Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[C:20]([C:26]1[CH:42]=[CH:41][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH:33]([C:37]([O:39][CH3:40])=[O:38])[CH2:32]2)=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:29]4[CH:41]=[CH:42][C:26]([C:20]([OH:25])([C:21]([F:22])([F:23])[F:24])[C:19]([F:44])([F:18])[F:43])=[CH:27][CH:28]=4)[CH2:32][CH:33]3[C:37]([O:39][CH3:40])=[O:38])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
4-(3-(Cyclopropylmethyl)ureido)benzoic acid (0.213 mmol, 0.05 g), methyl 4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-2-carboxylate (0.213 mmol, 0.085 g) and triethylamine (0.640 mmol, 0.089 mL, 0.065 g) were combined and stirred in dichloromethane. 1-Propanephosphonic acid cyclic anhydride (0.320 mmol, 0.191 mL, 0.204 g) was added and the reaction stirred for 2 hours at room temperature. This was washed with water and the resulting residue purified by acidic prep HPLC to afford the title compound (45 mg). MS (ESI) m/z 617.2 [M+H]+
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10].[CH:13]([C:15]([CH2:17][CH3:18])=[O:16])=[CH2:14]>CCCCCC.O1CCCC1>[CH3:6][O:7][C:8](=[O:12])[C:9]([CH3:11])([CH3:10])[CH:14]=[CH:13][C:15](=[O:16])[CH2:17][CH3:18]
Reactant: COC(=O)C(C)C
Reactant: C=CC(=O)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=O)C=CC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexane (224 ml; 2.2M) was added to tetrahydrofuran (THF, 300 ml) at -60° followed by diiospropylamine (52 g) and this mixture was then warmed to room temperature stirred for 5 min and then cooled to -72° C. Methylisobutyrate (50 g) was then slowly added and the mixture was stirred for 11/2 hr at -70° C. Freshly distilled ethyl vinyl ketone (42 g) in THF (60 ml) was added to the above mixture over 10 min and the mixture was then stirred for a further one half hr at -60° C and subsequently at room temperature for 2 hr.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:28][C:3]1[C:2]2[N:1]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:12]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc2ccccc2c(NCCC2CCN(C(=O)OC(C)(C)C)CC2)c1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 69.1 %

Procedure:
A solution of 0.65 g of tert-butyl 4-[2-[(3-amino-2-methylquinolin-4-yl)amino]-ethyl]-1-piperidinecarboxylate, 0.29 g of benzaldehyde and 0.08 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 5 ml of tetrahydrofuran was stirred at room temperature for 3 days. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried, and the solvent was evaporated to give a reddish brown liquid. The resulting liquid was purified by silica gel column chromatography using ethyl acetate—n-heptane (1:1) as an eluting solvent, and washed with diisopropyl ether to give 0.55 g of a colorless solid. Recrystallization from diisopropyl ether gave colorless crystals having the melting point of from 146 to 146.5° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:13]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]

Procedure:
To a solution of 4-bromo-2-nitroaniline (217 mg, 1 mmol) in DMF (6 mL) was added 3-pyridine boronic acid (148 mg, 1.2 mmol), potassium phosphate (276 mg, 1.3 mmol), and dichloro-(diphenylphosphinoferrocene)palladium (75 mg, 0.1 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7][NH2:8].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CCN(CC)CC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7][NH:8][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: NCCOc1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared from 2-(3,5-dichloro-phenoxy)-ethylamine, Et3N, and methanesulfonyl chloride using the procedure described in Step 2 of Preparation A1. Recrystallization from EtOH provided the title compound. 1HNMR (400 MHz, CDCl3) δ 6.93 (m, 1H), 6.74 (m, 2H), 5.09 (m, 1H), 4.01 (t, 2H), 3.47 (q, 2H), 2.96
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[N:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: BrCCCCCCCBr
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCCCCBr)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a chilled solution of 1-benzyl-4-tert-butoxycarbonylaminopiperidine (6.8 g, 23.4 mmol) in DMF (200 mL) was added sodium hydride (0.6 g, 60% dispersion in mineral oil). After 30 min, 1,7-dibromoheptane was added (12 mL) and the reaction mixture was stirred for 24 h. Another portion of sodium hydride (0.6 g, 60% dispersion in mineral oil) was added and the reaction mixture was stirred for 18 h. The DMF was removed in vacuo and the residue extracted with dichloromethane and 1 N HCl (3×). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give 18.5 g of the crude intermediate. This crude product was purified by silica gel column chromatography, eluting with 1% methanol in dichloromethane. The appropriate fractions were combined and concentrated to afford 4.7 g of the title intermediate (85% pure by HPLC, MS and NMR), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].C1(C)C(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=CC=1>CO>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([C:6]2[O:7][CH:25]=[N:24][CH:23]=2)=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: COc1cc(C=O)cc(OC)c1Br
Solvent: CO
Product: COc1cc(-c2cnco2)cc(OC)c1Br
Yield: 38.5 %

