Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[C:21](=[O:24])([O-])[O-].[K+].[K+].BrC[C:29]([C:31]1[N:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]2=[N:33][CH:32]=1)=O>CN(C)C=O>[ClH:1].[ClH:1].[N:33]1[CH:32]=[C:31]([CH2:29][C:21]([N:16]2[CH2:17][CH2:18][CH:13]([C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)=[O:24])[N:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=12
Reactant: O=C(CBr)c1cnc2ccccn12
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(C(=O)Cc3cnc4ccccn34)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 113.6 %

Procedure:
A suspension comprising 1.91 g (6.0 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride, 3.0 g of potassium carbonate and 40 ml of dimethylformamide was stirred at 80° C. for 1 h. After cooling to room temperature, 1.99 g of 3-bromoacetylimidazo[1,2-a]pyridine prepared in the above step (i) was added thereto and the mixture was stirred at room temperature for 6 h. The reaction mixture was filtered and the filtrate was concentrated to obtain a solid residue, which was then purified according to silica gel column chromatography (chloroform:methanol=96:4). The purified product was converted into its dihydrochloride with ethanolic hydrogen chloride and recrystallized from methanol/acetone to obtain 1.75 g (yield: 58%) of the intended compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:23]1([CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][Br:35])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[Br-:35].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: BrCCCCOCc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCCOCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 45 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0646 g, 0.220 mmol) and 4-bromobutyl phenylmethyl ether (0.090 mL, 0.472 mmol) in 2 CH3CN/3 CHCl3 (5.0 mL) were reacted to give the desired product (0.0531 g, 48.3%). EI-MS m/z 456 (M+) Rt (2.09 min).
Reaction SMILES: O1C=CC([CH2:6][C@:7]23[CH2:24][CH2:23][C@H:22]4[C@@H:12]([CH2:13][CH2:14][C@H:15]5[C@:20]4([CH3:21])[CH2:19][CH2:18][C@H:17]([OH:25])[CH2:16]5)[C@@:11]2([OH:26])[CH2:10][CH2:9][CH2:8]3)=C1.[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[CH2:31]Br)[CH3:28].[OH2:36]>O1CCCC1>[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[CH2:31][O:25][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:6])[C@:11]3([OH:26])[CH2:10][CH2:9][C@@H:8]2[C:7]2[CH:8]=[CH:9][O:36][CH:6]=2)[CH2:16]1)[CH3:28]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(Cc3ccoc3)CCC[C@]12O
Reactant: CCOC(CBr)OCC
Reactant: O
Solvent: C1CCOC1
Product: CCOC(CO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1)OCC

Procedure:
To a suspension of 5.5 g of Nail (60% dispersion in mineral oil) in 400 ml of dry tetrahydrofuran 7.0 g of 17β)-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref, comp.) (Minato H. and Nagasaki T., J. Chem. Soc.(C), 1966, 377) were added at room temperature in a nitrogen atmosphere. The mixture was kept at reflux for 6 hrs, then 26 ml of bromoacetaldehyde diethylacetal were added; the suspension was kept at reflux temperature for 4 hrs, 50 ml of water were added cautiously, and the tetrahydrofuran was distilled under reduced pressure. The residue was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 6.9 g of 3β-(2,2-diethoxy-ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, as a dense oil.
Reaction SMILES: C(OC(C1C(=O)[C:14]2[C:9](=[CH:10][C:11](C(=O)C)=C(F)C=2)[N:8](C2C=CC(F)=CC=2)C=1)=O)C.[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][C:37]([F:45])=[C:38]([C:42](=O)[CH3:43])[C:39]=3Cl)[C:34](=[O:46])[C:33]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:32]2[S:52][C:53]2C=CC=CC=2)[CH2:30][CH2:29]1>[Ni].[Pd]>[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][C:37]([F:45])=[C:38]([CH:42]4[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:43]4)[CH:39]=3)[C:34](=[O:46])[C:33]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:32]2[S:52][CH3:53])[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(C(C)=O)c(F)cc2c1=O
Reactant: CCOC(=O)c1c(Sc2ccccc2)n(C2CC2)c2c(Cl)c(C(C)=O)c(F)cc2c1=O
Agent: [Ni]
Agent: [Pd]
Product: CCOC(=O)c1c(SC)n(C2CC2)c2cc(C3CCC(N)CC3)c(F)cc2c1=O

