Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1.[CH2:19](O)[C:20]#[C:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:19][C:20]#[C:21][CH3:22])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1
Reactant: CCCn1nnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: CC#CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC#CCOc1cc(-n2nnn(CCC)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 20.7 %

Procedure:
To a stirred solution of 0.5 g (0.0017 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (Example 10, Step A) and 0.15 g (0.0021 mole) of 2-butyn-1-ol in 5 mL of acetonitrile was added 0.33 g (0.0016 mole) of dicyclohexylcarbodiimide. The reaction mixture was heated at reflux temperature for 4 days, cooled to room temperature, and filtered. The filtrate was washed with 10 mL of a 10% aqueous sodium hydroxide solution, diluted with methylene chloride, and washed with 10 mL of 6N hydrochloric acid. The washed organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated to leave an oil. The oil was purified by column chromatography on silica gel, eluting with ethyl acetate: heptane (20:80), to yield 0.12 g of 1-[2,4-dichloro-5-(2-butynyloxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one as a solid, mp 58°-60° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35](=[N:37]O)[NH2:36]>>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35]1[N:37]=[C:24]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:12]2)[O:25][N:36]=1
Reactant: NC(=NO)c1c(F)cccc1F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4c(F)cccc4F)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 57 mg (0.33 mmol) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 57 mg (52% of theory)
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH2:20]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Clc1nc2ccccc2[nH]1
Product: c1ccc(CN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1
Reaction time: 12 h

Procedure:
Combine 2-chloro-1H-benzimidazole (5.0 g, 33 mmol) and 1-benzyl-4-aminopiperidine (14.2 g, 75 mmol) and heat to about 150° C. After 12 hours, cool and partition between water and chloroform, warming if necessary. Separate the layers and add methanol and toluene to the organic layer. Evaporate the organic layer in vacuo to give a solid. Triturate the solid with ethyl acetate, collect by filtration, and dry to give (1H-benzimidazol-2-yl)(1-benzylpiperidin-4-yl)amine: Rf=0.30 (2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.1 %

Procedure:
A mixture of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (2.53 g, 8.33 mmol), indoline (0.933 mL, 8.33 mmol), and N,N-diisopropylethyl-amine (1.60 mL, 9.16 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 20 hours. The reaction mixture was partitioned between water and ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to a solid residue. Recrystallization from ether and heptane provided the title compound (1.99 g, 67%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>C(Cl)Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[O:19][CH2:18][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOc1ccc2ccccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Chloropyrimidine-2-one hydrochloride (5 mmol) and triethylamine were stirred together in CH2Cl2 (30 ml). When all the solid had dissolved there was added a solution of 2-chloromethoxynaphthalene [see Preparation 13] (5 mmol) in CH2Cl2 (10 ml) with stirring at room temperature for 5 minutes. The mixture was stirred at room temperature for 24 hours before the solvent was distilled off. The residue was triturated with water, extracted into CHCl3, dried (MgSO4) and evaporated to give a mixture of the title compound and the O-alkylated isomer in the ratio 4:1. Yield 1.27g (86%). The O-isomer was removed from the product by extraction with ether followed by recrystallization of the N-isomer from acetone m.p. 168° C. 1H NMR (CDCl3 δ): 5.85 (s, CH2), 7.10-8.1 (m, 8H. Ar+ H-4), 8.48 (H-6, d7 =4Hz) IR (KBr, cm -1): 1675 (CO).
Reaction SMILES: [C:1]1(=[CH:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]([C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1CCCCC1>C(OCC)(=O)C>[O:10]([C:17]1[CH:22]=[CH:21][C:20]([S:23][C:1]2([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C=C1CCCC1
Reactant: Sc1ccc(Oc2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1

