Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[CH:18][N:17]([CH3:20])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([N:6]1[C:5]2[CH:25]=[CH:26][C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]=[CH:18][N:17]([CH3:20])[N:16]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cn1cnc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 110 °C
Yield: 81.5 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(1-methyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (32 mg, 0.078 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (21 mg, 0.095 mmol), tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) and 2M aq. Na2CO3 (0.2 ml, 0.4 mmol). The reaction mixture is heated under Argon at 110° C. for 2 hours. The residue is diluted with EtOAc, washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-3% 7M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (27 mg, 82%) as an off-white solid. LCMS (ESMS): m/z 425.66 (M++1)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:32][CH2:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Yield: 95 %

Procedure:
A stirred mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (23.8 g, 70.5 mmol), 1-BOC-4-aminopiperidine (15.5 g, 77.5 mmol) and diisopropylethylamine (17.0 mL, 98.7 mmol) in propan-2-ol (250 mL) was heated to reflux for approximately 2 hours. After cooling, the resulting suspension was filtered and the solid washed with propan-2-ol and diethyl ether, then air dried to afford 33.6 g (95%) of 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 9.12 (br d, 1H), 9.09 (s, 1H), 8.21 (m, 2H), 7.66 (m, 2H), 7.53 (t, 2H), 6.69 (d, 1H), 4.14 (m, 1H), 4.01 (d, 2H), 3.12 (t, 2H), 2.11-2.08 (m, 2H), 1.65-1.64 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:16]1([CH2:15][CH2:14][CH2:13][C@@H:12]([C:22]2[O:23][CH:24]=[C:25]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[N:26]=2)[CH2:11][C:10]([NH:9][OH:8])=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CN(C)C(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of 2-((1R)-1 -{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-N,N-dimethyl-1,3-oxazole-4-carboxamide (Preparation 66) (100 mg, 0.23 mmol) in ethanol (5 ml) was treated with 5% palladium on barium sulphate (50 mg), pressurised to 1 atm with hydrogen in a sealed vessel and the mixture was stirred at room temperature for 2 hours. The solution was filtered through Arbocel® and the solvent removed from the filtrate under reduced pressure. The residue was azeotroped from dichloromethane (×3) then dichloromethane:ether (1 ml:4 ml) to afford the title compound as a foam (75 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>C(#N)C>[Br:27][C:22]1[C:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]=2[C:19]([O:25][CH3:26])=[CH:20][C:21]=1[C:23]#[N:24]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C#N)cc(OC)c21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C#N)cc(OC)c21
Yield: 44.5 %

Procedure:
A mixture of 110 mg (0.315 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonitrile and 56 mg (0.315 mmol) N-bromosuccinimide in 5 ml acetonitrile is stirred at reflux for 3 h. Then the solvents are evaporated and the residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) and recrystallized from EtOAc/diethyl ether/hexane to afford 60 mg of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](Cl)=[O:38])=[CH:33][CH:32]=1>CN(C=O)C>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:37](=[O:38])[CH2:36][O:35][C:34]3[CH:40]=[CH:41][C:31]([Cl:30])=[CH:32][CH:33]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (40 mg, 0.12 mmol) and pyridine (15 μl, 0.18 mmol) in DMF (1 ml) was added 4-chlorophenoxyacetyl chloride (27 mg, 0.13 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and was dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (32 mg, 53%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:16]([N:15]([CH3:19])[CH3:14])=[O:17])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 1.92 g 1-(1,1-dimethylethyloxycarbonyl)piperazine in 11 mL of dichloromethane and 1.5 mL of triethylamine at room temperature w,as added dropwise 1 mL of dimethylcarbamylchloride. After 16 hours 5% aqueous sodium hydrogencarbonate and dichloromethane were added, the organic layer separated, dried over magnesium sulfate and concentrated. Column chromatography on silica gel (dichloromethane/methanol=95/5 v/v) yielded 1.34 g 1-(1,1-dimethylethyloxycarbonyl)-4-(dimethylaminocarbonyl)piperazine. This compound was dissolved in a 3N hydrogen chloride solution in methanol at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and After stirring for 3 days at room temperature the reaction mixture was concentrated to give 1.06 g of 1-(dimethylaminocarbonyl)piperazine hydrochloride. rf=0.29, SiO2: dichloromethane/methanol=4/1 v/v.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.O.[NH2:24][NH2:25]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[N:3]=[C:2]([NH:24][NH2:25])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:17][CH:18]=1
Reactant: CC(C)Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: CC(C)Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-isobutyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: [S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17]2)[C:7]=1[C:8]#[N:9])(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+]>CCO>[NH2:9][C:8]1[C:7]2[C:10]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:27])[CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:17]3)=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][S:1](=[O:3])(=[O:4])[N:2]=1
Reactant: CC(C)CC(=O)N1CCC[C@H](COc2cccc(NS(N)(=O)=O)c2C#N)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)C1
Temperature: 65 °C
Yield: 90.8 %

