Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].C(O)CCC>C(Cl)Cl>[Cl:1][CH2:2][C@@H:3]([OH:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6]
Reactant: CCCCOC(=O)CC(=O)CCl
Solvent: CCCCO
Solvent: ClCCl
Product: CCCCOC(=O)C[C@H](O)CCl
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
In a 100 ml Hastelloy-made autoclave having been purged with nitrogen were charged 38.8 g (0.2 mol) of n-butyl 4-chloroacetoacetate and 50 ml of n-butyl alcohol, and solution of 73 mg of Ru2Cl2 [(R)-(+)-BINAP]2Et3N in 2 ml of methylene chloride was added thereto. The mixture was stirred at 100° C. under a hydrogen pressure of 11 to 12 kg/cm2 for 2 hours to conduct hydrogenation. The solvent was evaporated, and the residue was distilled under reduced pressure to give 35.0 g (percent yield: 90%) of n-butyl (S)-(-)-4-chloro-3-hydroxybutyrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:16][N:15]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:33][CH:34]([Cl:38])[C:35](Cl)=[O:36]>ClCCl>[Cl:33][CH:34]([Cl:38])[C:35]([N:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:19]=1)[CH2:21][O:22][CH:23]([CH3:25])[CH3:24])=[O:36]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)OCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-(2,6-Dichlorophenyl)isoxazol-5-yl)-N-(isopropoxymethyl)pyridin-4-amine (269 mg, 0.58 mmol) was dissolved in anhydrous dichloromethane with triethylamine (100 μL, 0.70 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (70 μL, 0.70 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 99:1 dichloromethane:methanol to yield 2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)-N-(isopropoxymethyl)acetamide (Cpd. No. 4). 1H NMR (CDCl3): 8.81 (d, 1H), 8.02 (s, 1H), 7.51-7.32 (m, 3H), 7.12 (s, 1H), 6.23 (s, 1H), 5.21 (s, 2H), 6.00 (s, 1H), 3.90 (m, 1H), 3.10 ppm (m, 6H). MW=489 confirmed by LC-MS, tr=14.57 min (Method Y) MH+=487-491.
Reaction SMILES: [CH2:1]([P:7](=[O:10])([OH:9])[OH:8])[CH2:2][P:3](=[O:6])([OH:5])[OH:4].C(Cl)(=O)C(Cl)=O.[F:17][C:18]1([F:34])[C@H:22]([OH:23])[C@@H:21]([CH2:24]O)[O:20][C@H:19]1[N:26]1[CH:33]=[CH:32][C:30]([NH2:31])=[N:29][C:27]1=[O:28]>CN(C=O)C>[CH2:1]([P:7]([O:9][CH2:24][C@H:21]1[O:20][C@@H:19]([N:26]2[CH:33]=[CH:32][C:30]([NH2:31])=[N:29][C:27]2=[O:28])[C:18]([F:17])([F:34])[C@@H:22]1[OH:23])(=[O:8])[OH:10])[CH2:2][P:3](=[O:5])([OH:4])[OH:6]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: O=P(O)(O)CCP(=O)(O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)CCP(=O)(O)O)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.9 %

Procedure:
Ethylenediphosphonic acid (173 mg, 0.91 mmol) was treated with oxalyl chloride (2 mL, as solvent) and anhydrous DMF (0.1 ml, cat.). After heating at reflux for 10 minutes under argon, a solution was obtained and after a further 3 h the reaction mixture was cooled to room temperature and evacuated in vacuo. The residue was co-evaporated with anhydrous acetonitrile (3×10 ml). The residue was dissolved in anhydrous trimethyl phosphate (2 mL), cooled to −15° C. and 2′deoxy-2′,2′-difluorocytidine (93 mg, 0.46 mmol) was added under argon. After stirring for 2 h the reaction mixture was quenched with ice-cold TEAB solution (1.0 M, mL) and stirred for 30 minutes. Purification by HPLC gave 7.8 mg of the titled compound 81.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:14])=[CH:6][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)=Cc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)=Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-(2-methylprop-1-en-1-yl)benzyl alcohol (0.60 g) and carbon tetrabromide (1.2 g) in dichloromethane (12 mL) was added triphenylphosphine (0.97 g) at 0° C., and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane) to give 4-(2-methylprop-1-en-1-yl)benzyl bromide. To a solution of methyl acetoacetate (0.44 mL) in tetrahydrofuran (17 mL) was added sodium hydride (60%, 0.18 g) at 0° C., and the mixture was stirred for 10 minutes. To the reaction mixture was added a solution of 4-(2-methylprop-1-en-1-yl)benzyl bromide in tetrahydrofuran (3 mL), and the mixture was heated under reflux for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in toluene (8 mL). To the solution was added hydrazine monohydrate (0.54 mL), and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to 0° C., and the resulting precipitates were collected by filtration, washed with water and hexane, and dried under reduced pressure to give 5-methyl-4-{[4-(2-methylprop-1-en-1-yl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-pyrazol-3-one (0.31 g).