Procedure:
In the described fashion as Example 16 (d and e), replacing ethyl 1-ethyl-6-fluoro-7-acetyl-1,4-dihydro-4-oxo-quinoline carboxylate (9) (A=CH, R10 =C2H5, R=C2H5,) with ethyl 1-cyclopropyl-2-methylthio-6-fluoro-7-acetyl-1,4-dihydro-4-oxo-3-carboxylate (13) of Example 40 and also replacing the catalyst Raney nickel in Example 16(e) with palladium on charcoal under a hydrogen atmosphere, one can obtain the ethyl 1-cyclopropyl-2-methylthio-6-fluoro-7-(4 aminocyclohexyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylate (16) (A=CH, R11 =CH3, R10 =C2H5, R=cyclopropyl, Z= ##STR76##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[CH:29]1([NH2:39])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:39][CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27]
Reactant: COc1cccc(CC2NCCc3cc(OC)c(OC)cc32)c1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Br)CBr
Product: COc1cccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCCc3ccccc32)c1

Procedure:
prepared by reaction of 1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: C(OC(=O)C[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[N:14]=1)(C)(C)C.F[C:22](F)(F)[C:23]([OH:25])=[O:24]>ClCCl>[F:19][C:15]1([CH2:22][C:23]([OH:25])=[O:24])[CH:16]=[CH:17][CH:18]=[C:13]([C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[NH:14]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Cn1ccnc1-c1cccc(F)n1
Solvent: ClCCl
Product: O=C(O)CC1(F)C=CC=C(c2ncc[nH]2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [2-(6-fluoropyridin-2-yl)-imidazol-1-yl]acetic acid tert-butyl ester (630 mg; 2.27 mmol) and trifluoroacetic acid (4 mL) in dichloromethane (4 mL) is stirred at room temperature for 5 hr. The reaction mixture is concentrated. The residue is treated with 3M HCl in ethyl acetate (10 mL) and the suspension stirred at room temperature for 1 hr. The precipitate is collected, washed with ethyl acetate, and dried to give 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine acetic acid as a tan solid (581 mg), 1H NMR (d6DMSO) δ 8.35-8.26 (m, 2H) 7.83 (s, 1H), 7.76 (s, 1H), 7.44-7.41 (m. 1H) 5.40 (s, 2H). LCMS: 222.1 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](=O)[NH:22][CH2:23][C:24](=[O:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21]1[O:26][C:24]([CH3:25])=[CH:23][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CNC(=O)[C@@H]1C[C@@H](OC(C)(C)C)CN1C(=O)OCc1ccccc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc([C@@H]2C[C@@H](OC(C)(C)C)CN2C(=O)OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
To a stirred solution of (2S,4R)-4-tert-butoxy-2-(2-oxo-propylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (2.5 g, 6.65 mmol) and hexachloroethane (3.148 g, 13.3 mmol) in dichloromethane (16 mL) was added triphenyl phosphine (3.458 g, 13.3 mmol). The mixture was stirred at 0° C. for 20 min. Then triethylamine (1.36 mL, 13.3 mmol) was added and the reaction mixture was stirred at room temp. for 14 h. Water was then added to the reaction mixture, extracted with dichloromethane and the combined organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude was then purified by column chromatography to give (2S,4R)-4-tert-butoxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester (1 g, 42% yield) as an off-white solid. MS calcd. for C20H27N2O4 [(M+H)+] 359.0, obsd. 359.0.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([OH:6])=O)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:33]([CH2:35][NH2:36])=[O:34])=[CH:27][CH:26]=1>C(Cl)Cl>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([NH:36][CH2:35][C:33]([O:32][CH2:31][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)=[O:34])=[O:6])[CH3:3]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Boc-D-Ala-OH (5.68 g, 30 mmole) and H-Gly-OBzl.TosOH (10.6 g, 1.05 eq) were suspended in CH2Cl2. WSCI (6 ml, 1.1 eq) was added dropwise while cooling, and the solution was stirred overnight. The CH2Cl2 was distilled off. The residue was dissolved in AcOEt (500 ml); washed with 1N HCl, water, 5% NaHCO3, and water in order; and dried over Na2SO4. AcOEt was distilled off, and the residue was recrystalized twice with AcOEt/n-hexane to give the desired product (9.16 g, 90.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[CH2:20]([O:19][C:17]([C:16](=[C:30]1[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:14]1[N:15]=[C:11]([NH:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[O:23])[S:12][CH:13]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2F)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2F)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.7 g of ethyl 2-(3-o-fluorophenylureido)thiazol-4-ylglyoxylate, 0.96 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:10][C:9]([NH2:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C@H:25]1[C:29](=[O:30])[NH:28][CH2:27][C@@H:26]1[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=3)=[CH:10][C:9]([NH:23][C:31]([C@@H:26]3[C@@H:25]([CH3:24])[C:29](=[O:30])[NH:28][CH2:27]3)=[O:32])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Reactant: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccccc2)n1
Yield: 57.3 %

