Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][C:6](/[CH:14]=[CH:15]/[CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]>>[Cl:4][C:21]([CH3:22])([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]([CH3:24])[CH2:16]/[CH:15]=[CH:14]/[C:6]([CH3:5])=[CH:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CC(=O)Cl
Reactant: CC(C)=CCCC(C)C/C=C/C(C)=CC(=O)OC(C)C
Product: CC(=CC(=O)OC(C)C)/C=C/CC(C)CCCC(C)(C)Cl
Reaction time: 0.25 h

Procedure:
To 40 ml. of ice cold isopropanol is added 2.49 g. of acetyl chloride. The resulting solution is stirred at 0° for 15 min. and 1.0 g. of trans isopropyl 3,7,11-trimethyldodeca 2,4,10-trienoate added. The solution is stirred for 1 hour at 0° and for 48 hours at 25°. Solvent is removed under reduced pressure and the concentrate taken up in hexane. The hexane solution is washed with water until the aqueous wash is neutral and then with brine. The solution is dried over calcium sulfate and solvent evaporated to yield trans isopropyl 11-chloro-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:5]2[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:6]=12.[ClH:22]>O1CCOCC1>[ClH:22].[Br:1][C:2]1[N:3]=[C:4]([C:18]([F:20])([F:19])[F:21])[N:5]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1nc(Br)c2n1CCNC2
Reaction time: 4 h
Yield: 56.5 %

Procedure:
Crude tert-butyl 1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11b (470 mg, 1.27 mmol) was dissolved in 50 mL of a 2 M solution of hydrogen chloride in 1,4-dioxane. After stirring for 4 hours, the reaction mixture was concentrated under reduced pressure to obtain 1-bromo-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride 11c (220 mg, yield 56.5%) as a light yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>N1C=CC=CC=1>[C:25]1([CH3:26])[CH:27]=[CH:28][C:22]([S:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: OCCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCCCCCCO)cc1

Procedure:
To a solution of 1.1 g of 1,16-dihydroxyhexadecane in 10 ml of dry pyridine 0.8 g of tosyl chloride was added. After 2 h mixture was concentrated diluted with 20 ml of acetone, 5 g of SiO2 was added and acetone was removed in vacuum. The solid was applied on SiO2 and eluted with pentane-ethyl acetate (2:1) to yield 748 mg (42%) of C-101.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>B(F)(F)F>[CH:2]1[C:6]2[C:6](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Agent: FB(F)F
Product: c1ccc2ccccc2c1

Procedure:
Naphthalene was polymerized at a temperature of from 200° to 400° C. in the presence of a HF.BF3 catalyst to obtain a pitch which had an optical anisotropy of 100% as observed under a polarization microscope, an optical anisotropic structure of a "rough flow type", a Mettler softening point of 250° C. and an elemental composition as analyzed of C: 94.8 wt % and H: 5.2 wt %. This pitch was finely pulverized. Then, pyridine (solubility parameter: 10.6) was added in an amount of 200 ml to 5 g of this pitch, and extraction was conducted at 100° C., followed by filtration with a 0.5 μm membrane filter to remove a pyridien-insoluble matter. Then, from the soluble matter, pyridine was removed to obtain a pyrildine-soluble pitch. The pitch had ΔTg of 33° C. and Qi of not more than 1% by weight.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>ClCCCl>[N+:10]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([OH:9])=[O:8])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=C(O)c1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
61 g of benzoic acid were suspended in 200 ml of 1,2-dichloroethane. The suspension was heated to 40° C. following the addition of 38.6 g (0.60 mol) of 98% nitric acid. 63.5 g of 100% sulphuric acid were then added dropwise over a period of 2 hours at that temperature, followed by stirring for another 3 hours. After cooling to 20° C., the deposit was filtered off. The filter residue was washed four times with 4 × 25 ml of 1,2-dichloroethane and then with water, followed by drying at 90° C. 32.6 g (39% of the theoretical yield) of 3-nitrobenzoic acid were obtained in this way.
Reaction SMILES: C(OC([N:6]1[CH2:27][CH2:26][C:10]2[C:11]3[CH:12]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.Br>C(O)(=O)C>[F:19][C:13]1([F:18])[CH:12]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:11]2[C:10]3[CH2:26][CH2:27][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(c1cccnc1)C(F)(F)C3
Agent: Br
Solvent: CC(=O)O
Product: FC1(F)Cc2ccc3c(c2C1c1cccnc1)CCNCC3
Temperature: 60 °C
Yield: 94.2 %