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH3:21][C@H:22]([C@H:26]([CH3:30])[CH2:27][CH2:28][CH3:29])C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C@H:22]([CH3:21])[C@H:26]([CH3:30])[CH2:27][CH2:28][CH3:29])[CH3:9]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a solution containing 1.0 g (6.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 10 mL of dichloromethane was added 1.1 g of chloromethylene dimethyl-ammonium chloride (8.3 mmol). The resulting solution was stirred under nitrogen for 1.5 hours. The solvent was subsequently evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. To a solution containing 2.5 g (14.6 mmol) of potassium monoethyl malonate in 50 mL of acetonitrile was added 1.7 g (17.3 mmol) of magnesium chloride and 1.2 g (11.4 mmol) of triethylamine. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction was cooled to 0° C. and a solution of the (2R,3R)-2,3-dimethyl-hexanoyl chloride in acetonitrile (20 mL) was slowly added followed by the addition of triethylamine (0.4 g, 0.4 mmol). The reaction was heated to 40° C. and stirred at that temperature for 6 hours. The reaction mixture was cooled to 25° C., quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 1.3 g (87.8% yield) of the titled compound as an oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:17][C@@H:18]([C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1)[CH3:19]>>[OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12]([NH:17][C@@H:18]([C:20]1[CH:21]=[C:22]([N:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:30][CH2:31]3)[CH:23]=[CH:24][CH:25]=1)[CH3:19])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[C@@H](N)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: Cn1c(=O)c(O)c(C(=O)Cl)c2ccccc21
Product: C[C@@H](NC(=O)c1c(O)c(=O)n(C)c2ccccc12)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 25 %

Procedure:
Following the same procedure as described for Example 3, Example 204 (12 mg, 0.022 mmol, 25% yield) was prepared as an off-white powder by using 3-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl chloride and (R)-benzyl 4-(3-(1-aminoethyl)phenyl)piperazine-1-carboxylate (Intermediate 33). LC-MS (ESI) m/z 541 (M+H), RT=1.64 min (Method C). Orthogonal HPLC (150×4.6 mm 3.5 μm, 254 nm): Sunfire {RT=8.9 min, 95%}; Xbridge {RT=8.5 min, 93%}. 1H NMR (500 MHz, MeOD) δ ppm 7.55 (1 H, d, J=7.7 Hz), 7.46-7.50 (2 H, m), 7.36-7.41 (4 H, m), 7.30-7.34 (3 H, m), 7.26 (1 H, s), 7.22-7.24 (1 H, m), 7.13 (1 H, d, J=7.7 Hz), 7.03 (1 H, dd, J=8.1, 2.1 Hz), 5.28 (1 H, d, J=7.2 Hz), 5.17 (2 H, s), 3.82 (3H, s), 3.71 (4 H, d, J=3.6 Hz), 3.29 (4 H, d, J=5.5 Hz), 1.55 (3 H, d, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[CH:29]=O.C([O-])(=O)C.[NH4+].[N+:36]([CH3:39])([O-:38])=[O:37]>>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1/[CH:29]=[CH:39]/[N+:36]([O-:38])=[O:37]
Reactant: C[N+](=O)[O-]
Reactant: Nc1c(C=O)cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Nc1c(/C=C/[N+](=O)[O-])cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 5-amino-1-(2-triphenylmethyloxyethyl)-1H-pyrazole-4-carbaldehyde (15 g) and ammonium acetate (4.07 g) in nitromethane (300 ml) was refluxed for 6.5 hours. The reaction mixture was evaporated under reduced pressure and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give 5-amino-4—[(E)-2-nitroethenyl]-1-(2-triphenylmethyloxyethyl)-1H-pyrazole (4.46 g). 1H-NMR(DMSO-d6) δ3.15 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 6.96 (2H, s), 7.1–7.3 (15H, m), 7.75 (1H, d, J=12.9 Hz), 7.83 (1H, s), 8.27 (1H, d, J=12.9 Hz)
