Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH3:22])[CH:20]=O)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:9][C:10]1[C:11](=[O:12])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:19]([CH3:22])[CH:20]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C=O)c1ccccc1C(=O)COC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(OC(=O)c2ccccc2)c(=O)c2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 2-[2-(N-methylformamido)phenyl]-2oxoethyl benzoate (84 g), potassium carbonate (39.2 g) and dry dimethylformamide (1100 ml) was stirred at 50 to 60° for 4 hours. The solvent was removed under reduced pressure at 60° and the residue was triturated with water (700 ml). The resultant solid was collected by filtration and washed with water (4×250 ml) followed by diethyl ether (250 ml) to give the novel compound 1-methyl-4-oxo-1,4-dihydroquinol-3-yl benzoate, m.p.2)5-21 7°.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=[O:29])=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[S:33]([C:37]1[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=1)(=[O:36])(=[O:35])[NH2:34]>>[S:33]([C:37]1[CH:38]=[C:39]([NH:43][C:28]([C:27]2[CH:26]=[N:25][N:18]3[C:19]([C:21]([F:22])([F:24])[F:23])=[CH:20][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:32])([F:31])[F:1])[CH:6]=4)=[N:16][C:17]=23)=[O:29])[CH:40]=[CH:41][CH:42]=1)(=[O:35])(=[O:36])[NH2:34]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 626.1 [(M−H)−]; mp 233° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](O)=[O:27])=[CH:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:26]([C:19]4[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[NH:17][CH:18]=4)=[O:27])[CH2:14][CH2:15]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccc(Br)cc2C12CCNCC2
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: O=C(c1c[nH]c2ccccc12)N1CCC2(CC1)C(=O)Nc1ccc(Br)cc12

Procedure:
Following the general procedure I as described above, the acylation of 5-bromospiro[indole-3,4′-piperidin]-2(1H)-one with 1H-indole-3-carboxylic acid (commercially available), gave the title compound. ES-MS m/e (%): 424.3(M+H+).
Reaction SMILES: C([O:4][CH:5]([CH3:29])[CH2:6][C:7]([CH2:18][P:19]([O:25]C(C)C)([O:21]C(C)C)=[O:20])=[CH:8][CH:9]([NH:15]C=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)C.C[Si](C)(C)Br>C(O)C>[NH2:15][CH:9]([CH:8]=[C:7]([CH2:18][P:19]([OH:25])([OH:21])=[O:20])[CH2:6][CH:5]([OH:4])[CH3:29])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C=C(CC(C)OC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CC(C)O)CP(=O)(O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
11.5 g (26.4 mmol) of ethyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate are dissolved in 70 ml of abs. CH2C12 and to this solution are added 13.7 ml (105.6 mmol) of trimethylbromosilane. The reaction mixture is allowed to stand for 24 hours at room temperature and, after addition of 70 ml of abs. ethanol, allowed to stand again for 24 hours. The reaction mixture is concentrated by evaporation and the residue is dissolved in 70 ml of ethanol. A mixture of 70 ml of propylene oxide and 70 ml of ethanol is then added dropwise. The white suspension so obtained is stirred for 30 minutes at room temperature and for 30 minutes at 0° C. and then filtered with suction. The filter product is dried giving white crystals of ethyl 2-amino-6-hydroxy-4-phosphonomethyl-hept-3-enoate with a melting point of 211°-212° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:16]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)Nc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
The present example sets forth a method whereby the benzthiozole compounds may be obtained. However, other methods may be used in the practice of the present invention. A solution of 4.5 g of 2-aminobenzthiazole in 40 mL of dichloromethane and 10 mL of pyridine was cooled in an ice bath. To this cooled solution was slowly added a solution of 2-methoxybenzoyl chloride in 10 mL of dichloromethane. The resulting mixture was stirred for 3 hours while the ice bath slowly warmed to room temperature. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with 1 N HCl (2×50 mL), saturated NaHCO3 (1×40 mL), and saturated NaCl (1×50 mL). After drying over Na2SO4, the solution containing the crude product was filtered and evaporated to dryness. The resulting 8.0 g of white solid was recrystalized from ethyl acetate to afford 4.0 g of 2-(2 methoxybenzoylamino)benzthiazole as white crystals, mp 196-197° C., as first crop.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:37])[CH2:11][NH:12][C:13]2[N:18]([CH3:19])[C:17](=[O:20])[C:16]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[C:15]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:14]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.[2H]C([2H])([2H])C#N.[2H]O[2H]>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:37])[CH2:11][NH:12][C:13]2[N:18]([CH3:19])[C:17](=[O:20])[C:16]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[C:15]([C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)CNc2nc(-c3ccncc3)c(-c3ccc4ccccc4c3)c(=O)n2C)cc1
Agent: BrB(Br)Br
Agent: [2H]C([2H])([2H])C#N
Agent: [2H]O[2H]
Solvent: ClCCl
Product: Cn1c(NCC(=O)Cc2ccc(O)cc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a chilled (0° C.) stirring solution of 2-[3-(4-methoxy-phenyl)-2-oxo-propylamino]-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (250 mg, 0.21 mmol ) in 20 mL dichloromethane under an atmosphere of nitrogen was added boron tribromide (39 μL, 0.42 mmol) in 0.4 mL of dichloromethane. The resulting precipitate was stirred for 18 h warming to room temperature. The solvent was removed under reduced pressure, then the product was dissolved in 4 mL methanol. The product was purified on on reverse phase high performance chromatography eluting with a water/acetonitrile (0.1% TFA) gradient. The final product was lyophilized from 50% acetonitrile/water to give a yellow powder. M+1=477.2 NMR (CD3CN/D2O 3:1) s (3H, 3.40 ppm), s (2H, 3.60 ppm), s (2H, 4.25 ppm), d (2H, 6.51 ppm), d (2H, 6.95 ppm), d (1H, 7.22 ppm), m (3H, 7.4-7.5 ppm), d (2H, 7.5 ppm), d (1H, 7.72 ppm), d (1H, 7.78), d (2H, 8.30 ppm).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([S:13][CH3:14])[N:7]=1>C1COCC1>[CH:1]([NH:4][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([S:13][CH3:14])[N:7]=1)([CH3:3])[CH3:2]
Reactant: CSc1nc(C)cc(Cl)n1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CSc1nc(C)cc(NC(C)C)n1
Reaction time: 8 h

