Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=C)=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC.CO>[CH2:21]([NH:28][C:12]1[C:11](=[CH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:15][C:14](=[O:16])[C:13]=1[N+:17]([O-:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=C1NC(=Cc2ccccc2)C(O)=C1[N+](=O)[O-]
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: O=C1NC(=Cc2ccccc2)C(NCc2ccccc2)=C1[N+](=O)[O-]
Yield: 60 %

Procedure:
An excess of diazomethane in ether is added to a suspension of 0.46 g (2 mmol) benzylidene-4-hydroxy-3-nitro-3-pyrrolin-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 20 ml methanol. When the evolution of nitrogen has subsided, the solvent is stripped off, the residue is dissolved in methanol and the solution is heated under reflux with an excess of benzylamine for five minutes, whereupon yellow crystals precipitate out, which are filtered off with suction and washed with methanol. 4-Benzylamino-5-benzylidene-3-nitro-1,5-dihydropyrrol-2-one was obtained with a melting point of 218° C. in a yield of 60%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([NH2:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].CO[CH:33]1[CH2:37][CH2:36][CH:35](OC)O1.O>C(O)(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([N:24]1[CH:33]=[CH:37][CH:36]=[CH:35]1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(N)cc12
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-n3cccc3)cc12
Yield: 66.3 %

Procedure:
A solution of tert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.41 g, 1 mmol) and 2,5-dimethoxytetrahydrofuran (0.19 ml, 1.5 mmol) in acetic acid (10 ml) was stirred at 80° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-pyrrol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.31 g, 67.4%) as crystals.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)c1ccccc1
Yield: 84.9 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.58 ml (4.96 mmol) of benzoyl chloride under ice-cooling with stirring and the mixture stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 960 mg of the desired compound (84.9%, colorless needles), mp: 120.0°-121.0° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>>[O:6]=[C:4]1[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[S:15][C:16]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=2)=[N:17]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#C[S-]
Reactant: O=C(O)c1cccnc1Cl
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Yield: 85.5 %

Procedure:
The reaction procedure of Example 6 was followed except that 5.00 g of chloronicotinic acid, 25 ml of thionyl chloride, 2.42 g of ammonium thiocyanate and 5.24 g of ethyl 4-aminobenzoate were used. As a result, 8.88 g of ethyl 4-[(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino)benzoate obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[O:38][N:37]=1.C(N(CC)CC)C>CS(C)=O>[C:41]([C:39]1[O:38][N:37]=[C:36]([NH:35][C:34]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]3[N:17]4[CH:18]=[CH:19][C:14]([C:11]5[CH:12]=[N:13][C:8]([N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[N:9][CH:10]=5)=[CH:15][C:16]4=[N:22][CH:21]=3)=[CH:24][CH:25]=2)=[O:33])[CH:40]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(N)cc5)cnc4c3)cn2)CC1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(NC(=O)Nc6cc(C(C)(C)C)on6)cc5)cnc4c3)cn2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Combine the amine (0.323 g, 0.838 mmol), (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.291 g, 0.922 mmol) and triethylamine (0.128 mL, 0.922 mmol) in DMSO (10 mL). Heat the mixture to 70° C., stir overnight, and cool to room temperature. Extract the mixture with ethyl acetate versus water. Wash the organic layer with saturated aqueous saturated sodium chloride. Dry the resulting organics over magnesium sulfate, filter, and concentrate. Purify by column chromatography (ethyl acetate→10% methanol in dichloromethane→10% 2 M NH3 in MeOH in dichloromethane) to afford product (0.057 g, 11%, two steps). MS(ES), m/z 552 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]([CH3:15])[CH3:14])=[C:4]([N+:16]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.C(O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]([CH3:15])[CH3:14])=[C:4]([CH:3]=1)[NH2:16]
Reactant: CC(C)c1nccn1-c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(C)c1nccn1-c1ccc(Cl)cc1N

Procedure:
A mixture of 1-(4-chloro-2-nitrophenyl)-2-isopropyl-1H-imidazole as synthesized in above Production Example 7, 0.98 g, tin (II) chloride dihydrate 4.16 g and ethanol 8.8 mL was heated under reflux for 2.7 hours. Neutralizing the reaction liquid with 2N aqueous sodium hydroxide solution under cooling with ice, chloroform was added to the reaction liquid and filtered through Celite. The Celite was washed with chloroform, transferred into a separating funnel and extracted twice with chloroform. The organic layer was washed with water, dried over magnesium sulfate and removed of the solvent by distillation, to provide 0.72 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:20])[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[CH:23](O)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:20])[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][CH:23]=[O:24])[CH:8]=2)[O:3]1
Reactant: O=CO
Reactant: Cn1cccc(C2c3cc(N)ccc3OC(C)(C)C2O)c1=O
Solvent: c1ccncc1
Product: Cn1cccc(C2c3cc(NC=O)ccc3OC(C)(C)C2O)c1=O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(1-methyl-1,2-dihydro-2-oxo-3-pyridyl)-6-amino-3-chromanol in15 ml of formic acid and 1 ml of pyridine is boiled for 24 hours and evaporated. Customary working up gives 2,2-dimethyl-4-(1-methyl-1,2-dihydro-2-oxo-3-pyridyl)-6-formamido-3-chromanol.
