Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH3:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[C:13]([C:36]#[N:37])[C:14](=[C:17]([O:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[C:15]#[N:16]>C(O)CC>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[C:13]2[C:14](=[C:17]([O:30][CH2:31][CH2:32][CH:33]([CH3:34])[CH3:35])[C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:22][CH:21]=1)[C:15](=[NH:2])[NH:16][C:36]2=[NH:37]
Reactant: N
Reactant: CC(C)CCOc1c(C#N)c(C#N)c(OCCC(C)C)c(Sc2ccccc2N)c1Sc1ccc(C(C)(C)C)cc1
Agent: [Na]
Solvent: CCCO
Product: CC(C)CCOc1c(Sc2ccc(C(C)(C)C)cc2)c(Sc2ccccc2N)c(OCCC(C)C)c2c1C(=N)NC2=N
Temperature: 55 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To a solution of sodium metal (0.6 g) in n-propyl alcohol (200 mL) was fed gaseous ammonia at a flow rate of 120 mL/min. at room temperature for 1 hour. Then, 27.0 g of 4-(2-aminophenylthio)-5-(4-tert-butylphenylthio)-3,6-diisopentoxyphthalonitrile was added and the mixture was stirred at 50-60° C. for 20 hours. After cooling, the reaction mixture was worked up in the same manner as in Example 1 to provide 20.9 g (yield 75.2%) of 5-(2-aminophenylthio)-6-(4-tert-butylphenylthio)-1,3-diimino-4,7-diisopentoxyisoindoline of the following chemical formula. ##STR12##
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:5])=[CH2:4].[N:6]1[CH:11]=[CH:10][C:9]([CH:12]=[N:13][OH:14])=[CH:8][CH:7]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH3:5])([O:14][N:13]=[CH:12][C:9]1[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=1)[CH3:4]
Reactant: ON=Cc1ccncc1
Reactant: C=C(C)OC
Solvent: ClCCl
Product: COC(C)(C)ON=Cc1ccncc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1.5 ml of 2-methoxy-propene were added all at once to a suspension of 610 mg of pyridine-4-aldoxime in 10 ml of methylene chloride and the mixture was stirred for 18 hours at 60° C. under reduced pressure. The mixture was cooled and evaporated to dryness under reduced pressure to obtain 950 mg of 4-[(1-methoxy-1-methyl-ethoxyimino)-methyl]-pyridine.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])=O.N[C:19]1[C:23]([C:24]#[N:25])=C[NH:21][N:20]=1>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:21]2[N:20]=[CH:19][C:23]([C:24]#[N:25])=[C:17]2[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=CC(=O)c1ccccc1C(F)(F)F
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3ccccc3C(F)(F)F)ccnc12

Procedure:
A mixture of 4.86 g. of 3-dimethylamino-2'-(trifluoromethyl)acrylophenone, 50 ml. of glacial acetic acid and 3.24 g. of 3-aminopyrazole-4-carbonitrile is refluxed for 9 hours and evaporated to a residue. The residue is treated as described in Example 1, giving the desired product, m.p. 195.5°-197° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([NH:28][C:29]([NH:5][C:6]1[C:7](=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCn1c2c(cc(N)c1=O)CCCC2
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCn1c2c(cc(NC(=O)NCc3ccccc3)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
3-Amino-1-butyl-5,6,7,8-tetrahydro-1H-quinolin-2-one acetic acid salt (6-001-01) (5 mg, 0.018 mmol) was dissolved in methylene chloride (1 mL), and to the reaction mixture were added benzylisocyanate (2.5 μL, 0.02 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol), and the reaction mixture was stirred at room temperature for 4 h. To the reaction mixture was added diluted hydrochloric acid (0.1 mol/L, 3 mL), and the reaction mixture was extracted with ethyl acetate (10 mL), washed with brine (3 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate) to give 1-benzyl-3-(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)urea (6-005) (5.0 mg, 79%) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:32]/[OH:33])/[CH2:9][C@@H:10]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(N3CCOCC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(N3CCOCC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (S)-1-(2-methylpyridin-4-yl)-3-(4-morpholino-phenyl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white solid, MS (ESI+): m/z=416.5 ([M+H]+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:16][CH:17]=2)[C:12]([CH3:25])([CH3:24])[C:11](=[O:26])[C:10]=1[C:27]([NH:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[O:28]>>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:16][CH:17]=2)[C:12]([CH3:24])([CH3:25])[C:11](=[O:26])[C:10]=1[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28]
Reactant: COCCCc1ccc2c(c1)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Solvent: O=C(O)C(F)(F)F
Product: COCCCc1ccc2c(c1)C(C)(C)C(=O)C(C(=O)NCC(=O)O)=C2O
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
TFA (2 mL) was added to 1,1-dimethylethyl N-((4-hydroxy-1,1-dimethyl-7-(3-(methyloxy)propyl)-2-oxo-naphthalen-3-yl)carbonyl)glycinate (284 mg, 680 μmol) at ambient temperature, and the reaction was stirred for 30 minutes. The resulting mixture was concentrated to give the title compound (108 mg) as a light yellow amorphous solid after purification via preparatory LC. MS m/e=362 (M+H)+. Calculated for C19H23NO6 361.15.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](Cl)=[N:11][N:10]=1)[CH3:7]>CO>[CH2:6]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([S:5][CH2:2][CH:3]=[CH2:4])=[N:11][N:10]=1)[CH3:7]
Reactant: CCOc1nnc(Cl)c2ccccc12
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OCC)c2ccccc12