Procedure:
Isopropylamine (100 mL) was added very slowly to 22.0 g (125.96 mmol) of crude 4-chloro-6-methyl-2-(methylthio)pyrimidine in 70 mL of THF in a 350 mL pressure tube. NOTE: Residual POCl3 caused smoking and bubbling, therefore the addition was done at 0° C. Once acid was quenched, an additional 50 mL of isopropylamine was added and the pressure tube was sealed. The reaction vessel was brought to 60° C. and stirred overnight. The LCMS indicate very little starting material. Solvent was evaporated leaving N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine as a viscous yellow oil. The crude material was taken directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br.ClCCl>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: BrCCCCBr
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCCC2)nc1

Procedure:
4.95 g (28.6 mmol) of 2-amino-5-bromopyridine was dissolved in 40 ml of toluene. 9.95 ml (57.2 mmol) of diisopropylethylamine, 6.15 g (28.6 mmol) of 1,4-dibromobutane and 100 mg (0.82 mmol) of 4-(dimethylamino)pyridine were added to the solution, and they were stirred for three nights. After the treatment with dichloromethane as the extractant in an ordinary manner, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:7]=[CH2:8])[CH:2]([CH3:4])[CH3:3].C(NC(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([N:5]([C@H:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH2:8])[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: C=C[C@H](NCC(C)C)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: C=C[C@@H](c1ccccc1)N(CC(C)C)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of (1S)-N-isobutyl-1-phenylprop-2-en-1-amine (9a) (25 mg) and diisopropylamine (19 mg) in DCM (2.5 ml) at RT under N2 was added benzoyl chloride (21 mg). This mixture was stirred for 1 h. The reaction was evaporated and purified by flash chromatography (2% EtOAc/hexane) to afford the title compound (15 mg, 44%) as a pale oil. 1H NMR (300 MHz, CDCl3) δ 0.70 (d, 6H, J=6.6 Hz), 0.81 (bs, 3H), 1.75 (bs, 1H), 2.99-3.06 (m, 1H), 3.25-3.32 (m, 1H), 5.20-5.28 (m, 1H), 5.41 (d, 1H, J=9 Hz), 6.16 (bs, 1H), 7.25-7.46 (m, 5H). MS APCI, m/z=294 (M+1), LC/MS, 2.78 min. Chiral SFC was used to determine ee % by comparing this sample to a known sample of the racemic compound N-isobutyl-N-[(1-phenylprop-2-en-1-yl]benzamide 2.128 min (2.92%) and 2.639 min (97.07%) or 94% ee. Chiral SFC method: 5 μm Chiralpak AS-H column 4.6 mm×250 mm. Isocratic method 10% MeOH in carbon dioxide @ 2.20 ml/mn over 4 minutes.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[N:18]=[C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O>CN(C)C=O>[Br:33][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2nc(-c3ccccn3)cc(-c3c4ccccc4cc4ccccc34)n2)cc1
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2cc(-c3ccccn3)nc(-c3ccccc3)n2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Dissolving 12 g (30 mmol) of 4-anthracen-9-yl-2-phenyl-6-pyridine-2-yl-pyrimidine obtained in the foregoing step (2) into 100 milliliter of N,N-dimethylformamide, and adding 5.9 g (33 mmol) of N-bromosuccinimide, stirred at room temperature for 8 hours. After completion of the reaction, precipitated solids were separated by filtration and washed with water and methanol, thereby obtaining 10.8 g of 4-(10-bromo-anthracen-9-yl)-2-phenyl-6-pyridine-2-yl-pyrimidine (yield: 73%).