Procedure:
To a stirred solution of (S)-2-sulfamoylamino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile (Example 5a, 19.5 g, 49.4 mmol) in EtOH (130 mL) was added 2N NaOH solution (84 mL) at room temperature. The reaction mixture was then heated at 65° C. until LC/MS confirmed that the starting material was consumed approximately 18 hours. The mixture was concentrated to remove ethanol, diluted with water (500 mL) and washed with ethyl acetate (50 mL×2). Ethanol (100 mL) was added to the aqueous phase and the mixture was acidified with 1M aq. HCl solution until pH=3. The precipitate that formed was collected by vacuum filtration to give a white solid that was further suspended in Ethanol (300 mL) and the solution was heated to reflux for 1 hr then cooled to 0° C. The precipitate was collected and dried under vacuum to give the title compound as an off-white solid (17.7 g, 82% yield). This material was combined with several other batches synthesized following the same procedure. A suspension of the combined batches (73.6 g, 186.57 mmol) in water (1500 mL) was treated with a solution of NaHCO3 (39.18 g, 466.43 mmol, 2.5 equivalents) in water (500 mL) and heated to 98° C. for 12 hrs until complete dissolution. The hot solution was then filtered to remove undissolved fine particles and the filtrate was cooled to room temperature and treated dropwise with 0.3M HCl until neutral pH, followed by 2M HCl until pH 3 and the solution was further stirred for 30 minutes. The precipitate that formed was collected by vacuum filtration, washed with water, and dried under vacuum to afford the title compound as an off-white powder (72.44 g). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ0.89 (d, 6H, J=4.0 Hz), 1.37-1.47 (m, 2H), 1.67-1.72 (m, 1H), 1.86-1.91 (m, 1H), 1.94-2.19 (m, 4H), 2.96 (br. s, 2H), 3.55-4.14 (m, 4H), 6.66 (d, 1H, J=4.0 Hz), 6.75 (d, 1H, J=8.0 Hz), 7.45 (t, 1H, J=8.0 Hz), 7.78 (br. s, 1H) 8.00 (br. s, 1H), 10.69 (s, 1H). MS 395 (MH+). Mp 237-238.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]4)=[CH:12][CH:11]=2)=[C:6]([CH:30]([CH3:32])[CH3:31])[O:5][N:4]=1.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[O:1][CH2:2][C:3]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]4)=[CH:12][CH:11]=2)=[C:6]([CH:30]([CH3:32])[CH3:31])[O:5][N:4]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CO)noc4C(C)C)cc3)ccc2n1
Reactant: Cc1cccc(C)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C(C)C)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.6 %