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]2([O:12][N:11]=[C:10]([C:13]([N:26]3[CH2:27][CH2:28][N:23]([C:19]4[S:18][CH:22]=[CH:21][N:20]=4)[CH2:24][CH2:25]3)=[O:15])[CH2:9]2)[CH2:16][CH2:17]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Reactant: c1csc(N2CCNCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)C1CCC2(CC1)CC(C(=O)N1CCN(c3nccs3)CC1)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid (120 mg, 0.51 mmol), 1-thiazol-2-ylpiperazine (110 mg, 0.51 mmol), 4-methylmorpholine (101 mg, 1.02 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (288 mg, 0.65 mmol) (HBTU) were dissolved in DMF (10 ml) and stirred overnight under a nitrogen atmosphere at RT. The solvent was removed under vacuum, the residue taken up in EtOAc and sat. aq. NaHCO3 solution and the phases were separated. The aqueous phase was extracted several times with EtOAc and the combined organic phases were washed with sat. aq. NaCl solution, dried over magnesium sulphate and the solvent was removed under vacuum. After purification by column chromatography (silica gel, hexane/EtOAc 3:1), the desired product (8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-(4-thiazol-2-ylpiperazin-1-yl)methanone was obtained as a trans isomer (50 mg, 26% of the theoretical amount) and as a cis isomer (100 mg, 51% of the theoretical amount).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=O)[C:9]=2[CH3:16])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>ClCCl.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:38][CH:37]=3)=[O:15])[C:9]=2[CH3:16])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)O)c[nH]c1-c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a suspension of 5-[4-fluoro-2-(trifluoromethyl)phenyl]-4-methyl-1H-pyrrole-3-carboxylic acid (7.7 g, 27 mmol) in dichloromethane (60 ml) was added oxalyl chloride (5.1 ml, 59 mmol). The mixture was stirred at room temperature for 2.0 h, after which time the solvent was removed on a rotary evaporator. To this brown residue was added 4-(methanesulfonyl)aniline hydrochloride (5.8 g, 28 mmol), tetrahydrofuran (THF) (80 ml) and diisopropylethylamine (DIEA) (14 ml, 80 mmol). The solution was stirred at room temperature for 2.0 h. The reaction mixture was concentrated and to the residue was added 2N HCl (80 ml) and water (80 ml) and resulting suspension was stirred for 30 min. The solid was filtered and washed with water and diisopropyl ether (IPE) to give the title compound as a white solid (11 g, 90%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].N1C(C)=CC=CC=1C.C(Cl)(=O)C(Cl)=O.[F:20][C:21]([F:57])([F:56])[CH:22]([C:49]1[CH:54]=[CH:53][N+:52]([O-])=[CH:51][CH:50]=1)[O:23][C:24]1[C:33]([N:34]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:1][N:2]([C:53]1[CH:54]=[C:49]([CH:22]([O:23][C:24]2[C:33]([N:34]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:47])([CH3:46])[CH3:48])[S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])=[N:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[C:21]([F:20])([F:57])[F:56])[CH:50]=[CH:51][N:52]=1)[C:3](=[O:5])[CH3:4]
Reactant: CNC(C)=O
Reactant: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1cc[n+]([O-])cc1)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1ccnc(N(C)C(C)=O)c1)C(F)(F)F
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
N-methylacetamide (0.097 mL, 1.30 mmol) was dissolved in dichloromethane (1.0 mL). To the solution were added at 0° C. 2,6-lutidine (0.30 mL, 2.5 mmol) and oxalyl dichloride (0.11 mL, 1.30 mmol). After stirring at the same temperature for 15 minutes, a solution of Compound B4 (145 mg, 0.253 mmol) obtained in Step 1 of Example 42 in dichloromethane (1.0 mL) was added and the mixture was further stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/10) to give Compound B7 (157 mg, 99% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:46])[CH2:29][N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][OH:38])[N:32]=1)([CH3:26])([CH3:25])[CH3:24].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:23]([O:27][C:28](=[O:46])[CH2:29][N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[O:38])[N:32]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CO)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of Dess-martin reagent (12.9 g, 30.4 mmol) in methylene chloride (130 ml) was added dropwise a solution of tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate (10.0 g, 29.6 mmol) obtained in Reference Example 3-(b) in methylene chloride (50 ml) over 20 minutes under ice cooling in argon atmosphere. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a 0.1% aqueous sodium thiosulfate solution (305 ml) was added to the reaction solution, followed by extraction with methylene chloride. The separated organic layer was washed sequentially with a 0.5N aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford the title compound (9.61 g) substantially quantitatively as a slightly yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:52][C:53]1[CH:58]=[CH:57][C:56]([C@@H:59]([NH2:63])[CH2:60][O:61][CH3:62])=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27]([NH:63][C@H:59]([C:56]3[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=3)[CH2:60][O:61][CH3:62])=[O:28])[CH2:25][CH2:26]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)cc3F)ccn2)cn1