Procedure:
Into a 250 ml flask, the product from step (c) (3.7 g, 9.9 mmol) dissolved in acetic acid (50 ml) and HBr (33% in acetic acid, 50 ml) was added. The stirred reaction mixture was heated to 60° C. for 6 hours. The reaction mixture was cooled and the volatiles were evaporated in vacuo. The crude product was dissolved in water (100 ml) and washed with diethyl ether (3×). The aqueous layer was basified with 2M NaOH and then extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title compound as tan oil (2.8 g) which solidified over time. 1H NMR (300 MHz, CDCl3) δ 8.52 (dd, J=4.5 Hz, J=1.8 Hz, 1H); 8.36-8.35 (m, 1H); 7.29-7.20 (m, 2H); 7.12-7.06 (m, 2H); 4.66 (d, J=18.9 Hz, 1H); 3.47-3.44 (m, 1H); 3.38 (d, J=6.9 Hz, 1H); 2.99-2.85 (m, 4H); 2.74-2.62 (m, 2H); 2.55-2.48 (m, 3H); MS: ESI (positive): 301 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4][N:5]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)[C:6]=1[CH3:7]
Reactant: Cc1[nH]nc(C(F)(F)F)c1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(Br)c(C(F)(F)F)nn1C1CCCCO1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
A solution of 4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazole (1.00 g, 4.37 mmol) and p-toluenesulfonic acid monohydrate (80 mg, 0.4 mmol) in CHCl3 (3.5 mL) was cooled to 0° C. and dihydropyran (480 μL, 5.2 mmol) was added dropwise. The reaction was stirred at 0° C. for 1.5 h. The solvent was removed in vacuo and the residue was purified by column chromatography to obtain the desired product (1.18 g, 86%). 1H NMR (400 MHz, CDCl3): δ 5.35 (dd, 1H), 3.98 (m, 1H), 3.65 (m, 1H), 2.40 (m, 1H), 2.37 (s, 3H), 2.12 (m, 1H), 1.96 (m, 1H), 1.64 (m, 3H).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH2:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3])(=[O:21])[CH3:20]
Reactant: C=Cc1ccc(C(C)(C)O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1ccc(C(C)(C)OC(C)=O)cc1
Yield: 48 %

Procedure:
A mixture of 6.7 g of 1-(1-hydroxy-1-methylethyl)-4-ethenyl-benzene and 4.0 g of pyridine in 100 ml of dichloromethane was stirred while 4.0 g of acetyl chloride in 20 ml of dichloromethane was added dropwise. After the addition was complete, the mixture was refluxed gently overnight. After cooling, an additional 30 ml of dichloromethane was added and the mixture was then washed with 50 m) of cold 5% aqueous HCl, and then several times with 30 ml portions of water. After drying over magnesium sulfate, filtering, and concentrating, the crude product was purified by HPLO using ethyl/acetate hexane as eluent. This method affords 4.05 g (47.5% yield) of the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH:17]([C:37](N1CCCCC1)=[O:38])[CH2:18][NH:19][C:20](=[O:36])[CH2:21][NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24]>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH2:21][C:20]([NH:19][CH2:18][CH:17]([C:37]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1)=[O:38])[NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:36])(=[O:24])=[O:25]
Reactant: NC(CNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NCC(NC(=O)C1CCN(c2ccncc2)CC1)C(=O)C1CCCCN1
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with N-[2-amino-2-(piperidinocarbonyl)ethyl]-2-(2-naphthalenesulphonamido)-acetamide to give 2-(2-naphthalenesulphonamido)-N-{2-piperidino-carbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide in 41% yield, m.p. 200-202° C.;
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.96 min; [M+H]+=476.03.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccccc1Nc1ccc(CCc2ccc(O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of 2-{4-[2-(3,4-dimethoxy-phenyl)-ethyl]phenylamino}-benzoic acid (0.28 g, 0.74 mmol) in CH2Cl2 (20 mL), BBr3 (3.5 mL, 1M in CH2Cl2, 3.5 mmol) was added at room temperature under a N2 atmosphere. The reaction mixture was allowed to stir at room temperature for 2 hours and then poured into ice water (50 mL). This mixture was extracted with EtOAc, and the organic layer was washed two times with water, dried (Na2SO4), filtered and concentrated in vacuo to yield 0.24 g (0.69 mmol, 93%) of the desired product. mp 215-217° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:10]1[CH2:9][CH:8]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cccs1)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cccs1)C2
Yield: 79.4 %

