Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I>CN(C=O)C>[Cl:17][CH2:18][CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: ClCCCI
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl

Procedure:
6-nitro-3,4-dihydroquinolin-2(1H)-one (1.50 g, 7.81 mmol) was dissolved in anhydrous DMF (30 mL) in an argon purged round bottom flask. The reaction was stirred in an ice-water bath and 60% sodium hydride in mineral oil (1.25 g, 31.25 mmol) was added in one portion. The reaction became dark red-orange. This solution was transferred using a cannulating needle to a solution of 1-chloro-3-iodopropane (2.52 mL, 23.47 mmol) in DMF (20 mL). The reaction was stirred at room temperature for 5 hours. The reaction was quenched with brine (25 mL), transferred to a separatory funnel and partitioned with ethyl acetate (30 mL). The aqueous was extracted twice more with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried with sodium sulphate, decanted and concentrated to afford a yellow solid. Purification by flash column chromatography afforded a yellow solid (Ethyl acetate:hexanes, 30:70-100:0); Yield: 1.58 g (75%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:40]=[C:39]([C:41]3[S:45][C:44](Cl)=[N:43][C:42]=3[C:47]([F:50])([F:49])[F:48])[CH:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]>C(#N)C>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:40]=[C:39]([C:41]3[S:45][C:44]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[N:43][C:42]=3[C:47]([F:49])([F:50])[F:48])[CH:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3sc(Cl)nc3C(F)(F)F)n2)c1
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cccc(Nc2nccc(-c3sc(NCCCCNC(=O)OC(C)(C)C)nc3C(F)(F)F)n2)c1
Temperature: 25 °C

Procedure:
Diisopropylethylamine (0.1 mL, 0.6 mmol) and 4-t-butoxycarbonylamino-butylamine (25 mg, 1.4 mmol) are added to a solution of N-[3-ethoxycarbonyl-phenyl]-4-[2-chloro-4-trifluoromethyl-5-thiazolyl]-2-pyrimidineamine (52 mg, 0.12 mmol) in 50 mL anhydrous acetonitrile. The mixture is then heated to reflux overnight. The reaction is stopped, cooled to room temperature and concentrated. Water (30 mL) is added and the reaction mixture is extracted with ethyl acetate (3×100 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The residue is used in the next step without further purification; ESI-MS (m/z): 567.2 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(CC)CC)C>ClCCl>[C:37]([N:11]1[CH2:12][CH2:13][C@H:9]([O:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]5[C@H:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=5[CH:24]=4)[CH:16]=3)=[C:4]([CH3:14])[CH:5]=2)[CH2:10]1)(=[O:39])[CH3:38]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCNC5)cc4C)c3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCN(C(C)=O)C5)cc4C)c3)ccc21
Reaction time: 2 h
Yield: 94.4 %

