure water several times, before removing the solvent in vacuo to obtain DCPDNO dihydrobenzoxazine solid. The solid was ground to light brown powder. Softening point (SP) 143° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.P(Cl)(Cl)(Cl)=O.N[C:14]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[C:23]3[C:18](=[CH:19][CH:20]=[C:21](N)[CH:22]=3)[C:17](=[O:30])[C:16]=2[CH:15]=1.[OH-].[Na+].CC#[N:35]>>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[N:35][C:15]1[C:16]2[C:17](=[O:30])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:28])[C:25]=2[CH:26]=[CH:27][CH:14]=1
Reactant: CC#N
Reactant: CN1CCCC1=O
Reactant: Nc1ccc2c(c1)C(=O)c1ccc(N)cc1C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCC1=Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 34.5 g of 1-methyl-2-pyrrolidinone in 150 ml. of CH3CN was added 18.4 g of phosphorous oxychloride at 5°-10° C. The mixture was stirred at room temperature for 1 hour. To the mixture was added 11.9 g of 2,6-diaminoanthraquinone. The resulting mixture was stirred at 60° C. for 10 hours, poured into 1000 ml of ice-water and basified with 5N NaOH. Reddish crystals thus obtained were collected by filtration and washed with water. Recrystallization from methyl cellusolve gave 14.0 g of reddish crystals, mp 267°-269° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][CH3:22])[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[C:39]([SiH:43]([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40].O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][CH3:22])[CH:13]([O:20][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)[C@H](CC)NC(=O)OCc1ccccc1
Reactant: C[SiH](C)C(C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCOC(=O)CC(O[Si](C)(C)C(C)(C)C)[C@H](CC)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxyhexanoate (63.2 g) and 2,6-lutidine (47.6 mL) in tetrahydrofuran (800 mL) was added tert-butyldimethylsilane trifluoromethanesulfonate (70 mL) under ice-cooling and, after warming to room temperature, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate-1/0→1/1) to give ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-(tert-butyldimethylsilyloxy)hexanoate as a colorless oil (yield: 64.0 g, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10])[NH2:5].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]=[C:12]=[O:13])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1c(Cl)cc(N)cc1Br
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(N=C=O)cc1Br
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 3-bromo-5-chloro-4-methoxyaniline (13.0 g) in toluene (100 ml) was dropwise added to a toluene solution containing 20 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-bromo-5-chloro-4-methoxyphenyl isocyanate (14.4 g). The thus obtained crude substance was added to an isopropanol solution (50 ml) containing triethylamine (1 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3-bromo-5-chloro-4-methoxyphenyl)carbamate (Compound No. 33) (16.4 g) in a yield of 92% (calculated from the starting 3-bromo-5-chloro-4-methoxyaniline).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:7][CH:8]([CH2:10][CH3:11])[O:9][C:4]=2[CH:3]=1.CCO[C:22]([CH3:24])=[O:23]>>[CH2:10]([CH:8]1[O:9][C:4]2[C:5](=[CH:17][C:18]3[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:24][C:22](=[O:23])[NH:1][C:2]=3[CH:3]=2)[N:6]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:7]1)[CH3:11]
Reactant: CCC1CN(CC(F)(F)F)c2ccc(N)cc2O1
Reactant: CCOC(C)=O
Product: CCC1CN(CC(F)(F)F)c2cc3c(C(F)(F)F)cc(=O)[nH]c3cc2O1

Procedure:
(±)-7-Amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (Structure 5 of Scheme I, where R6=Et, Rx=CF3). This compound was prepared by General Method 4 (EXAMPLE 1) from (±)-2-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (170 mg, 0.6 mmol) and purified by flash chromatography (CH2Cl2/MeOH, 20:1) to afford 151 mg (99%) of (±)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine. Data for (±)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf 0.62 (3:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.56 (d, 1H, J=8.0), 6.25-6.20 (m, 2H), 3.93 (m, 1H), 3.70-3.64 (m, 3H), 3.43 (br s, 1H), 3.31 (m, 1H), 3.12 (dd, 1H, J=11.9, 8.1), 1.74-1.59 (m, 2H), 1.04 (t, 3H, J=7.5).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>CN(C=O)C.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C:14]1[N:15]=[CH:16][NH:17][C:13]=1/[CH:12]=[C:5]1\[C:6](=[O:11])[NH:7][C:8]2[C:4]\1=[CH:3][C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:10][CH:9]=2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 90 °C

Procedure:
(Z)-5-Bromo-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (0.17 g, 0.56 mmol) (from Example 99) was dissolved in 3 mL DMF and 3 mL triethylamine. The solution was degassed for 30 minutes by bubbling argon through the solution. At this time (trimethylsilyl)acetylene (0.3 mL, 2.1 mmol) (Aldrich), CuI (34 mg) (Aldrich) and (Ph3P)2PdCl2 (34 mg) (Aldrich) were added and the reaction flask sealed. The reaction was heated, under argon, at 90° C. for 18 hours. After cooling, the mixture was filtered through Celite® (Fisher Scientific) and residue washed extensively with hot EtOAc and CH3CN. Combined filtrate and washing was concentrated under reduced pressure and the product was purified via flash column chromatography (SiO2, 230-400 mesh) with 5% MeOH in CH2Cl2. (Yield 0.1 g, 56%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][O:8][C:9]2=[O:10])=[CH:5][CH:4]=1.[OH-].[Ca+2].[OH-].[H][H]>CO.O1CCOCC1.[Pd]>[CH3:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][O:8][C:9]2=[O:10])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: O=C1OCc2ccc(CBr)cc21
Agent: [Pd]
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)OC2
Yield: 96 %

Procedure:
A total of 107 g (472 mmol) of 6-bromomethylphthalide was dissolved in 50 mL of methanol (dioxane was also used in different experiment). The solution was added to a parr bottle with 40 g (540 mmol) of calcium hydroxide and 2 g of 10% Pd/C. The suspension was hydrogenated at 40 psi until no more hydrogen uptake was recorded. All solids were filtered and filtrate was concentrated to a total of 67 g of brown solid in 96% yield. 1H NMR (CDCl3) (300 MHz) δ 2.53 (s, 3H), 5.30 (s, 2H), 7.49 (s 1H), 7.54 (d, 3JHCCH=7.9 Hz, 1H), 7.47 (d, 3JHCCH=7.9 Hz, 1H)