Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[O:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][O:15]2)=[O:21])[CH2:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)[C@@H]2CCCO2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3-dimethyl-6-nitroindoline (385 mg, 2 mmol), (S)-tetrahydrofuran-2-carboxylic acid (250 mg, 2.2 mmol), HOBt (266 mg, 2 mmol), EDAC (700 mg, 3.5 mmol), and DIEA (2 mL) in DCM (50 ml) was stirred at RT for overnight. The reaction mixture was washed in turn with aqueous NaHCO3 (sat., 50 mL), aqueous HCl (0.5N, 50 mL), H2O (50 mL), and brine (50 mL). The DCM layer was concentrated in vacuum to give the desired compound. MS: (ES+) 291(M+H). Calc'd. for C15H18N2O4—290.31.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Br)[CH2:10][CH2:11][CH3:12].C([O-])(O)=O.[Na+]>CO>[CH2:9]([NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Nc1cccc(O)c1
Reactant: CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCNc1cccc(O)c1
Yield: 57 %

Procedure:
One-tenth mol of m-aminophenol in 150 ml methanol is treated with 0.11 mol of n-butyl bromide and 0.1 mol of NaHCO3 and the mixture is heated under reflux for 5 h. After cooling, the reaction mixture is filtered and the solvent removed under reduced pressure. The residual oil is vacuum fractionated to give 3-(n-butylamino)phenol.
Reaction SMILES: [Na].C(O)C.[C:5](=[O:12])([O:9][CH2:10][CH3:11])OCC.[CH2:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:32])[CH3:14]>[Cl-].[Na+].O.C(Cl)Cl>[CH2:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:22]=2)[CH:17]([C:5]([O:9][CH2:10][CH3:11])=[O:12])[C:16]1=[O:32])[CH3:14]
Reactant: CCN1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1C(=O)N(CC)c2ccc(C(=O)c3ccccc3)cc21
Temperature: 65 °C

Procedure:
To a solution of 1.89 g. of sodium metal in 55 ml. of ethanol cooled to 0° C. was added 9.96 ml. of diethyl carbonate followed by 6.5 g. (27.43 mmoles) of 1-ethyl-5-benzoyloxindole. After heating for 2 hours at 65° C. on an oil bath, the reaction mixture was poured into a cold mixture of 250 ml. 1N hydrochloric, 250 ml. of a saturated brine solution and 200 ml. of methylene chloride. The organic phase was separated, dried and concentrated in vacuo. The excess diethylcarbonate was removed under high vacuum and the residue recrystallized from methylene chloride and cyclohexane, 2.1 g. 1st crop and 3.78 g. 2nd crop.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH3:15])=[O:6].Cl.[OH-:24].[K+]>CS(C)=O.O>[CH2:14]([N:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[CH2:8][NH:7][C:5](=[O:6])[C:4]1[C:3]([O:21][CH3:22])=[C:2]([OH:24])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[CH3:15]
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(OC)ccc(Br)c1OC
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCN1CCC[C@H]1CNC(=O)c1c(OC)ccc(O)c1OC

Procedure:
(S)-(-)-3-Bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide ×HCl×H2O (1.0 g, 0.0026 mol) was dissolved in 25 ml dimethylsulphoxide. A suspension of crushed potassium hydroxide (1.0 g, 0.018 mol) in 5 ml water was added and the mixture was heated at reflux for 2 h. After cooling 200 ml of water was added and the reaction mixture was neutralized and extracted with chloroform. Drying and evaporation of the solvent gave a residue containing a mixture of several products including the starting material. Separation on silica column with CH2Cl2 -C2H5OH-NH3 (90:9:1) gave 0.05 g of the title compound as a oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)=O.[OH:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][NH2:25].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]1([C:7]2[N:6]=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]([CH2:2][CH:1]=[N:25][CH2:24][CH:23]([OH:22])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OC(CN=CCc1cnc(-c2ccccc2)nc1-c1ccccc1)c1ccccc1
Yield: 82.1 %

Procedure:
A mixture of 61.2 g (0.223 mole) of 2,4-diphenyl-5-pyrimidyl methyl ketone, 30.6 g (0.223 mole) of β-hydroxyphenethylamine and 3.0 g p-toluenesulfonic acid monohydrate in 750 ml toluene was stirred and refluxed using a Dean-Stark apparatus for 11.0 hours, amt. H2O evolved: 4:10 ml; theoretical amt.: 4.0 ml. The toluene was removed in vacuo and the residue was dissolved in 1000 ml chloroform. The solution was washed with 300 ml H2O, dried (MgSO4), and concentrated to dryness in vacuo. Recrystallization of the residue from ethanol gave in three crops 72 g (82%) of the product, m.p. 140°-144°.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]C(C)(C)C([O-])([O-])[O-]>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)ccc1I
Temperature: 25 °C