Procedure:
To a solution of 1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (79 mg) in N,N-dimethylformamide (0.8 ml) were sequentially added (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (46 mg) prepared in Preparation 1, HOBt.H2O (57 mg) and WSC.HCl (71 mg), and the mixture was stirred at room temperature for 2 hours. To this reaction solution were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (63 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:19][C:20]3[CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)cc(C(=O)OC)c1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 11) (0.4 g, 1.3 mmol), dimethyl 5-amino-1,3-benzenedicarboxylate (0.29 g, 1 eq), HATU (0.69 g, 1.3 eq) and DIPEA (0.34 mL, 1.3 eq) in DMF (10 mL) was stirred at 45° C. for 24 hours. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate and concentrated. The title compound was obtained as a white solid (650 mg, 95%) after recrystallisation from acetonitrile. LC/MS: m/z 477 (M+H)+, Rt: 3.81 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)(Cl)=O.C([NH2:22])(C)(C)C.[C:23]1([CH3:29])[CH:28]=CC=C[CH:24]=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:22])=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[C:23]([CH3:29])([CH3:28])[CH3:24]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1c(F)ccc(C(N)=O)c1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Suspend 4-fluoro-2-nitro-benzoic acid (4.5 g, 24.3 mmol) in toluene (20 mL), add thionyl chloride (22.5 mL) seal the flask and warm to 50° C. for 3 hours. Concentrate the reaction in in vacuo and reconcentrate twomore times from toluene. Place under high vacuum for 1 hour. Dissolve the acid chloride in methylene chloride (40 mL) and add t-butylamine (13.5 mL). Stir the reaction at room temperature. Concentrate the reaction in vacuo to yield the 4-fluoro-2-nitro-tert-butylbenzamide as an off white solid (5.5 g, 95%); mp 142°-143° C.
Reaction SMILES: [C:1]([O:12][O-])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-])=O.[Mg+2].[OH2:15].[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]=1[C:25]#[C:26][C:27]1[CH:28]=C2C(=C[CH:36]=1)C=C(C(O)=O)C=C2>C(O)(C)C.[Cl-].[Na+].O>[O:15]1[C:17]2([CH3:16])[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]12[C:25]#[C:26][C:27]1[CH:28]=[C:7]2[C:3](=[CH:4][CH:36]=1)[C:2]([C:1]([OH:12])=[O:11])=[CH:10][CH:9]=[CH:8]2
Reactant: CC1=C(C#Cc2ccc3cc(C(=O)O)ccc3c2)C(C)(C)CCC1
Reactant: O
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1(C)CCCC2(C)OC12C#Cc1ccc2c(C(=O)O)cccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 0.135 g (0.218 mmol) of 80% magnesium monoperoxyphthalate acid (MMPP) and 2 ml iso-propyl alcohol was added enough water (0.20 ml) to just dissolve the solid. This solution was added to a solution of 0.058 g (0.182 mmol) of 6-[2-(2,6,6-trimethylcyclohex-1-enyl)ethynyl]-2-naphthoic acid (Compound 4) in 1 ml iso-propyl alcohol and stirred at ambient temperature for 3 days. The solution was treated with 2 ml of brine and extracted with 3×10 ml ethyl acetate. The organic extracts were combined and washed with 5 ml saturated aqueous NaCl and dried (MgSO4). The solvent was removed in-vacuo and the residue purified by flash chromatography (SiO2, 75:25 ethyl acetate in hexanes) to give the title compound as a white solid
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][O:32][CH3:33])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[CH3:34][NH2:35].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:34][NH:35][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][O:32][CH3:33])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCOC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[2-(methyloxy)ethyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (25 mg, 0.053 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added methyl amine (0.15 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (13.2 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (10.0 mg, 39%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:24][CH2:25][CH2:26][CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)(=[O:23])=[O:22]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[N:28]1([CH2:27][CH2:26][CH2:25][NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)(=[O:23])=[O:22])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Nc1ccccc1S(=O)(=O)NCCCn1ccnc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1S(=O)(=O)NCCCn1ccnc1)c1cccc(C(F)(F)F)c1
Yield: 58.9 %

