Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:28])[C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])([O-])=O.C([O-])=O.[NH4+].C(OCC)(=O)C>CO.[Pd].O>[NH2:1][C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:28])[C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1N)C(F)(F)F
Yield: 96 %

Procedure:
A suspension of N-[2-nitro-4-(phenylsulphonyl)phenyl]2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (J. Med. Chem., 1996, 39, 4592) (0.293 g) in methanol (5 ml) was added to a stirred suspension of 10% palladium on carbon (0.03 g) in methanol (2 ml) under an atmosphere of argon. A solution of ammonium formate (0.176 g) in water (2 ml) was added and the mixture was heated under reflux for 2 hours then cooled. Ethyl acetate (20 ml) was added and the mixture was filtered through diatomaceous earth. The filter was washed with ethyl acetate (2×10 ml) and the filtrates were combined, washed with water and brine then dried. Volatile material was removed by evaporation to give the title compound (0.261 g) as a solid. NMR: 1.55 (s, 3H), 5.3 (s, 2H), 7.1 (dd, 1H), 7.3 (d, 1H), 7.4 (m, 2H), 7.5-7.7 (m, 3H), 7.85 (d, 2H), 9.6 (s, 1H); MS (ESP−): 387.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:14]=3[S:15][C:16]=2[N:17]([CH3:19])[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[N:27]1([C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[OH:39])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[O:39][C:4]2[CH:5]=[CH:6][C:7]([C:10]([C:12]3[C:13]4[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:14]=4[S:15][C:16]=3[N:17]([CH3:19])[CH3:18])=[O:11])=[CH:8][CH:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc2sc(N(C)C)c(C(=O)c3ccc([N+](=O)[O-])cc3)c2cc1F
Reactant: O[C@@H]1CCCC[C@H]1N1CCCCC1
Product: COc1cc2sc(N(C)C)c(C(=O)c3ccc(O[C@@H]4CCCC[C@H]4N4CCCCC4)cc3)c2cc1F

Procedure:
The title compound was prepared in 51% from 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene-3-yl 4-nitrophenyl ketone (Example 117, Part C) and (±)-trans-2-(1-piperidyl)cyclohexanol by essentially following the procedure detailed in Example 117, Part D.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19]>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[CH2:4][CH2:3]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CN1CCC(N)CC1
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1NC1CCN(C)CC1