Reactant: COC[C@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](NC(=O)C1(C(=O)Nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(F)c2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of Example B3 (65 mg, 0.164 mmol), TBTU (79 mg, 0.246 mmol) and (R)-1-(4-fluorophenyl)-2-methoxyethanamine (40.5 mg, 0.197 mmol; prepared according to the published method: J. Med. Chem. (1999), 42(24), 4981) in DMF (2 ml) was added DIEA (0.171 ml, 0.984 mmol). The resulting clear solution was stirred at RT overnight. After stirring overnight, the reaction was diluted with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with satd. NaHCO3 (1×), satd. LiCl (2×), and brine (1×), dried (MgSO4), evaporated in vacuo and purified by reverse phase chromatography. Pure fractions were pooled, treated with satd. NaHCO3 (pH 8) and extracted with EtOAc (3×). The combined organics were washed with satd. NaHCO3 (1×), brine (1×), dried (MgSO4), and evaporated to afford N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′((R)-1-(4-fluorophenyl)-2-methoxyethyl)cyclopropane-1,1-dicarboxamide as an oil. This was dissolved in 4:1 MeCN/H2O, treated with certified 0.1N HCl (1.37 ml, 1.0 eq), frozen and lyophilized to afford 63 mg (66% yield) of the HCl salt as a solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.49-8.48 (m, 2H), 8.44-8.42 (m, 1H), 8.18 (brs, 1H), 7.89-7.85 (m, 1H), 7.54 (brs, 1H), 7.48-7.35 (m, 4H), 7.16-7.11 (m, 2H), 6.92 (brs, 1H), 5.13-5.06 (m, 1H), 3.89 (s, 3H), 3.61-3.56 (m, 1H), 3.49-3.46 (m, 1H), 3.25 (s, 3H), 1.45-1.33 (m, 4H); MS (ESI) m/z: 516.1 (M+H+).
Reaction SMILES: NC1C=CC(O)=C(F)C=1.FC1C=CC(CC(SC#N)=O)=CC=1.[F:23][C:24]1[CH:25]=[C:26]([NH:43][C:44]([NH:46][C:47](=[O:56])[CH2:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)=[S:45])[CH:27]=[CH:28][C:29]=1[O:30]C1C2=C(C)C(OC)=CN2N=CN=1.CCOC(C)=O>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([NH:43][C:44]([NH:46][C:47](=[O:56])[CH2:48][C:49]2[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=2)=[S:45])[CH:27]=[CH:28][C:29]=1[OH:30]
Reactant: COc1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Agent: N#CSC(=O)Cc1ccc(F)cc1
Agent: Nc1ccc(O)c(F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 4-amino-2-fluorophenol (50 mg, 0.3 mmol, Indofine Chemical Co.) in CH2Cl2 (5 mL) was added a 0.25 M solution of 2-(4-fluorophenyl)-1-thiocyanatoethanone (prepared using a similar procedure for the synthesis of Compound A of Example 2) in EtOAc (1.6 mL, 0.4 mmol). The reaction was stirred at room temperature for 20 minutes, concentrated in vacuo and purified by silica gel flash chromatography (eluted with 1-25% EtOAc/CH2Cl2) to give the title compound (100 mg, 95%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[OH-].[K+].Cl[CH2:21][C:22]1[CH:34]=[CH:33][C:25]2[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[CH:23]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:23]1[C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][C:25]=2[CH:33]=[CH:34][C:22]=1[CH2:21][C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=1[OH:17]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: ClCc1ccc2oc3ccccc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1nc(O)c(Cc2ccc3oc4ccccc4c3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (50 mg, 214 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.11 mL, 0.22 mmol) at RT followed by 2-(chloromethyl)dibenzo[b,d]furan CCH 34116-2 (47 mg, 217 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with a mixture CH2Cl2:MeOH=9:1 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave 4-(dibenzo[b,d]furan-2-ylmethyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol (10 mg, 11%). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.2 M HCl solution in MeOH (0.25 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(dibenzo[b,d]furan-2-ylmethyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol hydrochloride 6 as a pale brown solid (11 mg, 11% yield).