Procedure:
A solution of 4.24 g (0.0203 mol) of m-trifluoromethylbenzoyl chloride in 10 ml of dichloromethane was added dropwise to a solution of 4.35 g (0.0153 mol) of 2-amino-N-[(3-imidazol-1-yl)propyl]benzenesulfonamide, prepared as in Examples 1A and 1B, in 70 ml of pyridine, under nitrogen. When the reaction was complete, as determined by thin layer chromatography, the resulting reaction mixture was reduced to dryness under reduced pressure. The resultant oil was dissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated, the organic layer was washed with water and again reduced to dryness under reduced pressure to provide an oil. This oil was then purified using column chromatography (8000 ml of a gradient eluent of 0-15% methanol in chloroform). The fractions containing the desired product were combined, reduced to dryness under reduced pressure and then recrystallized from an ethanol/hexane/diethyl ether solution to provide 4.08 g of the desired titled compound (m.p. 145°-147° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][N:14](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9][N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.OS(O)(=O)=O.C(O)C>C(OCC)C>[CH3:1][N:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: CN1CCNCCNCCNCCNCC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
A mixture of 1-methyl-4,7,10,13-tetra(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 15C (3.6 g, 4.3 mmol) and concentrated H2SO4 (15 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 h. To the resulting brown solution, ethanol (30 mL) was added dropwise with stirring at 5° C. followed by ethyl ether (80 ml). The tan solid was filtered and dissolved in H2O (10 ml). The pH of the solution was adjusted to 10 with 1ON NaOH and the solution was extracted with 6 x CHCl3. The extracts were combined, dried (Na2SO4) and the solvent removed in vacuo. The crude solid was purified by crystallization from cold (-20° C.) CH3CN to give 0.50 g (51% yield) of the product as colorless needles: mp 71.0°-2.5° C.; 1H NMR (CDCl3) δ1.90 (br s, 4 H), 2.22 (s, 3 H), 2.52 (m, 4 H), 2.68 (m, 12 H), 2.78 (m, 4 H); Anal. calcd. for C11H27N5 : C, 57.60; H, 11.86; N, 30.53. Found: C, 57.17; H, 12 . 13; N, 30.12.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7](O)[CH:6]=[CH:5][C:3]=1[OH:4].[C:10]([O-:13])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>CC(C)=O>[CH3:20][CH:19]([CH3:21])[CH2:18][CH2:17][O:4][C:3]1[CH:5]=[CH:6][C:7]([O:13][CH2:10][CH2:1][CH:2]([CH3:8])[CH3:3])=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cc(O)ccc1O
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCBr
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCCC(C)C)ccc1OCCC(C)C

Procedure:
Under argon condition, methylhydroquinone (10.0 g, 81 mmol) and K2CO3 (5567 g, 403 mmol) were melted with 20 mL acetone and then added with 1-bromo-3-methylbutane (26.77 g, 177 mmol). Then, the mixture was agitated at reflux temperatures for 24 hours and then the temperature of the mixture was lowered to normal temperatures. After removing the solvent therefrom, the mixture was purified by column chromatography. (silica gel, CH2Cl2/hexane 1:4, Rf: 0.5). transparent oil. 1H NMR (CDCl3): 6.77 (d, 1H), 6.75 (s, 1H), 6.70 (d, 1H), 3.95 (m, 4H), 2.23 (s, 3H), 1.86 (m, 2H), 1.69 (m, 4H), 0.99 (m, 12H); 13C {1H} NMR (CDCl3): 152.9, 151.6, 128.2, 117.8, 112.2, 111.7, 67.2, 67.0, 38.4, 38.3, 25.3, 25.2, 22.8, 22.7, 16.5. Anal. Calcd, for C17H28O2: C, 77.22; H, 10.67. Found: C, 77.05; H, 10.58.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[OH-].[CH2:9]([N+](C)(C)C)[C:10]1C=CC=C[CH:11]=1.O[CH2:21]CC(=O)C>C(O)(=O)C>[CH3:6][C:5]1[CH2:7][CH2:21][C:3](=[C:10]([CH3:11])[CH3:9])[C:2](=[O:1])[CH:4]=1
Reactant: CC(=O)C=C(C)C
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CC(=O)CCO
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1=CC(=O)C(=C(C)C)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A 688 ml (6.0 mol) portion of mesityl oxide was put into a one liter capacity four neck flask, 4.18 ml (10 mmol) of 40% benzyltrimethylammonium hydroxide aqueous solution was added dropwise thereto and the mixture was heated to 80° C. To this was added dropwise 172 ml (2.0 mol) of 4-hydroxy-2-butanone spending 1 hour while keeping at 80° C. After completion of the dropwise addition, this was stirred for 30 minutes and then neutralized by adding dropwise 0.69 ml of acetic acid. By carrying out distillation of the reaction solution under a reduced pressure, 180 g of piperitenone was obtained. Yield 60%.