Procedure:
A solution of 4-bromo-3,5-dimethoxybenzaldehyde (5.04 g, 20.57 mmole) and toluenesulfonylmethyl isocyanide (4.22 g, 21.6 mmole) in MeOH (50 ml) was heated at reflux for 3 hrs. After evaporation to near dryness, H2O (50 ml) and EtOAc (200 ml) were added with stirring. The organic layer was separated and washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo. Et2O (50 ml) was added with swirling and the product was collected by filtration, washed with Et2O (2×25 ml) and dried giving 5-(4-bromo-3,5-dimethoxyphenyl)oxazole as a pale yellow solid (2.25 g, 39% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([F:13])=[CH:9][C:10]=1[O:11][CH3:12])=[O:4].[OH-].[Na+]>O1CCOCC1>[F:13][C:8]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[C:10]([O:11][CH3:12])[CH:9]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(F)c(-c2ccccc2)cc1C(=O)O
Yield: 97.1 %

Procedure:
To a stirring solution of 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid methyl ester (0.5 g, 2.3 mmol) in dioxane (8 mL, 0.3 M) was added 2N NaOH (6.0 mL, 12 mmol). After one'hour at room temperature, the reaction mixture was concentrated, and 2N HCl was added. The aqueous layer was diluted with ether. The organic layer was separated, dried over Na2SO4, filtered and concentrated to afford a 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid (0.55 g, 96%) as a pale yellow powder: Rf 0.18 (5% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 8.35 (d, J=9.0 Hz, 1H), 7.55-7.52 (m, 2H), 7.48-7.38 (m, 3H), 6.89 (d, J=11.7 Hz, 1H), 4.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:4].O.[ClH:23].[CH2:24](O)C>>[ClH:23].[ClH:23].[N:9]1([CH2:8][CH2:7][O:6][CH2:5][C:3]([O:2][CH2:1][CH3:24])=[O:4])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CCO
Reactant: COC(=O)COCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Product: CCOC(=O)COCCN1CCNCC1
Reaction time: 4 h
Yield: 97.3 %

Procedure:
2 g (0.0066 mol) of tert-butyl 4-(2-methoxycarbonylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.3. are dissolved in 10 ml of ethanol in a 50 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. 11 ml of a 3.8M solution of hydrochloric acid in ethanol are added in a single portion with stirring. The mixture is stirred at room temperature for 30 minutes and a further 11 ml of a 3.8M solution of hydrochloric acid in ethanol are added. The mixture is brought at the reflux temperature for 4 hours. The solvent is removed on a rotary evaporator under reduced pressure. 1.86 g (97.3%) of ethyl 2-(1-piperazinyl)-ethoxyacetate dihydrochloride are obtained in the form of a pale yellow oil which crystallizes. NMR: δ: 1.21 (3H, t, 7.1 Hz); 3.37 (2H, t, 4.8 Hz); 3.46 (1H, m); 3.55 (4H, m); 3.91 (2H, t, 4.8 Hz); 4.14 (2H, q, 7.1 Hz); 4.18 (2H, s); 10.1 (1H, bs); 12 (1H, bs). Mass spectrum: 216 (M+·).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].CCN(C(C)C)C(C)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Prepare a solution of 1-amino-2-propanol (5.0 g, 66.6 mmol) in methylene chloride (250 mL) at 0° C. under nitrogen. Add Hünig's Base (11.6 mL, 66.6 mmol) followed by benzoyl chloride (7.7 mL, 66.6 mmol). Warm the reaction mixture to room temperature and stir overnight. Wash the solution sequentially with brine (100 mL) and 1M HCl (75 mL), dry (Na2SO4), filter, and concentrate to afford 10.0 g of N-(2-hydroxypropyl)benzamide. MS: m/e=180 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[C:12]([O:14]C)=[O:13].[OH-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCc1cc(N)c(C(=O)OC)c(CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(N)c(C(=O)O)c(CC)n1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Methyl 4-amino-2,6-diethylpyridine-3-carboxylate (B) (3.94 g) was added to a mixture of 2M sodium hydroxide solution (9.5 ml) and methanol (40 ml) and the mixture was heated at reflux for 16 hours. The solution was cooled to ambient temperature and volatile material was removed by evaporation. The residue was partitioned between ethyl acetate and a mixture of 2M hydrochloric acid (9.5 ml) and water (20 ml). The aqueous phase was separated, water was removed by evaporation and the residue was extracted with ethyl acetate/methanol (1:1 v/v). The combined organic extracts were filtered and solvent was removed from the filtrate by evaporation to give 4-amino-2,6-diethylpyridine-3-carboxylic acid (C) (3.46 g) as a yellow-brown foam; NMR (d6 -DMSO): 1.18(m,6H), 2.64(q,2H), 3.12(q,2H), 6.94(s,1H), 8.28(broad s,2H); mass spectrum (chemical ionisation, ammonia): 195(M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:9]([CH:13]1[C:18](=[O:19])[CH2:17][CH:16]([C:20]2([CH3:40])[CH:25]=[C:24]([CH3:26])[CH2:23][C:22]([CH:28]3[CH2:33][C:32](=[O:34])[CH:31]([C:35](=[O:38])[CH2:36][CH3:37])[C:30](=[O:39])[CH2:29]3)([CH3:27])[CH2:21]2)[CH2:15][C:14]1=[O:41])(=[O:12])[CH2:10][CH3:11].Cl>ClCCl>[C:1]([C:24]1([CH3:26])[CH2:23][C:22]([CH:28]2[CH2:29][C:30](=[O:39])[CH:31]([C:35](=[O:38])[CH2:36][CH3:37])[C:32](=[O:34])[CH2:33]2)([CH3:27])[CH2:21][C:20]([CH:16]2[CH2:15][C:14](=[O:41])[CH:13]([C:9](=[O:12])[CH2:10][CH3:11])[C:18](=[O:19])[CH2:17]2)([CH3:40])[CH2:25]1)(=[O:3])[CH3:2]
Reactant: CCC(=O)C1C(=O)CC(C2(C)C=C(C)CC(C)(C3CC(=O)C(C(=O)CC)C(=O)C3)C2)CC1=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)C1C(=O)CC(C2(C)CC(C)(C(C)=O)CC(C)(C3CC(=O)C(C(=O)CC)C(=O)C3)C2)CC1=O
Reaction time: 15 h
Yield: 65 %