Reaction SMILES: C[S:2]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][CH:8]=2)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:4]([SH:2])[CH:5]=[N:6]2
Reactant: COc1cccc2ncc(S(C)=O)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cccc2ncc(S)cc12
Temperature: 35 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(methylsulfinyl)-5-methoxyquinoline (2.21 g, 10 mmol) in CH2Cl2 (50 mL) is added TFAA. The resulting solution is stirred at 20-50° C. for 1 hour. The solution is then treated with NEt3 affording the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([NH:18][CH:19]([CH3:34])[CH2:20][CH2:21][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])[CH3:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][N:18]([CH:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH3:17])[CH:19]([CH3:34])[CH2:20][CH2:21][CH2:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CCCN1C(=O)c2ccccc2C1=O)NC(C)c1ccccn1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(C(C)CCCN1C(=O)c2ccccc2C1=O)C(C)c1ccccn1
Yield: 58 %

Procedure:
Using General Procedure B: Reaction of 3-methyl-pyridine-2-carbaldehyde and 2-[4-(1-pyridin-2-yl-ethylamino)-pentyl]-isoindole-1,3-dione in CH2Cl2 with NaBH(OAc)3 gave 2-{4-[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-pentyl}-isoindole-1,3-dione, as (one diasteroisomer (0.101 g) and a mixture of two diastereoisomers (0.0770 g), with a total yield of 58%. Deprotection with H2NNH2.H2O using General Procedure E gave a colorless oil. Conversion to the HBr salt using General Procedure D gave a white solid, which was isolated as a pure diastereoisomer. 1H NMR (D2O) δ 1.08 (d, 3H, J=6.3 Hz), 1.32 (d, 3H, J=6.6 Hz), 1.37-1.59 (m, 3H), 1.61-1.85 (m, 1H), 2.50 (s, 3H), 2.71-2.76 (m, 1H), 2.90-2.95 (m, 2H), 4.35 (s, 2H), 4.68 (q, 1H, J=6.6 Hz), 7.84 (t, 1H, J=6.6 Hz), 8.01 (t, 1H, J=6.9 Hz), 8.20 (d, 1H, J=8.1 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.56-8.63 (m, 2H), 8.81 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 17.01, 17.19, 19.97, 24.75, 27.37, 39.88, 46.16, 56.59, 59.71, 125.76, 127.08, 127.18, 136.58, 138.12, 142.58, 148.25, 148.62, 153.57, 156.65. ES-MS m/z 313 (M+H). Anal. Calcd. for C19H28N4.3.1HBr.0.4H2O: C, 40.00; H, 5.64; N, 9.82; Br, 43.42. Found: C, 39.93; H, 5.66; N, 9.71; Br, 43.54.
Reaction SMILES: C1(OC(=O)N(CCS(C2C=CC([Cl:24])=CC=2)(=O)=O)C(C)C)C=CC=CC=1.C1(OC(=O)[N:34]([CH2:38][CH2:39][S:40]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45](Cl)[CH:44]=2)(=[O:42])=[O:41])[CH:35]([CH3:37])[CH3:36])C=CC=CC=1>>[ClH:24].[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([S:40]([CH2:39][CH2:38][NH:34][CH:35]([CH3:37])[CH3:36])(=[O:41])=[O:42])=[CH:48][CH:47]=1
Reactant: CC(C)N(CCS(=O)(=O)c1ccc(Cl)c(Cl)c1)C(=O)Oc1ccccc1
Reactant: CC(C)N(CCS(=O)(=O)c1ccc(Cl)cc1)C(=O)Oc1ccccc1
Product: CC(C)NCCS(=O)(=O)c1ccc(Cl)cc1
Product: Cl

Procedure:
When in the procedure of Preparation 29, N-[2-[(4-chlorophenyl)sulfonyl]ethyl]-N-(1-methylethyl)carbamic acid phenyl ester is substituted for N-[2-[(3,4-dichlorophenyl)sulfonyl]ethyl]-N-(1-methylethyl)carbamic acid phenyl ester, the title compound is obtained.