Procedure:
To a solution of 2-iodo-5-methyl benzoic acid (10.0 g, 0.038 mol) in toluene (200 mL) was added trimethylorthoacetate (25 mL) at room temperature. The reaction mixture was refluxed for 12 hours. The reaction mixture was cooled to room temperature and diluted with saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer washed with brine. The organic layer was dried (MgSO4) and solvent removed to give 1035 g of methyl 2-iodo-5-methylbenzoate (EX-25A) as a yellow oil with an m/z+1=277.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[N:31]1([C:37]2[N:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:34]3[CH2:35][CH2:36][N:31]([C:37]4[N:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[CH2:32][CH2:33]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Reactant: c1ccc2nc(N3CCNCC3)ncc2c1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ncc5ccccc5n4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 2-piperazin-1-yl-quinazoline.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.8 %

Procedure:
To a solution of phenol 4 (3.0 g, 9.88 mmol) in DMF (20 mL) were added TBDMSCl (1M in CH2Cl2, 20 mL, 19.8 mmol), imidazole (2.1 g, 29.6 mmol) and DMAP (0.25 g, 1.98 mmol) at room temperature. The mixture was stirred at ambient temperature for 14 hours. The mixture was extracted with EtOAc/H2O (75 mL/250 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 21 (4.12 g, 99%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:48])([F:47])[CH:38]([OH:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][CH:38]([OH:46])[C:37]([F:48])([F:36])[F:47])[CH2:41][CH2:42]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OC(CN1CCNCC1)C(F)(F)F
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(O)C(F)(F)F)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3,3,3-trifluoro-2-hydroxy-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1,1,1-trifluoro-3-piperazin-1-yl-propan-2-ol (example 18b) in an analogous manner as described in example 25. LR-MS: 691.4 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([F:35])[CH:37]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2cccc(F)c2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 3-fluoro-benzylbromide (135 μL). The reaction mixture is allowed to stir at room temperature for 18 h. The resulting suspension is poured into water (10 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 425 mg (81%) of the title compound as a white solid.
Reaction SMILES: O=C1C=CNCC1.C(Br)C=C.[C:12](=[O:15])([O-])[O-].[K+].[K+].[CH2:18]([N:21]1[CH:26]=[CH:25][C:24](=O)[CH2:23][CH2:22]1)[CH:19]=[CH2:20].C(N1CCC(=O)CC1)C=C.[CH3:38][O:39][S:40]([O:43]C)(=[O:42])=[O:41]>CC(C)=O.C(Cl)(Cl)Cl>[CH3:38][O:39][S:40]([O-:43])(=[O:42])=[O:41].[CH2:18]([N+:21]1[CH2:26][CH2:25][C:24]([O:15][CH3:12])=[CH:23][CH:22]=1)[CH:19]=[CH2:20]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: C=CCN1C=CC(=O)CC1
Agent: C=CCN1CCC(=O)CC1
Agent: O=C1C=CNCC1
Agent: [K+]
Solvent: CC(C)=O
Solvent: C=CCBr
Solvent: ClC(Cl)Cl
Product: C=CC[N+]1=CC=C(OC)CC1
Product: COS(=O)(=O)[O-]

Procedure:
The starting material was obtained as follows. Reaction of 1,2,3,4-tetrahydro-4-oxopyridine with 2 equivalents of allyl bromide and potassium carbonate in acetone under reflux for 15 hours gave, after purficiation by silica gel/EtOAc chromatography, 1,2,3,4,-tetrahydro-1-allyl-4-oxopyridine, nmr in CHCl3 :-2.5 tetrahydro-1-allyl4-oxopyridine, nmr in CHCl3 :-2.5 (t,2H); 3.46(t,2H); 3.8(d,2H); 5.0(d,1H); 5.24(m,1H); 5.4(m,1H); 5.4(m,1H); 5.8(m,1H); 7.06(d,1H). Reaction of this compound with dimethylsulphate at ambient temperature for 18 hours gave 1-allyl-2,3-dihydro-4-methoxypyridineium methyl sulphate. nmr in CDCl3 :-2.86(t,2H); 3.68(s,3H); 3.94(t,2H0; 3.96(s,3H); 4.5 (d,2H); 5.4(d,1H); 5.56(d,2H); 5.8(d,1H); 5.9(m,1H); 8.62(d,1H0.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+:24]>CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([O-:20])=[O:19])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Na+:24]
Reactant: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2)c2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])Cc1cc(C(=O)c2ccc(Cl)cc2)c2occc2c1