Procedure:
Acetyl chloride (0.3 ml) was added to a cooled, stirred suspension of aluminium chloride (1.5 g) and 1,3-bis (2-propionylcyclohexane-1,3-dione-5-yl) mesitylene (1.0 g) in dichloromethane (30 ml). Stirring was continued as the solution was allowed to come to room temperature and then for a further 15 hours. The solution was poured into dilute hydrochloric acid and the organic layer was separated, dried (Mg SO4) and evaporated to give 5-acetyl-1,3-bis(2-propionyl-cyclohexane-1,3-dione-5-yl)mesitylene (0.7 g, 65%) as a semi-crystalline foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]#[N:16]>>[N:7]1([CH:4]2[CH2:5][CH2:6][N:1]([CH2:14][C:15]#[N:16])[CH2:2][CH2:3]2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: N#CCBr
Reactant: C1CC(N2CCOCC2)CCN1
Product: N#CCN1CCC(N2CCOCC2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Piperidin-4-yl-morpholine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=210.1: 1HNMR(DMSO-d6) 3.65 (s, 2H), 3.55 (t, 4H), 2.80-2.75 (m, 2H), 2.40 (t, 4H), 2.15-2.00 (m, 3H), 1.80-1.70 (m, 2H), 1.40-1.30 (m, 2H).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:12](Cl)(=[O:16])[C:13](Cl)=[O:14]>CCOCC>[CH2:1]([N:6]1[C:13](=[O:14])[C:12](=[O:16])[C:8]2[S:9][CH:10]=[CH:11][C:7]1=2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1ccsc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CCCCCN1C(=O)C(=O)c2sccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 531.2 %

