Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[N:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:36])[C:32]([NH:34][CH3:35])=[NH:33])[CH2:27][CH2:26]2)=[CH:11][CH:10]=1.[OH-].[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[N:25]2[CH2:26][CH2:27][CH:28]([N:31]([CH3:36])[C:32]([NH:34][CH3:35])=[N:33][C:5](=[O:7])[CH3:6])[CH2:29][CH2:30]2)=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=N)N(C)C1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=NC(C)=O)N(C)C1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
0.48 ml of acetic anhydride dissolved in 5 ml of methylene chloride is added to a solution of 2 g (0.005 mole) of N-[1-[1-[(4-fluorophenyl)methyl]-2-(1H)-benzimidazolyl]-4-piperidinyl]-N,N'-dimethylguanidine in 20 ml of methylene chloride, cooled to 5° C. Stirring is continued for 2 h and the mixture is then poured into concentrated sodium hydroxide. The phases are separated, the organic phase is dried with MgSO4, is filtered and is evaporated down. On addition of acetone, the product crystallizes. It is purified by chromatography on a silica column (eluent 9/1 methylene chloride/methanol) N-[1-[1-[(4-fluorophenyl)methyl]-2(1H)-benzimidazolyl]-4-piperidinyl]-N,N'-dimethyl-N"-acetylguanidine is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]([OH:13])=O)[C:4]=2[N:3]=[CH:2]1.[NH2:14][CH:15]([CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([NH:14][C:11](=[O:13])[CH2:10][C:9]1[C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)[CH2:23][CH3:24])[CH:20]([CH3:21])[CH3:22]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1cccc2scnc12
Product: CCC(NC(=O)Cc1cccc2scnc12)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 4-benzothiazol-yl acetic acid (Chemservice) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=O)[C:6]([CH:8]1[CH2:10][CH2:9]1)=O)[CH3:2].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([NH:28][NH2:29])[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4]([C:5]1[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:29][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:30])[CH:23]=2)[C:6]=1[CH:8]1[CH2:10][CH2:9]1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(C(=O)c1ccncc1)C(=O)C1CC1
Reactant: NNc1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Yield: 12 %

Procedure:
In analogy to the procedure described in Example 164B], 3-cyclopropyl-3-oxo-2-(pyridine-4-carbonyl)-propionic acid ethyl ester (Example 162 A]) and 3-(trifluoromethyl)phenylhydrazine gave the title compound as a white solid (12%). MS: 402.4 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2nc(C)ccc2-n2nccn2)nc1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 406 [M+1]+.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[C:23]3[NH:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][C:27]([Br:34])=[CH:28][CH:29]=4)[N:24]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CC#N.O>[Br:34][C:27]1[CH:26]=[C:25]2[C:30]([C:31](=[O:33])[NH:32][C:23]([CH:19]3[CH2:20][CH2:21][CH2:22][NH:18]3)=[N:24]2)=[CH:29][CH:28]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCC1c1nc2cc(Br)ccc2c(=O)[nH]1
Solvent: C1CCNCC1
Solvent: CC#N
Solvent: O
Product: O=c1[nH]c(C2CCCN2)nc2cc(Br)ccc12
Yield: 53 %

Procedure:
A solution of (9H-fluoren-9-yl)methyl-2-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (305 mg, 1.04 mmol) and piperidine (2 mL) in CH3CN was stirred at room temperature for 2 h. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give 162 mg of the desired product. MS (ESI): 294, 296 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH:14]=2)[N:9]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:8]1=[O:29].[CH:35]([O-])=[O:36].[NH4+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH:14]=2)[N:9]([CH:23]2[CH2:28][CH2:27][N:26]([CH:35]=[O:36])[CH2:25][CH2:24]2)[C:8]1=[O:29]
Reactant: O=C[O-]
Reactant: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCNCC3)c2=O)cc1OC
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Yield: 47.2 %

Procedure:
A mixture of 0.070 g of N-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(piperidin-4-yl)-1,2,3,4-tetrahydroquinazolin-6-yl]methyl}acetamide obtained in stage 5.7 and 0.028 g of ammonium formate in 2 ml of ACN is irradiated under a microwave field at 140° C. for 1 h 00. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an MeOH/DCM mixture, (0.5/99.5, v/v) as far as (7/93, v/v), to give 0.035 g of the expected product.
Reaction SMILES: C(OC(=O)C[C@@H](C([N:16]1[C@@H:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][O:18][C:17]1=[O:24])=O)CCCCC)(C)(C)C.OO.O[Li].O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH:21]([C@H:20]1[CH2:19][O:18][C:17](=[O:24])[NH:16]1)([CH3:23])[CH3:22]
Reactant: CCCCC[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1
Reaction time: 3 h