Procedure:
In the same manner as in Production Example 5-1 but using 1-methylpiperidine-4-amine in place of N-ethylpiperazine used in Production Example 5-1, using 2-fluoro-5-nitrotoluene in place of 2-fluoro-5-nitrobenzyl alcohol and using dimethylsulfoxide in place of N-methylpyrrolidone, 1.2 g of the entitled compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+].CCOCC>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3cccnc3c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
3.77 g (6.15 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(quinolin-7-yl-methoxy)-piperidin-1-carboxylic acid tert-butyl ester and 0.73 g (3.08 mmol, 0.5 equiv.) of nickel(II) chloride hexahydrate were dissolved in 50 ml of methanol. 0.93 g (24.8 mmol) of sodium borohydride was added at 0° C. in small portions over a period of 30 minutes. The resulting black suspension was then stirred for 1 hour at 0° C., and 2 hours at room temperature. The reaction mixture was slowly poured into a vigorously stirred mixture of 150 ml 5% ammonium chloride solution and 400 ml of ether. After further stirring for 30 minutes, the organic phase was separated. The slightly blue aqueous phase was further extracted 5 times with 50 ml of ether. The combined organic phases were washed twice with distilled water, then dried over magnesium sulphate, filtered and concentrated. The crude product (3.2 g, yellow oil) was chromatographed on silica gel with ethyl acetate/hexane 1:1 to yield 2.92 g (4.73 mmol, 77.0% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil; MS: 617 (M+H)+.
Reaction SMILES: O.[CH3:2][N:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4]1.C(=O)([O-])O.[Na+].[C:23]([C:25](=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[C:26](ON1C(=O)CCC1=O)=[O:27])#[N:24]>O1CCOCC1>[C:23]([C:25](=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[C:26]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]([CH3:2])[CH:4]=1)=[O:27])#[N:24]
Reactant: Cn1cc(C[C@H](N)C(=O)O)c2ccccc21
Reactant: N#CC(=Cc1ccccc1F)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(C[C@H](NC(=O)C(C#N)=Cc2ccccc2F)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To water (60 mL)-dioxane (60 mL) suspension of 1-methyl-L-tryptophan (2.1 g) was added sodium hydrogencarbonate (0.8 g) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Dioxane (80 mL) solution of the compound obtained in Example 120 (2.6 g, 9.2 mmol) was added dropwise to the reaction mixture at 0° C., and the mixture was stirred for 21 hours at room temperature. The reaction mixture was concentrated to a ⅓ volume under a reduced pressure, water was added thereto, and the mixture was washed with diethyl ether. The aqueous layer was made acidic with a 10% aqueous citric acid solution, and thereafter extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel chromatography (BW-127ZH, chloroform:methanol=50:1), to give the captioned compound (0.6 g, 17%) as an amorphous solid product.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH2:19][NH:20][C:21](=[O:24])[CH2:22]Cl)([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH:1]([N:14]1[CH2:17][C:16]2([CH2:19][NH:20][C:21](=[O:24])[CH2:22][O:18]2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1COC2(CN1)CN(C(c1ccccc1)c1ccccc1)C2
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
N-((1-Benzhydryl-3-hydroxyazetidin-3-yl)methyl)-2-chloroacetamide (example 33, step d) (2.6 g) in THF (50 mL) was added dropwise over 90 minutes to a vigorously stirred solution at 75° C. of potassium tert-butoxide (1M in tert-butanol, 15.08 mL) and THF (150 mL) under nitrogen. After the addition was complete the mixture was stirred at 75° C. for 10 minutes and then cooled to room temperature. The solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure to afford the subtitled compound. Yield 2.05 g.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][OH:33])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:21](=[O:25])[NH:20][C:19]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[N:18][C:17]1=2)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][OH:33])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:21](=[O:25])[NH:20][C:19]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])=[N:18][C:17]1=2
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a solution of compound 15 (5.8 g, 12.7 mmol) in methanol (50 mL) was added 10% Pd/C (2 g) and formic acid (3 mL). The mixture was refluxed for 5 h, cooled to ambient temperature and filtrated through silica gel column. The column was washed with methanol (50 mL), all the filtrate was concentrated under reduced pressure to yield 4.55 g (98%) of compound 16 as a glass-like solid.
Reaction SMILES: [N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[NH:21][C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[N:4]2[CH2:3][CH2:2]1.I[CH2:30][CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]([CH2:30][CH3:31])[C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[N:4]2[CH2:3][CH2:2]1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(N2CCn3c2nc2cccnc23)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(N3CCn4c3nc3cccnc34)cc2)c2ncccc21
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 3-[4-(2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (165 mg), iodoethane (0.054 mL) and cesium carbonate (291 mg) in DMF (3 mL) was stirred at 50° C. for 6 h. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residual crystals were dissolved in THF, and the solution was filtered through NH-silica gel. The filtrate was concentrated under reduced pressure. The residual crystals were recrystallized from EtOH to give the title compound (94 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26]([C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:29]=[N:30][C:31]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[N:32][CH:33]=1)=[O:27]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1cnc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 132 from 4-chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 130, step 7) with methyl-2-chloropyrimidine-5-carboxylate [CAS Reg. No. 287714-35-6]. MS (neg. ion, m/e)=500.0 [(M−H)−].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:17][C:18]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[NH2:17][C:18]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:21]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: NCc1ccc(CNc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)ccc1C(=O)NCc1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of (4-aminomethyl-benzyl)-phenylamine described in Preparation Example 21 (369 mg, 1.74 mmol) and 2-amino-6-chloro-nicotinic acid (300 mg, 1.74 mmol) in N,N-dimethylformamide (10 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (924 mg, 2.09 mmol) and triethylamine (0.49 mL, 3.48 mmol), and the solution was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water, and then, dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and the title compound (479 mg, 75%) was obtained as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39]([CH:41]=[CH:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:40])[CH:41]=[CH:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][C:28](=[O:33])[NH:29][S:30]5(=[O:31])=[O:32])=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:45][CH:44]=1)[CH3:37]
Reactant: CCOC(=O)C=Cc1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CCOC(=O)C=Cc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (200 mg, 0.34 mmol) was treated as described in general procedure G using 4-(2-ethoxycarbonyl-vinyl)phenyl boronic acid to provide 3-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-acrylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[O:16][CH3:17])[NH:8][C:4]=2[CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:20][S:21]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:10]=3[O:16][CH3:17])[NH:8][C:4]=2[CH:3]=1)(=[O:23])=[O:22]
Reactant: COc1cc(O)ccc1-c1nc2ccc(N)cc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(NS(C)(=O)=O)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-amino-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: [H-].[Na+].CCCCCC.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].[CH3:17][O:18][CH2:19]Br>CN(C)C=O>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: COCBr
Reactant: Oc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COCOc1ccccc1Br
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
The oil was removed from 4.5 g (60% in oil, 112 mmol, Aldrich) of sodium hydride dispersion by three-20 mL washes with hexane then the residue was covered with 75 mL of dimethylformamide (Burdick and Jackson). The resulting mixture was heated to about 50° and 18.1 g (105 mmol, Aldrich) of 2-bromophenol was added dropwise over 15 minutes. Vigorous gas evolution was observed. The reaction was stirred for an additional 30 minutes then the resulting gray-brown solution was cooled to 0° and 9.6 mL (117 mmol, Aldrich) of bromomethyl methyl ether was added dropwise over 15 minutes. The reaction mixture was stirred for 1 hour at 0° then at room temperature for 16 hours. The resulting slurry was partitioned between 200 mL of 1M aqueous sodium hydroxide solution and 150 mL of 4:1 hexane/diethyl ether. The aqueous layer was separated and extracted with an additional 100 mL of 4:1 hexane/diethyl ether. The organic extracts were combined, washed with two-200 mL portions of water, dried (magnesium sulfate) and concentrated in vacuo to give 22.2 g (102 mmol, 97%) of title compound as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])=[CH:34][CH:33]=1>O1CCCC1>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([NH:41][C:42](=[O:43])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH:19]([N:22]5[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:29][CH:30]=2)=[O:40])=[CH:36][CH:37]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)CC1
Reaction time: 72 h
Yield: 18 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (86.9 mg) in tetrahydrofuran (2.5 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 2.12 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=97:3) to provide the titled compound (22.5 mg, 18%) as white powder.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:20]([O:19][C:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][NH:8][CH2:9][CH:10]12)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(Cc3ccccc3)CC21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC2CNCC21
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
In 50 ml of ethanol was dissolved 2.86 g of 6-benzyl-1-t-butoxycarbonyloctahydropyrrolo[3.4-b]pyridine, and 500 mg of 5% palladium-on-carbon was added thereto. While the reaction vessel was heated by a tungsten lamp, hydrogenation was conducted under a pressurized hydrogen gas atmosphere of 4 kg/cm2 for 1.5 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated to yield 1.98 g of the titled compound as an oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](OC)[C:10]=1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:19])[C:10]=1[CH:17]=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(OCc2ccccc2)c1CO
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: Cc1cccc(OCc2ccccc2)c1C=O
Reaction time: 1.75 h
Yield: 89.8 %