Procedure:
To a solution of N-pentylthiophen-3-amine (7.30 g, 4.30 mmol) in ether (50.0 mL) was added a solution of oxalyl chloride (6.00 mL, 42.0 mmol) in ether (50.0 mL) slowly at −10° C. The reaction mixture was stirred at ambient temperature for 3 h and quenched with cold water. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to afford the title compound (5.10 g, 53%): MS (ES+) m/z 246.3 (M+23).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:60])[C:17](=[O:59])[C:18]2[CH:58]=[CH:57][CH:56]=[C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:26][C:25]=3[C:36]3[CH:41]=[C:40]([C:42](=[O:55])[NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=4)[CH:39]=[CH:38][N:37]=3)=[O:22])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:61]OC(NC)C>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:61])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:60])[C:17](=[O:59])[C:18]2[CH:58]=[CH:57][CH:56]=[C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:26][C:25]=3[C:36]3[CH:41]=[C:40]([C:42](=[O:55])[NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=4)[CH:39]=[CH:38][N:37]=3)=[O:22])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: COCCNC(=O)N1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Reactant: CNC(C)OC
Product: COCCN(C)C(=O)N1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N1-(2-(4-((2-methoxyethyl)carbamoyl)piperazin-1-yl)ethyl)-N3-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N1-methylisophthalamide Example 207 substituting methoxy-N-methylethanamine in place of 2-methoxyethanamine LC-MS (ES, m/z): 843 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): 8.99 (d, J=5.1 Hz, 1H), 8.77 (d, J=9.0 Hz, 1H), 8.46 (s, 1H), 8.19 (m, 3H), 7.90 (m, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.74˜7.67 (m, 4H), 7.62˜7.53 (m, 2H), 4.72 (s, 2H), 4.00 (s, 2H), 3.90˜3.65 (m, 9H), 3.57 (d, J=5.1 Hz, 1H), 3.47 (d, J=4.8 Hz, 1H), 3.34 (s, 3H), 3.12 (s, 3H), 2.97 (s, 3H), 2.04 (d, J=4.8 Hz, 4H), 1.83 (d, J=4.2 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>C(#N)C>[N:29]1([CH2:28][CH2:27][NH:26][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NCCN1CCCCC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.775 mmol) in acetonitrile (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and 1-(2-aminoethyl)piperidine (119 mg, 0.93 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (266 mg, 94% yield) as yellow crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[Na].[CH3:20][CH:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>C(#N)C>[OH:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]3[CH2:23][CH2:24][CH2:25][CH:21]3[CH3:20])=[CH:7][CH:8]=2)[CH2:13][CH2:14]1
Reactant: CC1CCCN1
Reactant: O[C@H]1CC[C@H](c2ccc(OCCCCl)cc2)CC1
Agent: [Na]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc([C@H]2CC[C@H](O)CC2)cc1

Procedure:
A A mixture of trans-4-[4-(3-chloropropoxy)phenyl]cyclohexanol (403 mg), sodium hydrogenocarbonate (252 mg) potassium iodide (10 mg) and 2-methylpyrrolidine (153 mg) in acetonitrile (10 mL) is heated for 24 hours under reflux, then concentrated under reduced pressure. The residue is dissolved in ethyl acetate (25 mL). The organic phase is washed with water (5 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by chromatography over silica gel (eluent dichloromethane/methanol from 98/2 to 90/10). Fractions containing the expected product are pooled and concentrated under reduced pressure to give 120 mg of 1-{3-[trans-4-(4-hydroxycyclohexyl)phenoxy]propyl}-2-methylpyrrolidine as a white solid melting at 80° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](Cl)=[O:25])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:25])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Reactant: COCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCCNC(=O)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
3-Methoxypropylamine (0.026 g, 0.29 mmol) was added to a stirred solution of 3-(6-fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoyl chloride (intermediate 4) (26 mg 0.29 mmol) in tetrahydrofuran (2 ml) and the mixture stirred at room temperature for 15 min. Triethylamine (0.2 ml, 1.4 mmol) was then added and the resulting mixture stirred overnight. 1M Hydrochloric acid (3–4 ml) was added dropwise to precipitate a yellow solid which was filtered and dried under suction to give the amide (79 mg, 0.20 mmol) as a yellow solid, LCMS m/z 395.25 [M+H]+ @ RT 1.04 min; δH(400 MHz, (CD3)2SO) 8.59 (1H, m), 8.57 (1H, s), 8.39 (1H, app d J 9.3 Hz), 8.08 (1H, app d J 7.3 Hz), 7.66–7.53 (5H, m), 3.37–3.33 (4H, m), 3.27 (3H, s), 1.83–1.77 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[O:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(O)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-chloro-phenoxy)-piperidin-1-yl]-oxo-acetic acid (Example 29d) and 6-amino-3H-benzoxazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 242-244° C. (isopropanol)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:5][CH:4]=1.[Li]CCCC.[I:24]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[S:11][C:12]=2[I:24])=[CH:5][CH:4]=1
Reactant: II
Reactant: COc1ccc(Oc2csc3ccccc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(I)sc3ccccc23)cc1
Temperature: 25 °C

Procedure:
A solution of 133 mg (0.52 mmol) of 3-(4-methoxyphenoxy)benzo[b]thiophene (Part A) in 3 mL of THF was treated with 0.33 mL of 1.6 M n-BuLi in hexanes (0.54 mmol) at −78° C. for 15 min and then treated with 138 mg (0.54 mmol) of I2 in 3 mL of THF. The reaction was allowed to gradually warm to room temperature and then partitioned between brine and EtOAc/hexanes. The two phases were separated, the organic phase was washed with H2O, dried over Na2SO4, and concentrated in vacuo. The residue was crystallized from hexanes to afford 143 mg (0.37 mmol; 72%) of the title compound as a solid.