Procedure:
To a solution of 250 mg of (7-(4-chlorobenzoyl)benzofuran-5-ylacetic acid in 5 ml of methanol is added 1 molar equivalent of sodium hydroxide in the form of 0.1 N solution. The solvent is evaporated to dryness and the residue taken up in 2 ml of methanol, followed by precipitation with ether, to yield sodium 7-(4-chlorobenzoyl)benzofuran-5-ylacetate.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=[O:3].[C:7]([O:10][CH2:11][CH:12]1[CH2:24][CH2:23][N:15]2[C:16]3[C:21]([CH:22]=[C:14]2[CH2:13]1)=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:9])[CH3:8].C(N(CC)CC)C.Cl.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][C:43](=[NH:48])[O:44]C(C)C)=[CH:34]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C1(C)C=CC=CC=1>[C:7]([O:10][CH2:11][CH:12]1[CH2:24][CH2:23][N:15]2[C:16]3[C:21]([C:22]([C:1]4[C:2](=[O:3])[NH:44][C:43](=[O:48])[C:42]=4[C:35]4[C:36]5[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=5)[NH:33][CH:34]=4)=[C:14]2[CH2:13]1)=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:9])[CH3:8]
Reactant: CC(=O)OCC1CCn2c(cc3ccccc32)C1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)OC(=N)Cc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OCC1CCn2c(c(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c3ccccc32)C1
Reaction time: 0.25 h
Yield: 30.2 %

Procedure:
165 mg (1.38 mmol) of oxalyl chloride were added to a stirred solution of 300 mg (1.24 mmol) of 8-acetoxymethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole in 50 ml of dichloromethane at 0° C. The resulting solution was stirred for 15 minutes and the solvent was removed by evaporation. The residue was dissolved in 30 ml of toluene and added dropwise to a stirred solution of 496 mg (4.96 mmol) of triethylamine and mg (1.31 mmol) of isopropyl 3-indoleacetimidate hydrochloride in 20 ml of toluene. After 18 hours, 1.16 g (6.2 mmol) of p-toluenesulfonic acid were added and stirring was continued for 1 hour. The mixture was then partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (1:1) for the elution to give 170 mg (38%) of 3-[8-(acetoxymethyl) -6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-[3-indolyl)-1H-pyrrole-2,5-dione in the form of an orange colored solid of melting point 264°-265° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1>ClCCl>[CH2:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8].[CH2:8]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[CH3:1]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(C)cc1
Solvent: ClCCl
Product: CCc1ccc(C)cc1
Product: CCc1ccccc1
Yield: 89 %
Yield: 86 %

Procedure:
of the Dofasco Boatslip in 1992 resulted in the biodegradation of several organic compounds (mean of three samples, reductions as follows; toluene 80%, ethylbenzene 86%, m/p-xylene 76%, 3/4-ethyltoluene 89%, and dichloromethane 65%) (FIG. 29). These relatively rapid biodegradation rates are similar to those reported in laboratory studies where nitrate was added to enhance biodegradation (Hutchins 1991).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(C2C3SC(NC(=O)C4C=CN=C(CN5CCCC5)C=4)=NC=3C(OC)=CC=2)CCCCC1>>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][N:28]=[C:3]([CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:4]=3)[S:10][C:11]=2[C:17]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: C1CCNC1
Agent: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccnc(CN4CCCC4)c3)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(CN4CCCC4)c3)nc12

Procedure:
The title compound was prepared from 2-chloromethyl-N-[7-(tetrahydro-pyran-4-yl)-4-methoxy-benzothiazol-2-yl]-isonicotinamide (prepared from 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and 4-(2-chloromethyl)-isonicotinic acid chloride as described for 2-chloromethyl-N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-isonicotinamide) and pyrrolidine as described for N-(7-Cyclohexyl-4-methoxy-benzothiazol-2-yl)-2-pyrrolidin-1-ylmethyl-isonicotinamide and obtained as light yellow solid (62% yield), mp 200-202° C. MS: m/e=453 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[Cl:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:29]3[CH2:28][CH2:27][CH:26]([C:20]4[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=4[Cl:18])[CH2:31][CH2:30]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1cccc(C2CCNCC2)c1Cl
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cccc(F)c2Cl)CC1
Reaction time: 0.33 h
Yield: 48.1 %