Procedure:
A solution of 5 (25.5 g, 71.73 mmol) in THF (300 mL) and water (75 mL) under Ar is cooled to 0° C. To this is added via syringe H2O2 (30% in water, 30.6 mL, 0.300 mol) gradually over a period of 15 minutes. LiOH·H2O (4.92 g, 0.12 mol) in water (150 mL) is added via syringe. The mixture is stirred for 3 h after which the septum is removed and Na2SO3 (37.8 g, 0.300 mol) in water (225 mL) is added slowly. The bulk of the THF is removed by rotavap at a bath temperature between 25-30° C. The residue is extracted with CH2Cl2 (100 ml×3). The combined organic layer is washed consecutively with 0.5 N HCl (100 mL), sat. NaHCO3 (100 mL), water (100 mL) and brine (100 mL). The solution is then dried over Na2SO4 and concentrated in vacuo. The residue is recrystallized in hexane/ethyl acetate to afford the Evan's chiral auxiliary 2 as white needles. The aqueous layer from the first extraction was acidified to pH 1 and extracted with ethyl acetate (100 mL×3). The combined organic layer is washed with 0.5 N HCl (100 mL) and then brine (100 mL). It is then dried over Na2SO4 and concentrated to yield 6 as a colorless oil (17.198 g, 70.39 mmol, 98%). 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 3H), 1.21-1.37 (m, 6H), 1.43 (s, 9H), 1.40-1.70 (m, 2H), 2.61 (dd, J=9.3 Hz, 1H), 2.38 (dd, J=16.4, 5.1, 1H), 2.61 (dd, J=16.4, 9.3, 1H), 2.78 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 13.9, 17.5, 17.9, 22.3, 26.5, 27.9, 31.5, 37.0, 41.3, 94.9, 80.0, 171.1, 181.1. HRMS calcd for C13H25O4 (MH+): 245.1752. Found (DCI): 245.1766 (Δ=5.2 ppm).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2([CH2:36][C:37]([NH2:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:26]([Cl:40])=[CH:25][N:24]=1>>[Cl:40][C:26]1[C:27]([NH:29][C:30]2([CH2:36][C:37]([NH2:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(NC4(CC(N)=O)CCCCC4)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide in an analogous manner to Example 61e. Product isolated as a pale yellow foam (0.064 g, 49%). MP: 71-83° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 7.92 (s, 1H), 7.84 (s, 1H), 7.14 (s, 1H), 6.64 (s, 1H), 5.40 (br s, 1H), 5.24 (s, 1H), 5.05 (br s, 1H), 3.85 (s, 3H), 3.57-3.51 (m, 2H), 3.47-3.41 (m, 2H), 3.32 (s, 6H), 3.06-2.98 (m, 1H), 2.90 (s, 2H), 2.87-2.77 (m, 8H), 2.37-2.29 (m, 2H), 1.71-1.29 (m, 8H). MS: 561.29 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][N:8]([CH3:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[S:4][C:3]=1[CH2:19]O>[Pd].C(O)(=O)C.Cl>[ClH:1].[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][N:8]([CH3:12])[CH2:7][CH:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]=2[S:4][C:3]=1[CH3:19]
Reactant: CN1CCc2c(sc(CO)c2Cl)C(c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: Cc1sc2c(c1Cl)CCN(C)CC2c1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 3-chloro-2-hydroxymethyl-6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (0.20 g) and 10% palladium on carbon (50 mg) in acetic acid (2 ml) and concentrated hydrochloric acid (0.1 ml) was hydrogenated at 60 psi for 20 hours. The reaction mixture was filtered, evaporated and the residue chromatographed on silica eluting with 1% methanol-ammonia solution in dichloromethane. The combined fractions were dissolved in ethanolic hydrogen chloride, evaporated and crystallised from ethanol-diethylether to give the title product, m.p. 146° C.
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[CH:9]([OH:25])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][C:42]=1[CH2:51][C:52](Cl)=[O:53].O>ClCCl>[C:26]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:52](=[O:53])[CH2:51][C:42]4[CH:43]=[CH:44][C:45]5[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH:41]=4)[CH2:14]3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[CH:9]([OH:25])[CH2:8]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc4ccccc4c3)CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of 0.42 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol in 10 cm3 of dichloromethane is added 0.21 cm3 of diisopropylethylamine, followed by 0.23 g of 2-naphthylacetyl chloride in 5.5 cm3 of dichloromethane. After stirring at room temperature for 1 hour, 25 cm3 of water are added. The organic phase is separated off after settling, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 50 cm3 of ethyl acetate, 3 cm3 of 1N aqueous hydrochloric acid and 40 cm3 of water. The organic phase is separated off after settling, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized a first time in 5 cm3 of 2-propanol and then a second time in 5 cm3 of isopropyl ether. 0.3 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-naphthyl)acetyl]perhydro-4,5-isoindolediol is obtained, melting at 188°-190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([OH:7])=[O:6].Cl.[N:14]([O-])=O.[Na+].[OH-].[K+]>O>[CH3:12][N:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[N:14]1
Reactant: CNc1ccc(C(=O)O)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cn1nnc2cc(C(=O)O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.4 %