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 100 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 2.09 g(0.01 mol) of 1-ethoxy-4-chlorophthalazine obtained from Preparation 10. The reaction solution was refluxed for 3 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing white crystal.
Reaction SMILES: Cl[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[NH4+:12]>>[NH2:12][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [NH4+]
Reactant: Cn1nc(Cl)cc(Cl)c1=O
Agent: [OH-]
Product: Cn1nc(Cl)cc(N)c1=O
Temperature: 150 °C
Yield: 86.5 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyridazin-3(2H)-one (5.0 g, 27.9 mmol) and ammonium hydroxide (55 mL, 1412 mmol) was heated at 150° C. for 2 hours and then cooled to room temperature. The solvent was removed, and the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography (silica gel, eluted with 40% ethyl acetate in hexanes to afford 3.85 g (87%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.C(O)(=O)/C=C\C(O)=O.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:36][CH2:35][CH2:34][NH:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNc1ccc(Cl)cc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccc(Cl)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(p-chlorophenyl)ethylenediamine maleate and DBU in DME. ES-MS m/e (%): 357 (M{37Cl}+H+, 40), 355 (M{35Cl}+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20]([C:24](O)=[O:25])=[CH:19][CH:18]=[CH:17]4)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:27]1([NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33]>>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:34][C:24]([C:20]1[C:21]2[C:16](=[CH:15][C:14]([O:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:25]
Reactant: COc1ccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2c1
Reactant: Nc1ccccc1N
Product: COc1ccc2c(Oc3ccc4c(C(=O)Nc5ccccc5N)cccc4c3)ccnc2c1
Yield: 90.9 %

Procedure:
The title compound (39.6 mg, 91% yield) was prepared as a brown solid from 6-(7-methoxyquinolin-4-yloxy)-1-naphthoic acid (34.5 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 1H NMR (DMSO-d6) δ 3.95 (s, 3H, —OCH3), 4.97 (s, 2H, benzene-NH2), 6.60 (d, J=5.2 Hz, 1H, Ar—H), 6.64 (t, J=7.6 Hz, 1H, Ar—H), 6.82 (d, J=7.8 Hz, 1H, Ar—H), 6.99 (t, J=7.4 Hz, 1H, Ar—H), 7.31 (dd, J=2.5 and 9.1 Hz, 1H, Ar—H), 7.38 (d, J=7.6 Hz, 1H, Ar—H), 7.45 (d, J=2.4 Hz, 1H, Ar—H), 7.57 (dd, J=2.4 and 9.2 Hz, 1H, Ar—H), 7.65 (t, J=7.8 Hz, 1H, Ar—H), 7.87-7.88 (m, 2H, Ar—H), 8.07 (d, J=8.2 Hz, 1H, Ar—H), 8.25 (d, J=9.2 Hz, 1H, Ar—H), 8.43 (d, J=9.2 Hz, 1H, Ar—H), 8.65 (d, J=5.2 Hz, 1H, Ar—H), 9.84 (s, 1H, benzene-NH). 436 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([NH:8][CH2:9][C:10](O)=[O:11])[CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[CH3:16])[NH:13][C:10](=[O:11])[CH2:9][NH:8]2
Reactant: Cc1cc([N+](=O)[O-])c(NCC(=O)O)cc1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1Cl)NCC(=O)N2
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A solution of N-(5′-chloro-4′-methyl-2′-nitrophenyl)glycine (1.000 g, 4.088 mmol, as prepared above) and tin (II) chloride dihydrate (2.767 g, 12.26 mmol, Aldrich, used as received) in ethanol (20.0 mL) was refluxed for 30 min. It was then cooled to room temperature ad the precipitated solid was filtered, washed with ethanol (4.0 mL), and dried under vacuum to yield 0.251 g (31%) of the title compound as a yellow powder; 1H NMR (DMSOd6): δ 2.093 (s, 3H), 3.657 (d, 2H, J=1.5 Hz), 5.984 (s, 1H), 6.583 (s, 1H), 6.632 (s, 1H), 10.253 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24].CS(O)(=O)=O.C1C=CC=CC=1>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:4][CH2:3][C:2]([F:11])([F:1])[CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])=[O:24]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: OCC(F)(F)C(F)C(F)(F)F
Agent: CS(=O)(=O)O
Solvent: O
Solvent: c1ccccc1
Product: O=C(CCCCCCCCCCBr)OCC(F)(F)C(F)C(F)(F)F

