Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([CH:7]([CH:14]=[CH2:15])[CH2:8][C:9]([O:11]CC)=O)#[N:6].O>C(OCC)C>[CH:14]([CH:7]1[C:5]2([CH2:2][CH2:1]2)[NH:6][C:9](=[O:11])[CH2:8]1)=[CH2:15]
Reactant: C=CC(C#N)CC(=O)OCC
Reactant: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: C=CC1CC(=O)NC12CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl magnesium bromide (3.0 M in ether, 2.2 mL, 6.6 mmol) was added dropwise over a period of 1 hour to a solution of ethyl 3-cyanopent-4-enoate (500 mg, 3.27 mmol) and Ti(Oi-Pr)4 (1.1 mL, 3.6 mmol) in diethylether (16.4 mL) at room temperature. The reaction mixture was diluted by the dropwise addition of water (3.27 mL) and stirred at room temperature for an additional 30 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether, Rf=0.3) to afford 7-ethenyl-4-azaspiro[2.4]heptan-5-one as a white solid. MS ESI calc'd. for C8H12NO [M+H]+ 138. found 138. 1H NMR (400 MHz, CDCl3) δ 6.09 (br s, 1H), 5.68-5.60 (m, 1H), 5.08-5.00 (m, 2H), 3.01-2.96 (m, 1H), 2.70-2.64 (m, 1H), 2.40-2.36 (m, 1H), 0.83-0.75 (m, 2H), 0.65-0.58 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.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.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13]([C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 53.4 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (77 mg, 0.16 mmol), 3-tributylstannanyl-pyridine (0.075 mL, 0.23 mmol) and PdCl2(PPh3)2 (22 mg, 0.031 mmol) in 4 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH) to give 42 mg of the title compound as a yellow oil. MS: (+) m/z 492.56 (M+1).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)(O)O>C(OCC)C.O1CCCC1>[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[CH2:3][CH:2]=[CH2:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CCCCCCCCCCc1ccccc1
Reactant: C=CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)CCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a cooled solution of 1M allyl magnesium bromide in diethyl ether was added dropwise, under nitrogen, a solution of 18.2 g of 10-phenyldecanal (prepared as in Step 1) in 200 ml of dry tetrahydrofuran. The reaction mixture was stirred at about 5° for 15 minutes, at room temperature for 1 hour, and then at reflux for 15 minutes. The reaction mixture was cooled to room temperature and poured into a mixture of 400 g of ice and 40 ml of 9M sulfuric acid. Upon standing the mixture separated into aqueous and organic layers. The organic layer was stirred for 15 min with solid sodium bicarbonate and then concentrated. The aqueous layer was extracted with diethyl ether (2×200 ml) and the extracts were combined with the concentrated organic layer. The combined organics were washed with water (300 ml) and a half-saturated aqueous solution of sodium chloride (300 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. High pressure liquid chromatography of the oil using 10% diethyl ether/hexane as the eluent gave 6.98 g (30%) of 13-phenyl-1-tridecen-4-ol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24]C)=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[C:9]([CH3:26])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.C[C@H](NC)[C@H](O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[C:9]([CH3:26])[CH:10]=[CH:11][CH:12]=3)=[CH:27][CH:28]=1
Reactant: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(C)cccc21
Agent: CN[C@@H](C)[C@H](O)c1ccccc1
Product: COC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(C)cccc21