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=O>C(Cl)Cl>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: O=Cc1ccccn1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccccn1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of methyl triphenylphosphoranylideneacetate (31.2 g) in CH2Cl2 (120 mL) was added dropwise over 15 minutes 2-pyridine carboxaldehyde (8.9 mL, 0.093 mol) in CH2Cl2 (40 mL). The mixture was heated to reflux for 8 hours, additional ylide (3.1 g) was added and the mixture was refluxed overnight. The reaction mixture was cooled, concentrated to 1/2 value and allowed to stand for 2 hours. A solid was collected by filtration and was washed with CH2Cl2 /hexane. The filtrate was concentrated in vacuo and the residue was vacuum distilled at 80°-107° C. and 1.5 mm Hg to afford 12.2 g (80%) of methyl 3-(2-pyridyl)-2-propenoate.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:29])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:29])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccncc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccncc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of 4-{cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methoxy}benzoic acid (137 mg), ethyl 3-(methylamino)propanoate (52 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg), hydroxybenzotriazole monohydrate (61 mg) and triethylamine (56 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL), 1N sodium hydroxide (0.6 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (130 mg, 84%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].C1(P(=[CH:30][CH:31]=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:30][CH:31]=[O:32])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc(C=O)c1
Solvent: ClCCl
Product: N#Cc1cccc(C=CC=O)c1
Yield: 91.8 %

Procedure:
A mixture of 3-cyanobenzaldehyde (2.0 g) and (triphenylphosphoranylidene) acetaldehyde (5.0 g) in 100 mL CH2Cl2 was stirred at reflux for 16 hours. The reaction was cooled, concentrated and purified on silica gel column (ethyl acetate/hexane=3/7) to afford 2.2 g of 3-cyano-1-(2-formylethenyl)benzene as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].Cl[CH2:10][C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13].Cl.C(N(CC)CC)C>ClCCl.C(N(CC)CC)C>[CH3:10][C:11]1([CH3:16])[CH2:15][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:8][C:12]1=[O:13]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: NNc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CN(c2ccccn2)NC1=O
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
2-Pyridylhydrazine (10.9 g) in dichloromethane (120 ml) and dry triethylamine (28 ml) were chilled in an ice bath. -β-chloropivaloyl chloride (15.5 g) in dichloromethane (20 ml) was added dropwise with stirring for 15 minutes and the mixture was refluxed for 3 hours. When cool the triethylamine hydrochloride was filtered off and the filtrate evaporated to dryness and rinsed four times with the minimum quantity of ether to give the title compound (13.6 g) after recrystallisation from cyclohexane mp 141°-144°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.[Br:14][C:15]1[CH:28]=[CH:27][C:18](/[CH:19]=[N:20]/[S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[CH:17][CH:16]=1>C1COCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C@H:19]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[CH:27][CH:28]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The solution of 1-bromo-4-fluorobenzene (66.7 g, 0.38 mol) in THF (400 mL) was cooled to −78° C. Then n-BuLi (140 mL, 0.38 mol) was dropwise added at −78° C. and maintained at this temperature for about 1 h. (S,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide, 19-a, (70 g, 0.19 mol) in anhydrous THF (100 ml) was also dropwise added at −78° C. The mixture was stirred at −78° C. for 1 h, warmed to rt for 2 h, and then quenched by NH4Cl aq. The organic phase was dried and purified by column chromatography (PE:EA=10:1) afford the product 19-b as a light yellow solid, recrystallized by PE:EA=20:1 to give the white solid, (26 g, 35%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)ccc1F