Procedure:
To a solution of methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (60 mg, 0.14 mmol), 2,6-dimethylphenol (17 mg, 0.14 mmol) and triphenylphosphine (40 mg, 0.15 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.028 mL, 0.15 mmol) dropwise. The solution was stirred at ambient temperature for approximately 1.5 hours and then in a microwave reactor at 100° C. for 10 minutes. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-40% ethyl acetate gradient elution). The resulting residue was taken up with ether and sonicated until a solid precipitated. The solid was isolated by filtration to afford methyl 6-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (23 mg, 31%). 1H-NMR (400 MHz, CDCl3) δ 8.37-8.32 (m, 2H), 8.23-8.21 (m, 1H), 8.05-8.01 (m, 2H), 7.69 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 7.01-6.01 (m, 3H), 5.04 (s, 2H), 4.96 (s, 2H), 4.09 (s, 3H), 3.29 (septet, J=7 Hz, 1H), 2.23 (s, 6H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.O.C[Si](C)(C)[C:43]([F:46])([F:45])[F:44]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:19])[C:43]([F:46])([F:45])[F:44])[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)c1cccnc1Oc1cccc(C=O)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccnc1Oc1cccc(C(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-Formyl-phenoxy)-nicotinic acid ethyl ester (2.0 grams, 7.4 mmole) in 0.5 M trimethyl(trifluoromethyl)silane (18 ml) in tetrahydrofuran (20 ml) at 0° C. was added tetrabutyl ammonium fluoride (0.050 g). The mixture was stirred at 0° C. for 1 hour. To the mixture was added 1.0 N hydrochloric acid (10 ml) and stirred at room temperature for 30 minutes. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with saturated NaHCO3, and water, dried over magnesium sulfate and concentrated to give an oil which was purified via flash chromatography on silica using 60% ethyl acetate/hexane as eluent to give an oil (1.97 g). MW 341.31; MS (m/e) 341 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>CN(C=O)C.O>[O:30]=[C:29]1[NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=2[CH2:4][CH2:5][N:6]1[CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:11][CH2:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2N)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(2-aminophenethylamino)piperidine-1-carboxylate (6.9 g, 30 mmol) in DMF (110 ml) was added CDI (4.86 g, 30 mmol) in portions followed by stirring the reaction mixture at RT for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organics were combined, washed with water, brine, and evaporated to dryness to give the desired product. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=346; tR=3.24.
Reaction SMILES: [C:1]12([C:11](O)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH2:26][CH2:27][N:28]3[C:32]([CH3:33])=[C:31]([CH3:34])[S:30][C:29]3=[NH:35])[C:19]=2[O:18][CH2:17][CH2:16]1>>[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH2:26][CH2:27][N:28]3[C:32]([CH3:33])=[C:31]([CH3:34])[S:30][C:29]3=[N:35][C:11]([C:1]34[CH2:8][CH:7]5[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]5)[CH2:2]3)[CH2:10]4)=[O:12])[C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1sc(=N)n(CCOc2cccc3c2OCCO3)c1C
Agent: Br
Product: Cc1sc(=NC(=O)C23CC4CC(CC(C4)C2)C3)n(CCOc2cccc3c2OCCO3)c1C
Yield: 195.6 %

Procedure:
Adamantane-1-carboxylic acid (0.78 g, 0.12 mmol) and the product of Example 81A (0.15 g, 0.39 mmol) were processed according to the method of Example 77B. Purification by column chromatography (SiO2, 0-15% methanol/methylene chloride gradient) afforded 0.11 g (60%) of the title compound
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[C:10]([N+:25]([O-])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[C:10]([NH2:25])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1NCc1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)nc1NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-morpholino-N-(naphthalen-1-ylmethyl)-3-nitropyridin-2-amine (3.56 g, 9.78 mmol) and 10% Pd/C (300 mg) in MeOH (200 mL) was stirred at room temperature for 3 h under a balloon pressure of H2. It was filtered and the filtrate was concentrated in vacuo to afford the desired as a dark-green solid (3.2 g, 98%); LC/MS: MS (ES+) m/e 335 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.10 (t, J=4.5 Hz, 4H), 3.60 (t, J=4.5 Hz, 4H), 4.11 (s, 2H), 4.98 (d, J=5.4 Hz, 2H), 5.79 (d, J=8.1 Hz, 1H), 5.97 (t, J=5.4 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 7.42-7.53 (m, 4H), 7.81 (d, J=7.5 Hz, 1H), 7.93 (t, J=4.8 Hz, 1H), 8.21 (d, J=4.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.C[O:30][B:31](OC)[O:32]C>>[Cl:21][C:17]1[C:16]([CH3:22])=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:7]1[C:6]2[CH:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=[C:2]([B:31]([OH:32])[OH:30])[C:10]=2[N:9]=[C:8]1[CH:11]([F:13])[F:12]
Reactant: COB(OC)OC
Reactant: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(Br)cc(N3CCOCC3)cc21
Product: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(B(O)O)cc(N3CCOCC3)cc21