Procedure:
Following the method of Example 18, but using ethyl ester from Example 11 in Step I and using 1(-)ephedrine in Step II, there is obtained the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:1]([NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCN
Solvent: ClCCl
Product: C=CCNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
In a round bottom flask with a stir bar, a solution of allyl amine (10 mL, 133.6 mmol) in dichloromethane (350 mL) was cooled to 0° C. A solution of benzoyl chloride (17.05 mL, 147.0 mmol) in dichloromethane (20 mL) was added dropwise via addition funnel. Once the addition was complete, the solution was stirred at 0° C. for 2 h. The solution was concentrated and the residue was purified on silica gel chromatography (Combiflash. Rf system, 330 g RediSep cartridge) using EtOAc/hexanes as a mobile phase. The desired fractions were collected and concentrated to afford N-allylbenzamide (19.6 g, 91%) as a yellow oil. N-allylbenzamide (1.0 g, 6.21 mmol) was dissolved in dichloromethane (60 mL) and cooled to −78° C. A Tygon tube connected to an ozone generator was fitted with a gas dispersion tube and a stream of ozone was bubbled through the solution at −78° C. Once a pale blue color persisted in the solution, the ozone stream was removed and the solution was treated with dimethyl sulfide (13 mL, 186 mmol) and allowed to warm to ambient temperature over 30 min. The solution was concentrated to give a yellow residue that was subjected to high vacuum for 2 h. The resulting N-(2-oxoethyl)benzamide was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1)[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Zn]CC)[CH3:19].[Cl-].[NH4+].CCOC(C)=O>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH:7]([C:8]#[N:9])[C:10]1[CH:15]=[CH:14][C:13]([CH2:18][CH3:19])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C#N)c1ccc(Br)cn1
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1ccc(C(C#N)C(=O)OC(C)(C)C)nc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
The crude (5-bromo-pyridin-2-yl)-cyano-acetic acid tert-butyl ester (20.1 g) was dissolved in anhydrous THF (300 mL) and the dark red solution was cooled in an ice-water bath. After purging in a stream of nitrogen, diethylzinc (88.0 mL, 88.0 mmol, 1M in hexane) was slowly added over 50 minutes. The internal temperature was maintained below 4° C. The catalyst 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride-CH2Cl2 (1:1 complex) (1.61 g, 1.97 mmol) was added and the mixture was heated at 50° C. for 35 minutes. The reaction was cooled in an ice bath and saturated aqueous ammonium chloride solution was added. The mixture was stirred for 10 minutes and EtOAc was added. The mixture was filtered through Celite® with the aid of EtOAc. The filtrate layers were separated and the organic layer was washed with brine and was dried over anhydrous sodium sulfate. The organic solution was concentrated to dryness and the residue was purified by ISCO (Teledyne Isco Inc., Lincoln) column chromatography (EtOAc/heptanes gradient) to give cyano-(5-ethyl-pyridin-2-yl)-acetic acid tert-butyl ester as a dark yellow solid (7.31 g). This material was used directly in the next step.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: Nc1ccc(CCN2CCCC2)cc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc(CCN2CCCC2)cc1
Temperature: 110 °C
Yield: 71.4 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 4-(2-pyrrolidin-1-yl-ethyl)-phenylamine (95.2 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 129 mg (71%) of yellow solid mp 224-225° C.; MS (ESI) m/z 362.20 (M+1); Analysis for C22H23N3O2: Calcd: C, 73.11; H, 6.41; N, 11.63. Found: C, 72.33; H, 6.45; N, 11.59.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Br:18][C:19]1[CH:20]=[C:21]([SH:27])[CH:22]=[C:23]([Br:26])[C:24]=1[NH2:25]>>[Br:18][C:19]1[CH:20]=[C:21]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:22]=[C:23]([Br:26])[C:24]=1[NH2:25]
Reactant: Nc1c(Br)cc(S)cc1Br
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: Nc1c(Br)cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc1Br

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 3,5-dibromo-4-amino-thiophenol.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][N:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][S:38][CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)C(=O)C(F)(F)F)[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:41]1([CH2:40][CH2:39][S:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:25][CH2:24][CH2:23][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(N(CCCCCCSCCc1ccccc1)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(CCSCCCCCCNCCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
The product from step (b) (7.0 g, 0.011 mole) was heated to reflux for 2 hr with a solution of sodium hydroxide (0.93 g, 0.023 mole) in 90% ethanol (100 ml). The cooled solution was concentrated in vacuo and the residue diluted with water and extracted with dichloromethane. The extracts were washed with water, dried (MgSO4) and evaporated. The residue was dissolved in ether and treated with ethereal-HCl to give the sub-title compound as the hydrochloride salt, a white solid (5.5 g) mp 89°-91°.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12])([CH3:3])[CH3:2].[Br:14]Br>CCOCC>[Br:14][CH2:12][C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1OC(C)C
Solvent: CCOCC
Product: CC(C)Oc1ccccc1C(=O)CBr
Yield: 97.2 %