Procedure:
To a stirred suspension of the diamine 280 (1.08 g; 6.48 mmol) (or any other o-arylenediamine) in water (25 mL) at 0° C., concentrated HCl (5.4 mL) was added drop wise followed by slow addition of a solution of NaNO2 (643 mg; 9.3 mmol) in water (10 mL). The reaction mixture was stirred at 0° C. for 2 h and then was allowed to warm up to 10° C. over 4 h; neutralized with a solution of KOH (5.6 g) in water (30 mL) (final pH=6); concentrated and purified by preparative HPLC in reverse phase mode (column aquasil C-18, elution 5% to 95% MeOH in water), to afford the title compound 284 (211 mg; 18% yield). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 8.35 (s; 1H); 8.08 (dd, J=1.4, 8.6 Hz; 1H); 7.75 (d, J=1.4 Hz; 1H); 4.03 (s, 3H). MS: calc: 177.1; found: 178.1 (M+H).
Reaction SMILES: C([O:4][C:5]([C:7]1([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])(C)C.[I-].[Na+].Br>CC(O)=O.C(Cl)Cl>[CH2:17]([CH:14]([CH2:15][CH3:16])[CH2:13][C:7]1([C:5]([OH:6])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH3:18]
Reactant: CCC(CC)CC1(C(=O)OC(C)C)CCCCC1
Agent: Br
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 93.7 %

Procedure:
A mixture of 1-(2-Ethyl-butyl)-cyclohexanecarboxylic acid isopropyl ester (10 g, 39.4 mmol) and sodium iodide (886 mg, 5.91 mmol) in AcOH (80 mL) was stirred 50 min at room temperature and then heated to 100° C. 48% aq. HBr (30 mL, 265 mmol) was added dropwise over 30 min. and the reaction mixture was stirred 28 h at 100° C. The cooled reaction mixture was diluted with DCM (120 mL) and ice-water (120 mL). The organic phase was separated and washed with diluted aq. NaCl. The aqueous phases were extracted with another portion of DCM. The organic phases were combined, dried over sodium sulfate and concentrated. The residue (9.1 g) was taken up in 4N NaOH and ice (30 g). The alkaline solution (pH 12) was extracted with DCM (2×50 mL) and made acidic to pH 1 using aq. H2SO4. Extraction with DCM (3×100 mL), washing with diluted aq. NaCl, drying over sodium sulfate and evaporation afforded 7.84 g (94%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, purity 99.3% (GC area, after derivatization with diazomethane). 1H-NMR (CDCl3, 300 MHz): ppm 0.81 (t, 6H), 1.15-1.65 (m, 15H), 2.05-2.15 (m, 2H), 12 (broad s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12]C)=[C:6]([CH2:8][C:9](=O)[CH3:10])[CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]([CH3:10])=[CH:8][C:6]=2[CH:7]=1
Reactant: COc1ccc(Br)cc1CC(C)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc2cc(Br)ccc2o1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 57.2 %