Procedure:
A mixture of 4-methyl-7-(2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (0.52 g), aminoguanidine hydrochloride (0.25 g), concentrated hydrochloric acid (0.53 ml), water (0.53 ml) and ethanol (50 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether and concentrated under reduced pressure, and the residue was recrystallized from water-ethanol to give 5-guanidinoimino-4-methyl-7-(2-thienyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 70) (0.57 g) as colorless crystals.
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:19]1([CH:15]2[CH2:16][CH2:17][N:12]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:13][CH2:14]2)[CH2:22][CH2:21][CH2:20]1
Reactant: C1CNC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CN2CCC(N3CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.0 mL (17.5 mmol) glacial acetic acid were added to the stirred mixture of 3.0 mL (16.5 mmol) 1-benzyl-4-piperidone, 1.0 g (17.5 mmol) azetidine and 100 mL DCM. Then 6.0 g (39.5 mmol) sodium triacetoxy-borohydride was added batchwise within one hour while cooling with an ice bath and the mixture was stirred for a further 12 h at RT. The reaction mixture was extracted with 200 mL EtOAc, the organic phase was dried, evaporated down under reduced pressure and the residue was purified by chromatography.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]1[C:18](=[O:19])[O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:18]([OH:17])=[O:19])(=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCCCCCCCCC(=O)O1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCCCCCCCCCC(=O)c1ccccc1
Reaction time: 2.5 h