Procedure:
Dissolve 1-(2-isopropoxyphenyl)ethanone (1.0 g, 6 mmol) in Et2O (25 mL) and add bromine (0.3 mL, 6 mmol) drop-wise while stirring stir the mixture in the dark at ambient temperature. Wash the reaction mixture with a saturated aqueous Na2CO3 solution. Dry it over MgSO4; filter; collect the filtrate; removed the volatiles under reduced pressure to provide the title compound (1.5 g, 83%). MS (m/z): 258 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[N:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[OH-].[Na+]>C(O)C>[N:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[CH:2][C:1]([C:4]3[CH:13]=[CH:12][C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[CH:5]=3)=[O:3])=[CH:22][CH:21]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(N2CCOCC2)cc1)c1ccc2c(c1)CCCC2

Procedure:
A solution of 1.74 g of 1 (10 mmoles), 1.91 g of p-(4-morpholinyl)benzaldehyde (10 mmoles), and two pellets of sodium hydroxide (about 0.4 g) in 40 ml of ethanol was stirred under nitrogen at room temperature for 70 hr. The reaction mixture was cooled in an ice bath and the precipitated yellow solid 3-[4-(4-morpholinyl)phenyl]-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-propen-1-one was collected by filtration and washed with cold ethanol. Yield: 2.9 g (83%); m.p. 138° to 140°. λmax (EtOH): 390 nm (ε=28,100), 270 nm (ε=13,700). Calcd for C23H25NO2 : c, 79.51; H, 7.25; N, 4.03. Found: C, 78.72, 79.02, 78.75; H, 7.22, 7.26, 7.23; N, 3.88, 3.87, 3.91.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.Br.Br.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[NH:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[NH:33][CH:34]2[CH2:35][CH2:36][N:37]([CH2:11][CH:9]([CH2:8][O:7][C:6]3[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[OH:10])[CH2:38][CH2:39]2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: COc1ccc(OCC2CO2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COc1ccc(OCC(O)CN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Yield: 51 %

Procedure:
A mixture of 3.6 parts of [(4-methoxyphenoxy)methyl]oxirane, 4.9 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 2.1 parts of sodium carbonate, 40 parts of methanol and 90 parts of benzene is stirred and refluxed overnight. The reaction mixture is filtered and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 2.6 parts (51%) of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-α-(4-methoxyphenoxymethyl)-1-piperidineethanol; mp. 174.5° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=2)=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:39]1[CH2:38][CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][C:30]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:31][CH:32]=2)[CH2:41][CH2:40]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Reactant: O=C(CCCCCBr)Nc1ccccc1Cc1ccccc1
Product: O=C(CCCCCN1CC=C(c2ccc(Oc3ccccc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (12) synthesized in Reference Example 12 and the compound (3) synthesized in Reference Example 3 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[CH:32]([F:34])[F:33])=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]([NH:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[CH:32]([F:34])[F:33]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NC(c2ccc(Cl)cc2CN)C(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
Triphenylphosphine (0.344 g, 1.31 mmol) was added to a stirred solution of N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.463 g, 1.31 mmol) and water (0.02 mL, 1.31 mmol) in THF (2.6 mL). The solution was stirred at ambient temperature for 2 h and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (5 mL). One KOH pellet was added and the mixture was refluxed for 5 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 1M HCl. The aqueous layer was basicified with 1M NaOH and the solution was extracted with diethyl ether. The organic phase was dried (Na2SO4) and reduced in vacuo and the residue was purified by column chromatography on silica (eluting with ammonium hydroxide/methanol/chloroform, 1:9:90) to give N-{1-[2-(aminomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.314 g) as an oil: MS 327.5 (M+1).
Reaction SMILES: CS([C:5]1[N:14]2[C:8]([CH:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)(=O)=O.[CH3:25][O-:26].[Na+]>>[CH3:25][O:26][C:5]1[N:14]2[C:8]([CH:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1ccccc1C2c1ccccc1
Agent: [Na+]
Product: COc1nnc2n1C=Cc1ccccc1C2c1ccccc1

Procedure:
The reaction of 3-methylsulfonyl-11-phenyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 3-methoxy-11-phenyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless prisms (as recrystallized from aqueous methanol), melting point: 183°-184° C.
Reaction SMILES: CC1OC(=O)O[C:3]=1[CH2:8][O:9][C:10](=[O:29])[C@H:11]([OH:28])[CH2:12][C@H:13]([NH2:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.OC1C=C(C(O)=O)ON=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:8]([O:9][C:10](=[O:29])[C@H:11]([OH:28])[CH2:12][C@H:13]([NH2:27])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[CH3:3]
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: O=C(O)c1cc(O)no1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.03 h
Yield: 42.5 %