Procedure:
A 500 ml one-necked flask fitted with a Dean Stark trap was charged with 36.4 g (0.2 m) of 2,2,3,4,4,4-hexafluorobutanol, 53.0 g (0.2 m) of 11-bromoundecanoic acid, 0.5 g methane sulfonic acid and 100 ml of dry benzene. The reaction mixture was refluxed until the theoretical amount of water, 3.6 ml, was removed. The reaction mixture was washed with a 10% sodium carbonate solution. The benzene was removed under vacuum giving 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate. IR analysis showed the following major absorption bands: 2930, 2860, 1760, 1190, 1110 cm-1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=O)[CH3:11])[C:4]=2[N:3]=[CH:2]1.[CH3:13][NH2:14].Cl.O1CCOCC1.[BH4-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([NH:14][CH3:13])[CH3:11])[C:4]=2[N:3]=[CH:2]1
Reactant: CC(=O)c1cccc2[nH]cnc12
Reactant: CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CNC(C)c1cccc2[nH]cnc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A solution of 1-(1H-benzoimidazol-4-yl)ethanone (72 mg, 0.449 mmol), methylamine (2M in THF; 2.25 mL, 4.50 mmol) and HCl in 1,4-dioxane (4M; 0.337 mL, 1.35 mmol) in MeOH (2.7 mL) was stirred at room temperature for 3 days before it was cooled to 0° C. and NaBH4 (20 mg, 0.539 mmol) was added in a single portion. The mixture was stirred at room temperature overnight before it was diluted with MeOH, stirred for 1 hour and concentrated in vacuo. The residue was purified by SiO2 chromatography providing [1-(1H-benzoimidazol-4-yl)-ethyl]-methyl-amine (46 mg).
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S([O:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[CH:36]=[C:35]([Br:37])[CH:34]=[CH:33][C:32]=3[Cl:38])=[CH:26][CH:25]=2)(=O)=O)=CC=1>C1COCC1>[Br:37][C:35]1[CH:34]=[CH:33][C:32]([Cl:38])=[C:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][O:20][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:29][CH:28]=2)[CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of cyclohexanol (0.76 g, 7.56 mmol) in anhydrous THF (10 mL), NaH (60%, 0.18 g, 7.56 mmol) was added in portions at 0° C. The mixture was stirred at 0° C. for 0.5 h, and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (0.66 g, 1.26 mmol) was added in portions. Then the mixture was stirred at room temperature overnight, whereupon TLC showed the reaction was complete. Then the reaction mixture was quenched with saturated NH4Cl, extracted with EtOAc, washed with water and brine, dried with anhydrous Na2SO4, and concentrated to a crude oil. The crude oil was purified by column chromatography (PE:EA=100:1) to obtain oil AE (0.3 g, yield 56.6%). 1H NMR (400 MHz, CD3OD): δ 7.28-7.21 (m, 3H), 7.07 (d, 2H, J=8.8 Hz), 6.86 (d, 2H, J=8.4 Hz), 4.08 (t, 2H, J=4.8 Hz), 3.98 (s, 2H), 3.80 (t, 2H, J=4.8 Hz), 3.40-3.20 (m, 1H), 1.95-1.93 (m, 2H), 1.76-1.73 (m, 2H), 1.32-1.22 (m, 6H).
Reaction SMILES: [OH-].[K+].[CH2:3]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:12]([CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]1)=[C:11]2[C:43]([O:45]C)=[O:44])(=[O:7])=[O:6])[CH3:4].[K]>CO.O>[CH2:3]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:12]([CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH2:33][CH2:32]1)=[C:11]2[C:43]([OH:45])=[O:44])(=[O:7])=[O:6])[CH3:4]
Reactant: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Potassium hydroxide was added to a solution of methyl 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.0 g, 3.15 mmol) in methanol (60 mL) and water (20 mL) and reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature and diluted with water. The methanol was removed under reduced pressure. The solid was collected by filtration, washed with cold water, and air dried to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.0 g, 96% yield) as the potassium salt. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.13 (s, 1H), 7.92 (d, J=7.53 Hz, 1H), 7.79 (d, J=7.78 Hz, 1H), 7.68 (t, J=7.78 Hz, 1H), 7.55 (s, 1H), 4.04 (s, 3H), 3.49-3.55 (m, 4H), 3.43-3.49 (m, 4H), 2.53-2.57 (m, 2H), 2.33-2.38 (m, 4H), 1.93-2.04 (m, 1H), 1.84 (t, J=11.04 Hz, 2H), 1.52 (d, J=11.29 Hz, 2H), 1.12 (t, J=7.28 Hz, 3H), 0.95-1.08 (m, 2H); MS (m/z) 622.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:29]([OH:30])([CH3:31])[CH3:28])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(C)(C)O)nc3N21
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
A solution of 0.30 g (0.81 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 5 ml tetrahydrofuran was cooled to −78 deg C. and treated with 0.61 ml (0.98 mmol) n-butyllithium solution (1.6 M in n-hexane). After 30 min, 80 μL (71 mg, 1.22 mmol) acetone was added. After 30 min, the reaction was quenched with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The solvent was removed on a rotary evaporator and the residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to afford the compound as a light yellow foam (24.4%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)CCC.[Li+].[Cl-]>C1(C)C=CC=CC=1>[N:27]1[CH:28]=[CH:29][C:24]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]3)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2-c2ccncc2)C1
Temperature: 110 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
(Tet. Lett, 1995, 36, 5247) To tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.989 g, 3.17 mmol), 4-(tributylstannyl)pyridine (1.75 g, 4.75 mmol), LiCl (1.343 g, 31.7 mmol) in toluene (15 mL) was added dichlorobis(triphenylphosphine) palladium (II) (0.222 g, 0.317 mmol) and the reaction was heated to 110° C. After 72 h, the reaction was partitioned with 10% aq KF (20 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (15 mL) and dried (MgSO4). Purification by silica gel chromatography afforded 0.63 g of Intermediate 17A as clear oil (64%). 1H NMR (400 MHz, CDCl3) δ 8.66 (2 H, d, J=6.06 Hz), 7.23-7.33 (3 H, m), 7.17-7.21 (1 H, m), 7.13 (1 H, d, J=7.58 Hz), 4.65 (2 H, s), 3.55 (2 H, br. s), 2.72 (2 H, t, J=5.68 Hz), 1.50 (9 H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][C:25]1([CH3:37])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:33]2[C:27]3[O:26][C:25]([CH3:37])([CH3:24])[CH2:29][C:28]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:8])[N:6]=1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: CC1(C)Cc2cccc(C(=O)NC[C@@H]3[C@H]4C[C@H]4CN3C(=O)c3nc(N)sc3-c3cccc(F)c3)c2O1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[C:25]([O:27]C(C)(C)C)=[O:26])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][C@H:13]2[C:25]([OH:27])=[O:26])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)[C@@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O)c1ccc(Cl)c(Cl)c1
Reaction time: 3.5 h
Yield: 58.6 %