Procedure:
In a nitrogen stream, a solution of (2-benzyloxy-6-methoxyphenyl)-methanol (3.46 g, 15.16 mmol) and N-methylmorpholine N-oxide (NMO, 2.66 g, 22.73 mmol) in dichloromethane (10 mL) was cooled in a water bath and tetra-n-propyl-ammonium perruthenate (TPAP, 152 mg, 0.43 mmol) was added thereto. The reaction mixture was stirred at the same temperature for 1.75 hours, and then subjected to Celite filtration and the solvent was distilled under reduce pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (3.08 g, 90%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:15](Br)=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:12]1)=O)(C)(C)C.[ClH:29].C=O.[OH-].[Na+]>C(O)C>[Cl:29][C:15]1[N:11]2[CH2:10][CH2:9][NH:8][CH2:6][C:12]2=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1
Reactant: CCOC(=O)c1cn(CCNC(=O)OC(C)(C)C)c(Br)c1-c1cccc(F)c1
Reactant: Cl
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To a solution of 38.4 g (84.3 mmol) of ethyl 1-(2-tert-butoxycarbonylaminoethyl)-5-bromo-4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in 80 ml of ethanol are added slowly 271 ml (949 mmol) of aqueous 3.5N hydrochloric acid solution. The formation of a white precipitate is rapidly observed and then, after 45 minutes, the medium becomes clear, while the mixture is heated to 70° C., and 3.00 g (31.2 mmol) of paraformaldehyde are added. Heating is continued at 70° C. for 1 hour. After cooling, the reaction medium is poured into a mixture of ice and aqueous 4N sodium hydroxide solution. The product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a brown oil, which is chromatographed on a column of 330 g of silica gel, eluting with a mixture of 3% methanol in dichloromethane, to give 14.3 g of ethyl 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate after crystallizing from 50 ml of diisopropyl ether.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1C=CC=CC=1>[CH2:1]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCBr
Reactant: c1c[nH]cn1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCn1ccnc1

Procedure:
A stirred mixture of 9.96 g. of dodecyl bromide (40 mM), 5.44 g. of imidazole (80 mM), 100 ml. of 0.97N NaOH (97 mM), 100 ml. of PhH, and 336 mg. of Aliquat 336 (1 mM; methyltricaprylylammonium chloride) was refluxed for 23 h. The benzene layer was separated, washed with brine containing a little NaOH, and evaporated. The residue was purified of a little front-running and some origin impurities by quick chromatography on 150 g. of silica gel with 1:1 CH2Cl2 --EtOAc (Rf 0.35), affording 7.48 g. of single-spot material which was distilled at ca. 0.5 Torr (bp 144° C.) to give 6.97 g. of pure product (74%): NMR 7.5 (s, 1H), 7.1 (br s, 1H), 6.95 (br s, 1H), 3.95 (t, J=7 Hz, 2H), 1.85 (m, 2H), 1.3 (s, 18H), 1.0 ppm (m, 3H).