Procedure:
To a stirred suspension of 18 gms AlCl3 (0.135 mole) in 150 ml dry benzene was added 13 gms 1,10-decanedicarboxylic anhydride in small portions over 15 minutes, then the mixture was refluxed for 6 hours. The solid was filtered off, stirred for 2.5 hours in 350 ml 2N HCl, removed by filtration, and stirred in 300 ml 1N NaOH which was then heated to 70° and filtered hot. As the solution cooled, solid material (sodium salt of the product) crystallized out. This salt was dissolved in hot water, acidified to pH 3 with concentrated HCl, filtered after cooling, and dried to give 5.5 gm of the desired 11-benzoylundecanoic acid m.p. 83°-6°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH2:10][CH2:9]S[CH:7]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:6]=12.OO[S:20]([O-:22])=[O:21].[K+]>CO.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH2:10][CH2:9][S:20](=[O:22])(=[O:21])[CH:7]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:6]=12
Reactant: O=S([O-])OO
Reactant: NS(=O)(=O)C1=CC2=C(OCCO)CCSC2S1
Agent: [K+]
Solvent: CO
Solvent: O
Product: NS(=O)(=O)C1=CC2=C(OCCO)CCS(=O)(=O)C2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5,6-dihydro-4-(2-hydroxyethoxy)thieno[2,3-b]thiopyran-2-sulfonamide (1.0 g, 0.0034 mole) in CH3OH (20 ml) was added dropwise a solution of OXONE® (3.15 g, 0.005 mole) in water (20 ml). The mixture was stirred at ambient temperature overnight and then filtered, washing the filter cake thoroughly with CH3OH. Methanol was stripped from the filtrate in vacuo and the residue was extracted repeatedly with ethyl acetate. Evaporation of the dried extract left the crude product as a yellow gum that was purified by column chromatography on silica gel (75 g, 230-400 mesh). The product was eluted with 90 CHCl3 :10CH3OH:1H2O. Evaporation of the eluate left a colorless glass (0.8 g) that was triturated with ether, collected, dried in vacuo, and recrystallized from water. The yield of white crystalline product, m.p. 159°-164° C., was 430 mg (39%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:55][CH2:56][CH2:57][N:58]([CH2:70][CH2:71]Cl)[C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[C:64]([Cl:69])[CH:65]=2)[N:60]=1>ClCCl>[Cl:69][C:64]1[CH:65]=[C:66]2[C:61](=[CH:62][CH:63]=1)[N:60]=[C:59]([N:58]1[CH2:70][CH2:71][N:55]([C:19](=[O:20])[CH2:18][O:17][CH:14]3[CH2:13][CH2:12][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:23])([F:24])[F:25])[CH:6]=4)[CH2:16][CH2:15]3)[CH2:56][CH2:57]1)[CH:68]=[CH:67]2
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: NCCN(CCCl)c1ccc2cc(Cl)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (79.4 mg, 0.41 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine (111.6 mg, 1.10 mmol, 4 eq), and N-(2-aminoethyl)-6-chloro-N-(2-chloroethyl)quinolin-2-amine (93.8 mg, 0.33 mmol, 1.2 eq). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml), extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The crude material was purified by Pre-TLC using 4% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (69.8 mg, 42%). (ES, m/z): [M+H]+ 592.35; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J=9.0 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.61 (s, 2H), 7.52 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.91 (s, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.65 (m, 1H), 4.45 (d, J=7.5 Hz, 1H), 4.26 (s, 2H), 3.75-3.78 (m, 7H), 3.37-3.50 (m, 2H), 2.14 (d, J=10.5 Hz, 4H), 1.44-1.51 (m, 2H), 1.24-1.35 (m, 2H).
Reaction SMILES: [H-].[Na+].O[C:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:25][O:6][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:9][CH:8]=2)[CH2:5][O:6][CH2:4][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(O)(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COCC(OCc2ccccc2)c2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reaction time: 18 h

Procedure:
At 0° C., 50% NaH in oil (37 mg) was added portionwise to a solution of 1-hydroxy-1-(4-2(-quinolinylmethoxy)phenyl)ethanol (Step 1) (104 mg) and benzyl bromide (92 mg). Stirring was continued for 18 h and the reaction was quenched with 25% aqueous NH4OAc. The product was extracted with EtOAc, dried over MgSO4 and purified by flash chromatography on silica gel using EtOAc:hexane (1:4) to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (274 mg, 0.728 mmol) in tetrahydrofuran (10 mL) was added cyclopropylmagnesium bromide in tetrahydrofuran (1.0 M, 2.2 mL, 2.2 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. Aqueous ammonium chloride was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-80% ethyl acetate/n-hexane gradient mixture to give the title compound (261.7 mg, 0.57 mmol, 77%) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:33](=[O:34])[C:12]2=[CH:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH3:44][S:45]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:33](=[O:34])[C:12]2=[CH:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1)(=[O:47])=[O:46]
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-[2-(Hydroxymethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 654, 0.23 g, 0.51 mmol) was suspended in dichloromethane (5 mL), treated with diisopropylethylamine (0.20 mL, 1.1 mmol, 2.2 equiv) and cooled to −78° C. Methanesulfonyl chloride (60 μL, 0.77 mmol, 1.5 equiv) was added and the mixture was stirred at −78° C. for 30 minutes. The dry ice/acetone bath was removed, the mixture was warmed to ambient temperature and stirred for an additional 45 minutes. The mixture was poured into ammonium chloride (20 mL, aqueous saturated) and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:17](N1CCCCC1)=[O:18].C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([CH:17]=[O:18])=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=CN1CCCCC1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=Cc1c(Cl)ccnc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 2,4-dichloropyridine (10 g) in THF (100 mL) was added dropwise lithium diisopropylamide solution (2M, 37 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added dropwise 1-formylpiperidine (7.7 g) at −78° C. The reaction mixture was stirred at −78° C. for 2 hr. The reaction mixture was added to 10% aqueous acetic acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (7.0 g).