Procedure:
The tert-butyl ester of Example 14 (301 mg, 0.65 mmol) was dissolved in trifluoroacetic acid (3 ml) and stirred for 3.5 h after which time the reaction was concentrated in vacuo. The residue was suspended in CH2Cl2 and filtered to give 155 mg (58%) of the title compound as a solid. Anal Calcd for C19H16N2O4Cl2.1/4H2O: C,55.42; H,4.04; N,6.80. Found: C.55.43; H,4.13; N,6.83. DSC=217.26°-219.87° C. at 104.8 J/g. MS M+1 calcd for C19H16N2O4Cl2 408, found 408.
Reaction SMILES: Cl[CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3]
Reactant: C[O-]
Reactant: CC(Cl)c1nc2ccccc2[nH]1
Agent: [Na+]
Solvent: CO
Product: COC(C)c1nc2ccccc2[nH]1

Procedure:
2-(1-chloroethyl)-1H-benzo[d]imidazole (0.39 g) and 25 wt % solution of Sodium Methoxide in Methanol (0.96 mL) in 10 mL of Methanol was heated for 20 minutes at 150° C. in a microwave synthesizer. The reaction mixture was extracted with EtOAc and sat NH4 chloride. The organic layer was dried, filtered and concentrated to afford crude 2-(1-methoxyethyl)-1H-benzo[d]imidazole in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH2:9]([CH2:11][NH2:12])[OH:10]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:11][CH2:9][OH:10])=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: NCCO
Product: OCCNc1ccc(Br)cn1
Yield: 13.2 %

Procedure:
Prepared from 5-bromo-2-fluoropyridine (2.5 g, 14 mmol) and ethanolamine (4.34 g, 70 mmol) as described in example B.45. Obtained as a colorless oil (400 mg, 13%). MS (ISP) 217.2 [(M+H)+], 219.1 [(M+2+H)+].