Procedure:
The crude methyl 2-((S)-6-((2′,6′-dimethyl-4′-((S)-pyrrolidin-3-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 8a (45 mg, 0.09 mmol) were dissolved in 3 mL of dichloromethane, followed by addition of acetic anhydride (13 mg, 0.11 mmol) and triethylamine (18 mg, 0.18 mmol). The reaction solution was stirred for 2 hours. The resulting solution was mixed with 20 mL of dichloromethane. The organic phase was washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound methyl 2-((S)-6-((4′-(((S)-1-acetylpyrrolidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 9a (45 mg, yield 92.5%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:18])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[N:8]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C.[Fe]>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][C:12]2[NH:13][C:3](=[O:2])[CH:4]([CH3:18])[CH2:5][NH:6][C:7]=2[N:8]=1
Reactant: COC(=O)C(C)CNc1nc(OC)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(n1)NCC(C)C(=O)N2
Temperature: 90 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
To a solution of methyl-3-((6-methoxy-3-nitropyridin-2-yl)amino)-2-methylpropanoate (4.0 g, 14.86 mmol) in anhydrous ethanol (50 mL) was added iron powder reduced (8.30 g, 148.56 mmol) and acetic acid (17.84 g, 297.12 mmol). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was neutralized to pH 8 with solid sodium hydrogencarbonate, concentrated in vacuo and washed with water (20 mL), filtered. The filtrate was extracted with acetic ester (200 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: dichloromethane/Methanol: 80:1→50:1) to give 7-methoxy-3-methyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-one (3 g, 96%) as a yellow solid.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[NH:22][NH2:23].C(N(CC)CC)C>CCO>[CH2:26]([O:25][C:21](=[O:24])[NH:22][N:23]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: NNC(=O)OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3ccccc3)n(NC(=O)OCc3ccccc3)cc2n(C)c1=O
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (1.15 g, 3.41 mmol), benzyl carbazate (commercial) (2.83 g, 17.05 mmol) and triethylamine (1.426 ml, 10.23 mmol) were combined in EtOH (15 ml) and the mixture heated at reflux for 15 mins. The reaction mixture was cooled to RT and evaporated under reduced pressure. The residue was partitioned between water and DCM and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was triturated with Et2O and cooled in ice until precipitation occurred. The precipitate was collected by filtration, affording the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[C:24]([C:27]2[N:31]4[CH:32]=[CH:33][C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:35][C:30]4=[N:29][CH:28]=2)[CH:23]=[CH:22]3)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl>O1CCOCC1>[F:1][C:2]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[C:24]([C:27]2[N:31]4[CH:32]=[CH:33][C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:35][C:30]4=[N:29][CH:28]=2)[CH:23]=[CH:22]3)[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OCC5(F)CCN(C(=O)OC(C)(C)C)CC5)c4n3)cnc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COCCOc1ccn2c(-c3ccc4cccc(OCC5(F)CCNCC5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
tert-Butyl 4-fluoro-4-((2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)methyl)piperidine-1-carboxylate (0.011 g, 0.020 mmol) was dissolved in dioxane (0.5 mL) and treated with 4 M hydrogen chloride in dioxane (0.126 ml, 0.504 mmol). The reaction was stirred at ambient temperature for 24 hours. The mixture was concentrated in vacuo, redissolved and re-concentrated from MeOH three times. The crude material was loaded onto a SiO2 column and eluted with a gradient from 1 to 20% (6% NH4OH in MeOH)/ethyl acetate to provide the desired product (3 mg). 1H NMR (400 MHz, CDCl3) δ 10.67 (d, 1H), 8.22 (s, 1H), 8.08 (d, 1H), 7.83 (s, 1H), 7.41-7.33 (m, 2H), 7/09-6.98 (m, 2H), 6.90-6.84 (m, 1H), 4.29-4.16 (m, 3H), 3.87-3.79 (m, 2H), 3.49 (s, 3H), 3.23-3.10 (m, 3H), 2.29-2.15 (m, 1H), 2.14-1.94 (m, 2H), 0.93-0.81 (m, 1H). MS APCI (+) m/z 451.2 (M+1) detected.
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]([CH2:11][C:12]23[CH2:19][CH2:18][CH2:17][N:16]2[C:15](=[O:20])[N:14]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:13]3=[O:29])=[CH:9][CH:8]=1)=[O:6]>CO.O.O>[Cl:28][C:23]1[CH:22]=[C:21]([NH:14][C:15]([N:16]2[CH2:17][CH2:18][CH2:19][C@@:12]2([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([OH:4])=[O:6])=[CH:31][CH:30]=2)[C:13]([OH:1])=[O:29])=[O:20])[CH:26]=[C:25]([Cl:27])[CH:24]=1
Reactant: COC(=O)c1ccc(CC23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C[C@@]2(C(=O)O)CCCN2C(=O)Nc2cc(Cl)cc(Cl)c2)cc1
Temperature: 45 °C
Yield: 87.2 %

Procedure:
NaOH (0.406 g) was added to a solution of 5-(4-methoxycarbonylbenzyl)-3-(3,5-dichlorophenyl)-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.601 g) in MeOH/H2O (20 mL/4 mL) and the mixture was heated at 45° C. for 18 hours. The reaction mixture was cooled, acidified, diluted with water and extracted with EtOAc. The extract was washed with water, brine, dried (MgSO4), filtered, and concentrated. The residue was recrystallized from EtOAc/hexane (1:1) to give N-[N-(3,5-dichlorophenyl)carbamoyl]-2-(4-carboxybenzyl)proline (0.529 g). mp. 144.6° C.; MS (m/z) 459 (M++Na). (2) A mixture of the compound obtained above (0.074 g) and SOCl2 (1.0 mL) was heated at 100° C. for 1 hour. The solution was evaporated. The residue was dissolved in toluene, evaporated and dried under vacuum. The residue was dissolved in THF (4 mL) and the solution was added to an ice cold solution of dimethylamine (1 mL, 2M in THF) in THF (1 mL). The reaction mixture was stirred for 3 hour at room temperature and diluted with EtOAc and water. The organic layer was separated and washed with 0.5 N HCl (10 mL), water and brine. It was dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc, Chromatotron) afforded the titled compound (47 mg). MS (m/z) 468 (M++Na).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution (400 mL) of 1-(2,5-dihydroxyphenyl)ethanone (25.0 g) in acetonitrile were added benzylbromide (19.6 mL) and potassium carbonate (25.0 g) at room temperature, and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. Saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a solid. The obtained solid was washed with ethanol-isopropyl ether to give the title object compound (31.0 g, 80%) as a yellow-green solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10]C(C)=O)[CH:5]=[CH:4][C:3]=1[O:14][C:15]([CH3:17])=[O:16].CO.C([O-])([O-])=O.[K+].[K+].Cl>ClCCl>[C:15]([O:14][C:3]1[CH:4]=[CH:5][C:6]([OH:10])=[C:7]([C:8]#[N:9])[C:2]=1[Br:1])(=[O:16])[CH3:17]
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(C#N)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Oc1ccc(O)c(C#N)c1Br
Reaction time: 8 h
Yield: 62.5 %