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([NH:33][CH2:32][CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCCC1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(C(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(C(=O)NCCC3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid and 2-(tetrahydro-2H-pyran-4-yl)ethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[OH:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CN1CCCC1=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:11][CH2:10][CH2:9][O:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1ccccc1COCCBr
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCCOCc1ccccc1F
Temperature: 0 °C
Reaction time: 5 h

Procedure:
108 ml of triethylamine were added dropwise to a mixture of 165 g (0.71 mol) of 1-bromo-2-(2-fluorobenzyloxy)-ethane, 116 g (0.7 mol) of N-hydroxylphthalimide and 710 ml of N-methyl-2-pyrrolidinone at from 20° to 25° C. in the course of 1 hour. After 5 hours at 60° C., the cold reaction mixture was poured into 200 ml of ice water and the precipitate was filtered off under suction, washed with water and isopropanol and dried under reduced pressure over phosphorus pentoxide.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 499.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[ClH:12].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: ClCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
To a toluene (20.0 mL) solution of (5-bromo-pyridin-2-yl)-methanol (4.70 g, 25.0 mmol) described in Manufacturing Example 54-1-1 was added dropwise thionyl chloride (3.65 mL, 50.1 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 5 minutes at room temperature. The solvent was evaporated under a reduced pressure to obtain the title compound (4.2 g, 69.2%) as a hydrochloride.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23].[Cl-].[NH4+]>O.C1COCC1>[F:20][C:21]([F:28])([F:27])[C:22](=[O:23])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: C#Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(C#Cc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Phenylacetylene (10.8 mL, 0.098 mole) was added into a 3-Neck round bottom flask under an atmosphere of Nitrogen. THF (100 mL) was added and the reaction was stirred and cooled to 0° C. 2.5 M n-butyllithium in hexane (36 mL, 0.089 mole) was added via syringe at 0° C. over 30 min. The reaction was stirred at 0° C. for 30 minutes. Ethyl trifluoroacetate (5.31 mL, 0.045 mole) was added via syringe at −60 to −50° C. over 10 minutes. The reaction was stirred at −70° C. for 1 h. Ammonium chloride 28% w/w in water (60 mL) was added and the mixture was extracted with Ether (2×50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo, and then allowed to stand under high vacuum for 2 h to afford an orange oil. The oil was chromatographed on silica gel with 2:1 hexanes, methylene chloride to afford the title compound as a yellow oil; 1H NMR (CDCl3, 400 MHz) δ 7.44-7.48 (tt, 2H), 7.55-7.60 (tt, 1H), 7.67-7.70 (m, 2H); 19F NMR (CDCl3, 400 MHz) δ 77.54 (s).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)=[CH:6][C:5]2[O:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[C:3]1=[O:25].[CH3:26][NH:27][CH3:28]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:27]([CH3:28])[CH3:26])=[CH:10][CH:9]=2)=[CH:6][C:5]2[O:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[C:3]1=[O:25]
Reactant: CNC
Reactant: Cn1c(-c2ccc(CBr)cc2)cc2onc(-c3ccccc3)c2c1=O
Solvent: Cc1ccccc1
Product: CN(C)Cc1ccc(-c2cc3onc(-c4ccccc4)c3c(=O)n2C)cc1

Procedure:
A mixture of 21.2 g. of the product of Example 4, containing 62% of 5-methyl-3-phenyl-6-(p-bromomethylphenyl)-isoxazolo[4,5-c]pyridin-4(5H)-one 0.0332 mole of bromo compound) and 7.2 g. (0.160 mole) dimethylamine in 300 ml. toluene is stirred overnight at room temperature. The mixture is filtered and the solid washed with toluene and the solvent evaporated in vacuo. The resulting solid is dissolved in methylene chloride and treated with 2N hydrochloric acid, the precipitate is then filtered, washed with water and ether. The solid is then dissolved in methylene chloride and 2N sodium dioxide and the organic phases separated and washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 5-methyl-3-phenyl-6-(p-[dimethylaminomethyl]phenyl)-isoxazolo[4,5-c]pyridin-4(5H)-one; m.p. 159°-161° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=[N:34][NH2:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)C(C)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:35][N:34]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CCCN(Cc3ccccc3)C2)cc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)CO