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (102 mg, 0.38 mmol) in THF (3.1 mL) was added a solution of LiOH monohydrate (16 mg, 0.38 mmol) in H2O (2.0 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (4.0 mL) under an atmosphere of N2. To this mixture was added 4-(2-chloro-3-fluorophenyl)piperidine hydrochloride (14, 94 mg, 0.38 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (334 mg, 0.76 mmol), and diisopropylethylamine (0.20 mL, 1.1 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-3-fluorophenyl)piperidin-1-yl)methanone as a white solid (80 mg, 48%): 1H NMR (300 MHz, DMSO-d6) δ 9.11 (br s, 1H), 8.03-7.95 (m, 1H), 7.71 (dd, J=9.6, 1.8 Hz, 1H), 7.43-7.23 (m, 3H), 5.27-5.17 (m, 1H), 4.80-4.69 (m, 1H), 3.48-3.34 (m, 2H), 3.12-2.96 (m, 1H), 2.02-1.59 (m, 4H); ESI MS m/z 438 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[CH:15]1[CH2:20][CH2:19][N:18](C(=O)C)[CH2:17][CH2:16]1)=[O:4].[ClH:24]>CO>[ClH:24].[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc2cc(F)ccc2c1C1CCN(C(C)=O)CC1
Agent: Cl
Solvent: CO
Product: COC(=O)c1sc2cc(F)ccc2c1C1CCNCC1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 24.4 g (66.8 mmol) of 3-(1-acetyl-piperidin-4-yl)-6-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester in 400 mL of MeOH and 50 mL of concentrated HCl was heated a reflux for 2 days. When the solution was allowed to cool to room temperature the white precipitate was filtered, washed with methanol and dried to give 17.9 g (74%) of product as a white powder. MS (electrospray): exact mass calculated for C15 H16FNO2S, 293.09; m/z found, 294.1 [M+H]+. 1H NMR (DMSO-d6, 400 MHz): 9.38 (br s, 1H), 9.02 (br s, 1H), 8.60 (dd, J=9.19, 5.09 Hz, 1H), 7.98 (dd, J=9.00, 2.54 Hz, 1H), 7.36 (dt, J=9.00, 2.54 Hz, 1H), 4.37 (br t, J=12.72 Hz, 1H), 3.87 (s, 3H), 3.40 (br d, J=11.93 Hz, 2H), 3.02 (q, J=11.35 Hz, 2H), 2.61 (dq, J=13.30, 3.72 Hz, 2H), 1.77 (br d, J=12.91 Hz, 2H).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]([C:28]1[C:36]([NH:37][C@H:38]([CH3:41])[CH2:39][CH3:40])=[CH:35][C:31]([C:32](O)=[O:33])=[C:30]([CH3:42])[CH:29]=1)=[O:27].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN(C=O)C>[CH3:42][C:30]1[CH:29]=[C:28]([C:26]([NH2:25])=[O:27])[C:36]([NH:37][C@H:38]([CH3:41])[CH2:39][CH3:40])=[CH:35][C:31]=1[C:32]([NH2:2])=[O:33]
Reactant: CC[C@@H](C)Nc1cc(C(=O)O)c(C)cc1C(N)=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](C)Nc1cc(C(N)=O)c(C)cc1C(N)=O
Yield: 130.5 %

Procedure:
A solution of [6-(3-endo-amino-8-azabicyclo[3.2.1]oct-8-yl)pyridin-3-yl](cyclopropyl)methanone (100 mg, 0.37 mmol), HATU (210 mg, 0.55 mmol), 4-(aminocarbonyl)-2-methyl-5-{[(1R)-1-methylpropyl]amino}benzoic acid (synthesized in reagent preparation 41) (138 mg, 0.55 mmol), and diisopropylethyl-amine (256 μl, 1.47 mmol) in DMF (3 mL) was stirred at room temperature for 2 h. Concentration and column chromatography on silica (dichloromethane:methanol 100:0 then 95:5) followed by trituration of the residue obtained on concentration of the combined pure fractions with ethyl acetate afforded N-{8-[5-(cyclopropyl-carbonyl)pyridin-2-yl]-8-azabicyclo[3.2.1]oct-3-endo-yl}-2-methyl-5-{[(1R)-1-methylpropyl]amino}benzene-1,4-dicarboxamide (179 mg, 96% yield) as a pale yellow powder. 1H NMR (400 MHz, methanol-d4): 8.84 (d, 1H), 8.11 (dd, 1H), 7.45 (s, 1H), 6.78 (d, 1H), 6.68 (s, 1H), 4.68 (br s, 2H), 4.02 (t, 2H), 3.77-3.67 (m, 1H), 3.25-3.19 (m, 2H), 2.76-2.70 (m, 1H), 2.32-2.25 (m, 7H), 2.18-2.14 (m, 2H), 1.97 (br s, 1H), 1.70-1.59 (m, 1H), 1.60-1.50 (m, 1H), 1.25-1.18 (m, 4H), 1.12-1.09 (m, 2H), 1.06-1.01 (m, 2H), 0.97 (t, 3H); MS (EI) for C29H37N5O3: 504 (MH+).