Procedure:
12C (15 g, 0.05 mol) was added to MeOH (52 ml) and dichloromethane (52 mL). To the mixture was added K2CO3 (7 g, 0.05 mol) in batches at room temperature. The reaction mixture was stirred overnight at room temperture, then neutralized with diluted hydrochloric acid to pH=6˜7, extracted with dichloromethane, dried over anhydrous Na2SO4 and concentrated to give 12D (8 g, 62.1% yield).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[OH:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([OH:26])[CH2:28]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: OC1CCCNC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCCC(O)C1

Procedure:
5-(3-Hydroxy-piperidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-hydroxypiperidine. Mass spectrum (ES) MH+=421.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[C:19]([C:13](=[CH:12][NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(=O)Cl
Reactant: CCOC(=O)C=CNc1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)C(=CNc1ccccc1OC)C(=O)OCC
Temperature: -30 °C
Yield: 62.6 %

Procedure:
50% Sodium hydride (4.8 g, 0.1 mol) was washed with petroleum ether and then suspended under nitrogen in dry tetrahydrofuran (50 ml) at -30° C. Ethyl 3-(2-methoxyphenylamino)acrylate (17.4 g, 0.1 mol) in dry tetrahydrofuran (100 ml) was added dropwise to the stirred suspension keeping the temperature below -20° C. Cooling was removed and the mixture was stirred until a deep red colour was obtained. The mixture was re-cooled to -30° C. and hexanoyl chloride (13.8 ml, 0.1 mol) in dry tetrahydrofuran (50 ml) was added dropwise. Cooling was again removed and the mixture was stirred for 2 hours. The mixture was partitioned between 10% hydrochloric acid and dichloromethane then washed with water and brine, dried and evaporated to afford an oil which was chromatographed (silica gel, chloroform) to give ethyl 2-hexanoyl-3-(2-methoxyphenyl-amino)acrylate, (20 g, 62.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(N(CC)CC)C.[F:40][C:41]([F:49])([F:48])[CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:27]=[CH:28][C:29]([O:32][S:44]([CH2:43][CH2:42][C:41]([F:49])([F:48])[F:40])(=[O:46])=[O:45])=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one (0.40 g, 0.85 mmol) in dichloromethane (20 ml) at 0° C. was added triethylamine (0.14 ml, 1.02 mmol) followed by 3,3,3-trifluoropropanesulfonyl chloride (0.20 g, 1.02 mmol). The reaction mixture was subsequently stirred at room temperature for two hours. Concentration and purification by flash chromatography (heptane:EtOAc gradient) afforded 200 mg (37%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14](O)=[O:15])=[CH:10][C:9]=2[C:19]([N:21]2[C@H:30]([CH2:31][OH:32])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:6]=1[CH3:7].[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH2:35]([N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14](=[O:15])[NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:10][C:9]=2[C:19]([N:21]2[C@H:30]([CH2:31][OH:32])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[N:4]=1)=[O:43])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OCC(=O)O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OCC(=O)Nc3ccccc3)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.6 %