Procedure:
A mixture of cyclopentylideneacetic acid (2 mmol) and p-(phenoxy)-thiophenol (2 mmol) was heated at 110° C. under nitrogen in the presence of piperidine (100 μL) for 24 hours. The residue was dissolved in ethyl acetate and washed with dilute hydrochloric acid. The organic layer was separated, dried and evaporated under reduced pressure to give crude 2-[-(4-phenoxyphenylthio)-cyclopent-1-yl]-acetic acid, which can be used in the next reaction without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:8]([O-])([OH:10])=[O:9]>C1C=CC=CC=1>[N+:8]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
Phenol dissolved in benzene is nitrated continuously by means of 58% nitric acid and the organic layer containing the mixture of ortho- and para-nitrophenol is separated from the residual nitric acid by decantation. The acid organic layer is successively neutralised by means of an aqueous solution of sodium sulphite, distilled until the benzene is removed and treated with steam in order to remove ortho-nitrophenol by steam distillation. An aqueous distillation residue of para-nitrophenol is thus obtained, the composition of which is substantially as follows:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Reactant: COc1cccc(CC(=O)O)c1
Product: COc1cccc(CC(=O)Nn2nc(S(=O)(=O)c3ccccc3)c3ccccc3c2=O)c1

Procedure:
The product from Example 68B and 2-(3-methoxyphenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.56 (d, J=8.1, 1H), 8.38 (dd, J=8.0, 0.9, 1H), 8.15-8.06 (m, 1H), 8.05-7.96 (m, 3H), 7.84-7.76 (m, 1H), 7.72-7.62 (m, 2H), 7.26 (t, J=7.9, 1H), 6.95-6.88 (m, 1H), 6.85 (dd, J=8.2, 2.6, 2H), 3.77 (s, 3H), 3.64 (s, 2H); MS (ESI+) M/Z 467 (M+NH4)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:19]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:26]
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CON(C)C(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccncc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a pre-cooled −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy)silane (5.0 g, 0.03 mol) in dry THF (150 mL), n-BuLi (23.82 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over a period of 10 minutes under an inert atmosphere. The reactions was stirred for 30 minutes at −78° C. and then a solution of N-methoxy-N-methylisonicotinamide (6.34 g, 0.03 mol) in dry THF (30 mL) was added to the reaction mixture and stirring was continued for an additional 40 min at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and finally concentrated in vacuo to obtain a residue. The residue was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (2.2 g, 27%) as oil.
Reaction SMILES: [CH3:1][SH:2].[CH2:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.[OH-].[K+]>C(COC)OC>[CH2:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:2][CH3:1])[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1
Reactant: BrCCCCCCCCCCCCOCc1ccc2c(c1)OCO2
Reactant: CS
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CSCCCCCCCCCCCCOCc1ccc2c(c1)OCO2

Procedure:
Methyl mercaptan, 1.6 g. (0.032 mole) was bubbled into a solution of 13.0 g. (0.032 mole) of 12-bromododecyl piperonyl ether, and 5.6 g. (0.1 mole) of potassium hydroxide in 150 ml. of dimethoxyethane. When all had been added the resulting mixture was heated at reflux for 3 hours. After cooling and filtering, the solvent was removed by evaporation. The crude product was then dissoved in hexane and filtered. The filtrate was evaporated to give 8.5 g. of oily product. The NMR spectra was consistent with the assigned structure. The infrared spectra had strong adsorption peaks at 3.4, 3.5, 6.7, 6.95, 8.0, 9.0, 9.6, 10.6 and 12.2 microns. Analysis was as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](N(OC)C)=[O:13])[CH:6]=[CH:5]2.[CH3:18][Mg]Br.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:13])[CH3:18])[CH:6]=[CH:5]2
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2cc(Br)ccc2c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
6-bromo-N-methoxy-N-methyl-2-naphthamide (82.9 g, 282 mmol, 1 equiv.) was dissolved in tetrahydrofurane (600 mL) in a 4-neck flask under nitrogen. The reaction mixture was cooled in an ice bath and methyl magnesium bromide (3.2 M in methyl-tetrahydrofurane, 197 mL, 2.2 equiv.) was added drop wise during 1 hour, while maintaining the temperature of the reaction mixture between 10-15° C. The reaction mixture was stirred 30 minutes further in an ice bath. Aqueous hydrochloric acid (2 M, 100 mL) was then carefully added drop wise while cooling on an ice bath. The organic solvent was evaporated and the precipitated product extracted with dichloromethane (500 mL). The solution was dried over sodium sulphate, filtered and concentrated. The solid residue was dried in vacuum at 40° C. yielding 1-(6-bromonaphthalen-2-yl)-ethanone (70.6 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: CCO
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(Cl)c1