Procedure:
(2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (100 mg, 0.3 mmol, 1.0 eq.) and 3-hydroxyisoxazole-5-carboxylic acid (50.5 mg, 391 μmol, 1.5 eq.) were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA was added and the resulting mixture was stirred for 1 hour. The material was dried under vacuum then purified using reverse phase chromatography to yield the title compound (40 mg, 98% purity). MS m/z [M+H]+ calc'd for C26H24N2O9, 509.15. found 509.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[N:13]O)[CH:8]=2)[CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl>C(O)(=O)C>[C:15]([NH:13][C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:17])[CH3:16]
Reactant: ON=C1C=C(c2cccnc2)CCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2cccnc2)c1
Reaction time: 3 h

Procedure:
To a mixture containing 28.9 g. of 3-(3-pyridinyl)-2-cyclohexen-1-one oxime, 42 ml. of acetic acid and 42 ml. of acetic anhydride was passed gaseous hydrogen chloride whereupon the temperature rose to about 120° C. The hydrogen chloride was passed continuously into the reaction mixture until the temperature fell to about 50° C. The reaction mixture was allowed to stand for three hours and then concentrated in vacuo to yield, as a glassy material, 3-(3-acetamidophenyl)pyridine. To this material was added 100 ml. of water and 25 ml. of concentrated hydrochloric acid and the resulting mixture was refluxed for sixteen hours and concentrated in vacuo to yield a yellow solid. The solid was taken up in water and the solution was made alkaline with 35% aqueous sodium hydroxide solution. The alkaline solution was extracted three times with ethylene dichloride. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield an oil. The oil was distilled under reduced pressure, collecting the fraction boiling at 141°-145° C. at 0.15 mm. to yield, first as a yellow oil which crystallized on cooling, 17.7 g. of 3-(3-aminophenyl)pyridine, m.p. 72°- 74° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC[C@H]1CC[C@H]([C@@]23CCC(=O)N2[C@@H:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:28][O:27]3)CC1)C1C=CC=CC=1>C1COCC1>[C:35]1([CH2:29][CH2:28][OH:27])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1CC[C@@]2([C@H]3CC[C@H](COCc4ccccc4)CC3)OC[C@H](c3ccccc3)N12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) mixture of anhydrous AlCl3 (4.70 g, 35 mmol) in THF (120 mL) is slowly added lithium aluminum hydride (4.34 g, 115 mmol), and the resulting mixture is stirred at the same temperature for 30 min. To the resulting stirred and cooled (−78° C.) THF mixture is added a solution of trans-(3S,7aS)-7a-[4-(benzyloxymethyl)cyclohexyl]-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5-one (15.5 g, 38 mmol) in THF (80 mL) over 30 min. The resulting mixture is stirred at the same temperature for 1.5 hours, and then warmed to room temperature and stirred for additional 15 min. The resulting mixture is cooled to 0° C., quenched with the careful addition of Na2SO4-10H2O (5.0 g), and stirred for additional 30 min at room temperature. The insoluble matter is filtered and the filtrate is concentrated in vacuo to afford crude trans-(S)-2-{(R)-2-[4-benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-2-phenylethanol, which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([S:12][CH3:13])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(=O)([O-])[OH:17].[Na+].[OH-].[Na+].BrBr.Cl>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([S:12]([CH3:13])=[O:17])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: O=C([O-])O
Reactant: CSC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Product: CS(=O)C1=NS(=O)(=O)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 7-chloro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.5 g) in an aqueous solution of sodium hydrogen carbonate (0.22 g/25 mL) was supplemented dropwise with 2M NaOH until complete dissolution. Liquid bromine (0.1 mL) was added under stirring at room temperature. After 10 min., the resulting suspension was adjusted to pH 2-3 with 6N HCl and the insoluble material was collected by filtration and washed with water. The white precipitate was suspended in methanol (20 mL), stirred for 1 h and then collected by filtration, washed with methanol and dried (yield: 0.45 g); m.p. 260-261° C.