Procedure:
The obtained 2-fluoro-5-hydroxybenzoic acid (3e) (780 mg, 5 mmol) was dissolved in 100 mL methanol. Thionyl chloride (0.8 mL, 10 mmol) was added dropwise under the condition of ice bath (0° C.) and stirring, and then refluxed for two hours. The reaction solution was concentrated, and then column chromatography (petroleum ether:ethyl acetate=2:1) was performed to isolate methyl 2-fluoro-5-hydroxybenzoate (3f), 833 mg white solid (yield 98%). 1H NMR (600 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.20-7.18 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.97 (m, 1H), 3.80 (s, 3H); ESI-MS m/z: calculated for 170.04. found 171.25 [M+H]+.
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: C[C@@H](CCl)COc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 4-bromophenyl (2R)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[NH:8][C:7](=[O:13])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=1)([CH3:14])[C:5]2=[O:26]>C(O)(=O)C>[NH2:23][C:17]1[CH:16]=[C:15]([C:6]2([CH3:14])[C:5](=[O:26])[C:4]3[C:9](=[C:10]([Br:12])[CH:11]=[C:2]([Br:1])[CH:3]=3)[NH:8][C:7]2=[O:13])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(C2(C)C(=O)Nc3c(Br)cc(Br)cc3C2=O)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(C2(C)C(=O)Nc3c(Br)cc(Br)cc3C2=O)cc1N
Yield: 42.5 %

Procedure:
A solution of 6,8-dibromo-3-(4-methoxy-3-nitro-phenyl)-3-methyl-1H-quinoline-2,4-dione (0.14 g, 0.29 mmol) in acetic acid (5.0 mL) was treated with SnCl2-2H2O (0.26 g, 1.16 mmol) for 4 hours at room temperature. After the reaction was completed, yellow residue was obtained by evaporating solvent under reduced pressure. The residue was diluted with 1N HCl solution (200 mL), and was extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with brine (200 mL×2) and water (200 mL×2) and dried over anhydrous MgSO4. After evaporation of the solvent, the pure objective compound (56 mg, 42%) was obtained as yellow solid by a flash column chromatography (n-hexane:EtOAc=2:1): 1H NMR (200 MHz, CDCl3) δ 1.73 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 4.11 (br s, 2H, NH2), 6.44-6.58 (m, 2H, ArH), 6.65 (d, J=8.6 Hz, 1H, ArH), 7.77 (d, J=2.2 Hz, 1H, ArH) ; HRMS m/e cacld. for C17H14N2O3Br2 451.9371, found 451.9385.
Reaction SMILES: C([NH:4][C:5]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:8]2[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:21])[CH2:10][C:11]([CH3:14])([CH3:13])[O:12][C:7]=2[CH:6]=1)(=O)C.Cl.C(=O)([O-])O.[Na+]>C(O)C>[NH2:4][C:5]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:8]2[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:21])[CH2:10][C:11]([CH3:13])([CH3:14])[O:12][C:7]=2[CH:6]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(c1cccc[n+]1[O-])CC(C)(C)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CN(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])c(N)cc2O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
In 6 ml of ethanol was suspended 0.50 g of 2-(7-acetamido-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine-N-oxide followed by addition of 6 ml of 5 N hydrochloric acid, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was poured into ice-water, neutralized with excess sodium hydrogen carbonate, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The-resulting residue was recrystallized from ethanol to give 359 mg of 2-(7-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]([NH2:19])=O)[CH:14]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]1([CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH2:19])[CH:14]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccc2c(c1)CN(Cc1ccccc1)C2
Yield: 74 %

Procedure:
Prepared analogously to Example 45b) from 2,3-dihydro-2-(phenylmethyl)-1H-isoindole-5-carboxamide by reduction with lithium aluminium hydride. The desired compound was obtained as a colourless oil in a yield of 74% of theory.