Procedure:
To a suspension of 4-bromo-3-chlorobenzoic acid (5.00 g, 21.2 mmol) in ethanol (50 mL) was added sulphuric acid (5 mL) and the resultant mixture heated to reflux for 60 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with further ethyl acetate and the combined organic fractions dried (phase separator) and concentrated in vacuo to give the title compound as a brown oil/solid (5.09 g, 19.3 mmol). δH (d6-DMSO, 400 MHz): 8.06 (1H, d), 7.96 (1H, d), 7.80 (1H, dd), 4.33 (2H, q), 1.33 (3H, t).
Reaction SMILES: [F:1][C:2]1([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:5][O:4][CH2:3]1.Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[C:21]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[N:22]2[CH3:25])=[C:18]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:17]=1>>[F:1][C:2]1([C:6]2[N:7]([C:16]3[N:24]=[C:23]4[C:19]([N:20]=[C:21]([CH2:26][N:27]5[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]5)[N:22]4[CH3:25])=[C:18]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)[N:17]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3][O:4][CH2:5]1
Reactant: FC1(c2nc3ccccc3[nH]2)COC1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4(F)COC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(3-fluorooxetan-3-yl)-1H-benzimidazole and 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol were reacted to give 262. LCMS m/z: 565.3 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.[I-:15].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][I:15])[CH2:7][CH2:6][CH2:5]2
Reactant: [I-]
Reactant: ClCCN1CCCc2cc(Br)ccc21
Agent: [Na+]
Solvent: CC(C)=O
Product: Brc1ccc2c(c1)CCCN2CCI
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A suspension of 6-bromo-1-(2-chloroethyl)-1,2,3,4-tetrahydroquinoline (compound 2, 1.80 g, 6.56 mmol) and sodium iodide (9.83 g, 65.6 mmol) in acetone (50 mL) was heated to reflux for 2 days at which time TLC analysis showed residual starting material 2. At this time a further portion of sodium iodide (19.66 g, 132.0 mmol) was added and the suspension refluxed for 5 days. The mixture was cooled to room temperature, filtered through a pad of celite and the filtrate concentrated to yield a yellow solid. The solid was taken up in a mixture of ethyl acetate/hexanes (150 mL) and filtered through a pad of silica gel, and the pad rinsed further with EtOAc/Hexanes. The filtrate was concentrated to yield a yellow oil, 3 (2.19 g, 91%). 1H-NMR (CDCl3) δ 7.12 (dd, 1H, J=8.7, 2.5 Hz), 7.09-7.04 (m, 1H), 6.42 (d, 1H, J=8.7), 3.65-3.60 (m, 2H), 3.33 (t, 2H, J=5.6 Hz), 3.25-3.19 (m, 2H), 2.72 (t, 2H, J=6.3 Hz), 1.98-1.90 (m, 2H). MS (ESI+): 366/368 (MH+, 100).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:20]([C:26]([O:28]CC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C.[OH-].[Na+]>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:26](=[O:28])[CH:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)C1C(=O)N(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of N,N′-dibenzylethylenediamine (14.12 mL, 60.2 mmol) in acetonitrile (100 mL) was added diethyl bromomalonate (5.14 mL, 30.1 mmol), and the mixture was heated with an oil bath at 90° C. (reflux) for 7 hours. The solvent was evaporated to provide a residue that was dissolved in 1 M NaOH (aqueous), and the mixture was extracted with ethyl acetate twice, dried over Na2SO4, and the solvent was evaporated. The crude mixture was purified by silica gel chromatography (Analogix IntelliFlash 280, SF40-150) eluting with 15%-30% ethyl acetate/hexanes to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.38-7.20 (m, 10H), 4.54 (dd, J=15.0, 154.2, 2H), 4.20-4.10 (m, 2H), 4.03 (q, J=7.1, 1H), 3.96 (s, 1H), 3.61 (dd, J=13.5, 41.7, 2H), 3.27-3.14 (m, 2H), 3.05-2.95 (m, 1H), 2.60-2.52 (m, 1H), 1.23 (t, J=7.1, 3H); MS (ESI+) m/z 353.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (S)-tert-butyl pyrrolidin-3-ylcarbamate. LC-MS (Condition 6) tR=1.46 min, m/z=488.9 [M+H—H2C═C(CH3)2], m/z=544.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([NH2:15])=O)=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]#[N:15])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(N)=O)c(I)cc1OCc1ccccc1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C#N)c(I)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 74.4 %