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-1H-benzo[d]imidazol-6-yl)morpholine (430 mg, 0.913 mmol) using Method A with trimethylborate to give the product (55 mg, 0.126 mmol, 13.82% yield) as a light brown solid. LC/MS: MS (ES+) m/e 436.2 [M+H]+; 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.44-7.58 (m, 1H), 7.27-7.38 (m, 1H), 7.15 (d, J=2.27 Hz, 1H), 7.00 (t, J=7.96 Hz, 1H), 6.26 (d, J=7.58 Hz, 1H), 5.75 (s, 2H), 3.81-3.94 (m, 4H), 2.50 (s, 3H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:25])[CH2:20][O:21][CH2:22][CH2:23]Cl)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[CH3:28][NH:29][CH3:30].C(O)C>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:25])[CH2:20][O:21][CH2:22][CH2:23][N:29]([CH3:30])[CH3:28])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: OC(COCCCl)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCOCC(O)c1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
A mixture of 4.5 g of 1-(6-benzyloxy-2-naphthyl)-2-(2-chloroethoxy)ethanol, 1 g of potassium iodide, 10 ml of a 50% aqueous dimethylamine solution and 20 ml of ethanol was refluxed for 3 hours. To the reaction mixture was added 10 ml of a 50% aqueous dimethylamine solution. The resulting mixture was further refluxed for 6 hours. The reaction mixture was cooled and concentrated to about a half volume under reduced pressure. To the concentrate were added 100 ml of ethyl acetate and 100 ml of water. The mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 30 ml of diethyl ether. The resulting crystals were collected by filtration and dried to obtain 3.9 g of 1-(6-benzyloxy-2 -naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol (compound No. 284).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:13])=[O:4].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H]1CCCCCC[C@@H]1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCCCCC[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
cis-2-Amino-cyclooctanecarboxylic acid methyl ester (0.66 g, 3.56 mmol) was dissolved in methanol (20 mL). 4-Fluoro-benzaldehyde (0.44 g, 3.56 mmol) was added followed by acetic acid (1 mL). The solution was stirred at 25° C. for 10 min. Sodium cyanoborohydride (0.56 g, 8.9 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into 1/2 saturated aqueous sodium bicarbonate solution (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, cis-2-(4-fluoro-benzylamino)-cyclooctanecarboxylic acid methyl ester (0.7 g, 2.39 mmol, 67%), as a clear oil. LC-MS (ESI) calcd for C17H24FNO2 293.18, found 294.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH:17]([OH:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(O)CCC>[O:19]([CH2:18][CH:17]([OH:26])[CH2:16][CH2:15][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(C)O
Product: OC(CCN1CCN(c2ccc(F)cc2)CC1)COc1ccccc1

Procedure:
This compound was prepared according to the procedure of Example 6. A mixture of 3.6 g (0.02 mole) of 1-(4-fluorophenyl)piperazine, 4.0 g (0.02 mole) of 4-chloro-1-phenoxy 2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 5.1 g (74%) of offwhite powder, m.p. 97°-99° C. Recrystallizing solvent used was isopropyl alcohol.