Product: c1ccc(CN2CCCC(c3ccc(NN=C(c4ccccc4)c4ccccc4)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
A mixture of (F1), benzophenone hydrazone (1.8 eq.), ground NaOH (1.4 eq.), Pd(AcO)2 (0.05 eq.) and XPhos (0.1 eq.) in degassed iBuOH (0.18 M) was stirred under argon at RT for 20 min and then was heated at 80° C. for 3 h. After cooling down, evaporation of the solvent gave a residue that was dissolved in DCM and washed with sat. aq. NH4Cl (2×) and sat. aq. NaHCO3 (2×) and dried (Na2SO4). Evaporation of the solvent gave a crude that was purified by flash chromatography column on silica (EtOAc/Petroleum ether 2:98 to 1:4) yielding (90%) the title compound as a yellow foam. 1H NMR (300 MHz, DMSO-d6, 300K) δ 8.68 (1H, s), 7.67-7.49 (3H, m), 7.46-7.39 (2H, m), 7.37-7.25 (10H, m), 7.13 (2H, d, J=8.3 Hz), 7.04 (2H, d, J=8.3 Hz), 3.47 (2H, s), 2.92-2.75 (2H, m), 2.70-2.56 (1H, m), 2.06-1.86 (2H, m), 1.83-1.50 (3H, m), 1.48-1.32 (1H, m). MS (ES+) C31H31N3 required: 445, found: 446 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>>[OH:30][C@:26]([C:23]1[N:22]=[C:21]([CH3:20])[O:25][N:24]=1)([CH3:27])[C:28]#[C:29][C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: NC(=O)c1nc2c(s1)C1CC(C1)c1ccc(Br)cc1-2
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2C2CC3C2)no1
Yield: 14 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-5,6-dihydro-4H-4,6-methanobenzo[6,7]cyclohepta[1,2-d]thiazole-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid (5.2 mg, 14%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)=[O:8])[CH3:2].Cl.[NH2:19]O>CO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[O:8][N:19]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)on1

Procedure:
A solution of the title compound of Example 3.1 (3.00 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol) in methanol (60 mL) was heated at 80° C. for 4 hours. After cooling, the mixture was filtered and washed with cold methanol to afford the title compound in mixture with the methyl ester analog (2.0 g, 71%, white solid).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[Cl-].[CH2:12]([NH2+:16]CCCC)[CH2:13]CC.[N+:21]([CH2:24][CH2:25][OH:26])([O-:23])=[O:22].[BH3-]C#N.[Na+]>C(OCCCCC)(=O)C.O>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][CH2:13][CH:12]([NH2:16])[CH2:7]2.[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:26][CH2:25][CH:24]([N+:21]([O-:23])=[O:22])[CH2:7]2
Reactant: O=Cc1cc(Br)ccc1O
Reactant: O=[N+]([O-])CCO
Reactant: CCCC[NH2+]CCCC
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCOC(C)=O
Product: NC1COc2ccc(Br)cc2C1
Product: O=[N+]([O-])C1COc2ccc(Br)cc2C1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
6-Bromo-chroman-3-ylamine was prepared according to the literature procedure described by Andersson, B. R. et al. WO9012795. Thus, a mixture of 5-bromosalicylaldehyde (9.5 g, 47 mmol), di-n-butylammonium chloride (3.8 g, 23 mmol), and 2-nitroethanol (6.8 g, 75 mmol) in amyl acetate (60 mL) was heated at reflux for 3 hours with a Dean-Stark apparatus under nitrogen atmosphere. The solvent was removed in vacuo and the product was dissolved in CH2Cl2 (280 mL) followed by the addition of NaCNBH3 (9.6 g, 150 mmol). The mixture was stirred for 30 minutes and water (100 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed on silica gel by eluting with 1:1 hexane/CH2Cl2 to give 4.4 g (40%) of pure 6-bromo-3-nitro-chroman as a light yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.18 (m, 2H), 6.68 (d, J=8.4 Hz, 1H), 4.88 (m, 1H), 4.62 (m, 1H), 4.32 (m, 1H), 4.47 (m, 1H), 3.28 (dd, J=17.4, 6.0 Hz, 1H).