Procedure:
To a mixture of 4-benzyloxy-2-iodo-5-methoxybenzamide (reference example 6-3) (5.25 g) and dichloromethane (70 mL) were added triethylamine (8.2 mL) and trifluoromethanesulfonic anhydride (4.6 mL) at 0° C. The mixture was stirred at 0° C. for 20 minutes, at room temperature for 3.5 hours and at reflux temperature for an hour. After cooling to 0° C., to the mixture were added triethylamine (4 mL) and trifluoromethanesulfonic anhydride (2.3 mL). After stirring at room temperature overnight, to the mixture were added ice-water and 1 mol/L hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A mixture of the residue, ethyl acetate, dichloromethane, silicagel and aminopropylsilicagel was stirred for 30 minutes. The mixture was passed through a layer of Celite (registered mark). The filtrate was concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (3.72 g).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1.Cl.[OH:30][CH:31](COC1C=CC=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl>C(OCC)C>[ClH:1].[OH:2][CH:3]([CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)[CH2:4][NH:5][C:6]([CH3:15])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:30][CH3:31])=[CH:12][CH:13]=1
Reactant: CC(C)(Cc1ccc(F)cc1)NCC(O)COc1cccc2ccccc12
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc3ccccc3c2)cc1

Procedure:
Using the method of Example 4, supra, 2-naphthyl glycidyl ether (400 mg, 2 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (358 mg, 2 mmol) were used to prepare the free base of the title compound: GC/EI-MS, m/z (rel. int.) 364 (M−15, 1), 253 (100), 183 (2), 163 (3), 144 (4), 127 (10), 121 (22), 115 (20), 71 (11). The free base in diethyl ether was treated with excess 1M HCl (diethyl ether). The resulting solid was recrystallized from hot acetonitrile to afford 496 mg of the hydrochloride product as a white solid.
Reaction SMILES: [P:1]([O-:35])([O:31][CH2:32][CH2:33]Br)([O:3][CH2:4][CH:5]([O:29][CH3:30])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2].[CH3:36][N:37]([CH3:39])[CH3:38]>C1(C)C=CC=CC=1>[P:1]([O-:35])([O:31][CH2:32][CH2:33][N+:37]([CH3:39])([CH3:38])[CH3:36])([O:3][CH2:4][CH:5]([O:29][CH3:30])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2]
Reactant: CN(C)C
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)OC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[N+](C)(C)C)OC
Reaction time: 72 h

Procedure:
In 60 ml of toluene containing 10 g of trimethylamine is dissolved 2.0 g of the phosphate ester obtained in Example 10, and the solution is allowed to stand at room temperature for 3 days. The reaction mixture is concentrated to dryness under reduced pressure, the residue is dissolved in 50 ml of methanol, and 2 g of silver carbonate is added. The mixture is refluxed for 1 hour and, then, filtered. The filtrate is evaporated to dryness, and the residue is separated and purified by silica gel chromatography [eluent: chloroform-methanol-water (65:25:4)] and crystallized from chloroform-acetone. By this procedure is obtained 640 mg of the contemplated product as colorless powders.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[C:8]=1[S:9]([O:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)(=[O:11])=[O:10].[C:24]1([NH:30][NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([NH:30][N:31]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][O:12][S:9]([C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[O:22][CH3:23])(=[O:11])=[O:10])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(OC)c1S(=O)(=O)OCC(=O)c1ccccc1
Reactant: NNc1ccccc1
Product: COc1cccc(OC)c1S(=O)(=O)OCC(=NNc1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
The 3,5-dimethoxy-4-benzenesulphonyloxy-acetophenone obtained as described above was reacted with phenylhydrazine following the procedure set out in Example 1b and 3,5-dimethoxy-4-benzenesulphonyloxy-acetophenone phenylhydrazone was obtained with a yield of 100% in crude product, which was recrystallized from methanol and directly used for the following step.