Procedure:
(5-Bromo-2-methoxyphenyl)acetone (6.6 g, 28.6 mmol) was dissolved in methylene chloride (50 ml) and cooled to −70° C. Thereto was dropwise added a 1 M solution (28.6 ml, 28.6 mmol) of boron tribromide in methylene chloride over 15 min. After the dropwise addition, the mixture was heated to room temperature and stirred for 1.5 hr. Then, the reaction mixture was ice-cooled and water (50 ml) was added. The insoluble matter was filtered off and the filtrate was partitioned. The aqueous layer was extracted with methylene chloride. The organic layers were combined, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1) to give the objective compound (3.45 g, 57%) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:59][NH:60][C@H:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][CH2:63][CH2:62]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:59][N:60]([C@H:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][CH2:63][CH2:62]1)[C:21]([C:19]1[N:20]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:27])([F:26])[F:25])=[N:5]3)[CH2:15][CH2:14]2)[S:17][CH:18]=1)=[O:22]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
2-[4-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-1-piperazin yl]-4-thiazolecarboxylic acid (200 mg, 0.5 mmol) (i.e. the product of Example 30, Step D) was suspended in 5 mL of dry dichloromethane and treated with triethylamine (150 μl, 1.08 mmol) to give a homogeneous solution. To this reaction mixture was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 210 mg, 0.55 mmol) followed by (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (106 mg, 0.60 mmol) (i.e. the product of Example 6, Step A). The reaction mixture was stirred at ambient temperature for 3 h, passed through a Varian Chem Elut™ CE1010 column pretreated with 5 mL of 20% aqueous citric acid solution. The column was flushed with three column volumes of dichloromethane, concentrated and purified by silica gel chromatography eluting with ethyl acetate to give 223 mg of the title product, the compound of present invention as white foam.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=O>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]=2)=[CH:8][CH:7]=1
Reactant: NCCCCC(=O)O
Reactant: ClCCCOc1ccccc1
Product: ClCCCOc1ccc(C2=NCCCC2)cc1
Yield: 30.4 %

Procedure:
Following the procedure described in example 15§A, but starting from O-(3-chloropropyl)phenol (3.55 g), 5-aminopentanoic acid (2.39 g) and polyphosphoric acid (36 g) gives 1.563 g of 6-[4-(3-chloropropoxy)phenyl]-2,3,4,5-tetrahydropyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([F:29])[CH:15]=1)[C:10](=[O:12])[CH3:11].BrC1C=C[C:34]([O:37]C)=[CH:33]C=1N(CC1C=CC(OCCN2CCCCC2)=C(F)C=1)C(=O)C.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:10]([N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([F:29])[CH:15]=1)[C:3]1[CH:4]=[C:5]([O:8][C:34](=[O:37])[CH3:33])[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:12])[CH3:11]
Reactant: CC(=O)N(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1Br
Reactant: COc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the total amount of N-(2-bromo-5-hydroxyphenyl)-N-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]acetamide crude product, which was synthesized from N-(2-bromo-5-methoxyphenyl)-N-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]acetamide (380 mg) synthesized according to an analogous synthetic method to Example 364 described below, were added pyridine (2 ml) and acetic anhydride (2 ml), and the solution was stirred for 1 hour at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-methanol system) to provide the title compound (350 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([CH:18]=O)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][OH:21]>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([CH:18]=[N:20][OH:21])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)c1cccc2c(C=O)cccc12
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cccc2c(C=NO)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-formyl-1-naphtoic acid tert-butyl ester (Example 9.3) (1.5 g) in ethanol (7.6 ml) was added aqueous hydroxylamine (50% w/v) (0.48 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give 5-(hydroxyimino-methyl)-1-naphtoic acid tert-butyl ester (1.4 g). 1H-NMR (CDCl3, 400 MHz): 8.90 (d, 1H), 8.81 (s, 1H), 8.62 (d, 1H), 8.10 (d, 1H), 7.80 (d, 1H), 7.50-7.65 (m, 2H), 1.70 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:8])=[CH:5][N:4]=[CH:3]1.N#C[Br:20].[Al]>C(#N)C>[Br:20][C:3]1[N:2]([CH3:1])[C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:8])=[CH:5][N:4]=1
Reactant: N#CBr
Reactant: Cn1cncc1C(=O)NCCN1CCOCC1
Agent: [Al]
Solvent: CC#N
Product: Cn1c(C(=O)NCCN2CCOCC2)cnc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 115 (550 mg, 2.31 mmol) in acetonitrile (5 mL) was added cyanogen bromide (489 mg, 4.6 mmol). The reaction flask was covered with aluminum foil and the mixture was allowed to stir at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (eluents 100% EtOAc to 30% MeOH/EtOAc), to afford title compound 116 as a beige solid (230 mg (31%). MS (m/z) 317.1/319.1 (M+H).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide hydrochloride and ethyl chloroformate. Yield: 62% of theory, C30H32N6O5 (556.6); Rf value: 0.51 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=557; (M+H+Na)++=290; (M+2H)++=279.