Procedure:
To a stirred solution of [4-(4-chloro-3-dibutylcarbamoyl-5-methyl-pyrazol-1-yl)-3-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenoxy]-acetic acid (15 mg, 0.025 mmol) and aniline (3.4 uL, 0.037 mmol) in dichloromethane (0.2 mL) under nitrogen atmosphere was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (7.1 mg, 0.037 mmol) and hydroxybenzotriazole (5.6 mg, 0.037 mmol). The mixture was stirred at ambient temperature for 5 minutes. Triethylamine (10 uL, 0.074 mmol) was added to the mixture. The reaction was stirred for 12 hours. After eluting through a short pad of silica gel column, the crude material was purified by HPLC to afford the title compound (8 mg, 50% yield). MS (ESI) [m/e, (M+H)+]=686.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.82-7.69 (m, 12H), 4.13-5.38 (m, 5H), 2.38-3.75 (m, 8H), 2.15-2.32 (m, 3H), 1.12-1.70 (m, 8H), 0.66-0.99 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=O)=O)=CC=1>>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CCc2ccc(Cl)cc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 22 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.38 g) and 2-(4-chlorophenyl)ethyl p-toluenesulfonate (0.57 g) were reacted under the same conditions as in Example 1 to give (S)-N-(1-(2-(4-chlorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.13 g), melting point 94-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C=O.[C:34](O)(=O)C>C(Cl)Cl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]5[CH2:25][CH2:26][N:27]([CH3:34])[CH2:28][CH2:29]5)[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(OC2CCNCC2)n1
Agent: C=O
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(Oc2cccc(Cn3ncc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chlorophenyl)-6-{[6-(piperidin-4-yloxy)pyridin-2-yl]methyl}thieno[2,3-d]pyridazin-7(6H)-one (0.16 g, 0.34 mmol) in DCM/MeOH (1:1, 10 mL) was added (polystyrylmethyl)trimethylammonium cyanoborohydride (0.25 g, 1.03 mmol), 36% aq. formaldehyde (0.05 mL, 0.69 mmol) and acetic acid (one drop). After 3 hours of stirring one additional amount of (polystyrylmethyl)trimethylammonium cyanoborohydride, formaldehyde and acetic acid added to the reaction mixture and stirred for two hours. The reaction mixture was filtrated, concentrated in vacuo and purified by flash chromatography using a gradient with EtOAc:MeOH:TEA (1:0.1:0.05) in n-heptane, which gave the product. Yield: 0.084 g (52%). 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.57-7.64 (m, 2H), 7.30-7.49 (m, 4H), 6.71 (d, 1H, J=7.31 Hz), 6.52 (d, 1H, J=8.16 Hz), 5.47 (s, 2H), 4.69-4.79 (m, 1H), 2.49-2.58 (m, 2H), 2.13 (s, 3H), 1.87-1.99 (m, 2H), 1.75-1.84 (m, 2H), 1.58-1.69 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 163.0, 157.4, 153.5, 152.3, 140.3, 139.3, 136.4, 136.0, 133.1, 131.3, 129.8, 128.1, 113.8, 110.1, 70.5, 55.6, 53.3, 46.4, 31.0 MS (ESI+) 467.08 (M+1H+).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13]>O.CC(C)=O>[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]([OH:2])=[O:13]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1OC
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)c([N+](=O)[O-])c1OC

Procedure:
A solution of 823 g. potassium permanganate in about 8.5 liters of H2O was gradually added to a refluxing solution of 3,4-dimethoxy-2-nitrobenzaldehyde (550 g., 2.60 moles) in 5.6 liters of acetone. The reaction mixture was refluxed for four more hours, then filtered through diatomaceous earth while hot and the filter cake washed with hot water. The acetone was removed in vacuo and a small amount of unreacted solid was filtered off. The aqueous solution was acidified with 2 N hydrochloric acid (1.8 liters) to yield 505 g. (85% ) of the essentially pure title compound. Recrystallization from water afforded colorless crystals, M.P. 200°-202° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH2:22])=[N:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[CH3:20][N:19]([CH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([NH:22][C:23](=[O:25])[CH3:24])[N:5]=1)[CH3:21]
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (1.0 g), acetic anhydride (0.35 g) and pyridine (50 ml) was stirred at 25° for 12 h. The pyridine was removed and the residue was dissolved in ethyl acetate. The organic solution was washed with aqueous sodium carbonate and evaporated to give the title compound as a pale yellow oil (1.1 g). TLC silica, methanol/0.88 ammonia 80:1, Rf 0.49. NMR (CDCl3) 1.42 brs (1H); 2.81 m (1H); 3-3.4 m (3H); 5.34 t (1H); 5.98 t (2H); 6.52 s (3H); 6.65 s (2H); 6.5 m (2H); 7.8 s (6H); 7.5-8.1 m (2H); 7.9 s (3H).