Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CC1C=CC(S(OC[C@@H]2O[C:18]3[C:20]([CH3:25])=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3OC2)(=O)=O)=CC=1.[C:26]([O-:29])(=O)[CH3:27].[K+].C(OC(=O)C)(=O)C.[N:38](OCCC(C)C)=O>C1C=CC=CC=1>[C:26]([C:25]1[C:20]2[C:21](=[CH:22][CH:23]=[CH:17][CH:18]=2)[NH:24][N:38]=1)(=[O:29])[CH3:27]
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(C)c3O2)cc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)c1n[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 10 h
Yield: 197.5 %

Procedure:
To a heterogeneous mixture of [(2R)-7-amino-8-methyl-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate hydrochloride (0.93 g, 2.75 mmole) in benzene (10 mL) was added anhydrous potassium acetate (0.50 g, 5.1 mmole) and acetic anhydride (0.80 mL, 8.3 mmole). The temperature was increased to 50° C., and isoamyl nitrite (0.55 mL, 4.1 mmole) was added dropwise. The temperature was further increased and held at 80° C. for a period of 10 hours. When the reaction was complete, the solvent was removed in vacuum and replaced with ethyl acetate in equal volume. The solution was washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate, brine and then dried over magnesium sulfate. After the solution was filtered and concentrated in vacuum, the crude residue was triturated with methylene chloride/methanol (3:1, 6 mL) to obtain the intermediate acetyl indazole as yellow solid (0.87 g, 82%). The acetyl group was hydrolyzed by refluxing in concentrated hydrochloric acid for a period of 12 hours. After cooling to room temperature, the reaction was neutralized with ammonium hydroxide, extracted with methylene chloride and the extract dried over magnesium sulfate, filtered and concentrated in vacuum to yield 0.76 g (99%) of the (R)-enantiomer of the title compound as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][CH:39]=2)=[CH:34][CH:33]=1.CCOC(C)=O.CCCCCC>C1COCC1>[CH3:8][O:9][CH:10]=[CH:44][C:41]1[CH:42]=[CH:43][C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:47])([F:46])[F:30])=[CH:33][CH:34]=2)=[CH:39][CH:40]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To an ambient temperature suspension of potassium tert-butoxide (449 mg, 4.00 mmol) in THF (20 mL) is added (methoxymethyl)triphenylphosphonium chloride (1.37 g, 4.00 mmol) and is stirred at room temperature for 30 min. 4′-trifluoromethyl-biphenyl-4-carbaldehyde (500 mg, 2.00 mmol) is added and the reaction mixture continues to stir at room temperature. After 2 h TLC (30% EtOAc/hexane) indicates complete consumption of starting material. The reaction is quenched with saturated aqueous NH4Cl and concentrated. The residue is partitioned between EtOAc (50 mL) and water (20 mL). The aqueous layer is extracted with EtOAc (50 mL) and the combined organic layers are washed with brine (100 mL), dried (MgSO4), filtered, concentrated and chromatographed (40 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (482 mg, 87%).
Reaction SMILES: N[C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].C(C=O)=O.O1C[CH2:24][CH2:23][CH2:22]1>O>[N:12]1[C:11]2[C:2](=[C:3]([C:13]([O:15][CH3:16])=[O:14])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(N)c(N)c1C(=O)OC
Agent: O=CC=O
Solvent: O
Product: COC(=O)c1ccc2ncccc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
A mixture of dimethyl 3,4-diaminophthalate (11.2 g, 0.05 mol) in tetrahydrofuran is treated with glyoxal (2.9 g, 0.05 mol) in water at reflux temperature, stirred for 4 hours at reflux temperature and overnight at room temperature, and concentrated in vacuo. The resultant residue is partitioned between water and methylene chloride. The organic phase is dried (MgSO4) and concentrated in vacuo to give a brown solid residue. Recrystallization from methanol gives the title product as a pink powder (9.67 g, 78.6%) mp 124°-125° C., identified by H1NMR, C13NMR, and IR spectral analyses.
Reaction SMILES: [CH2:1]([NH:8][S:9](Cl)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([NH:17][C:18](=[NH:21])[O:19][CH3:20])(OC)=O.C([N:24](CC)CC)C>C1COCC1>[NH2:24][C:13]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9](=[O:11])(=[O:10])[N:21]=[C:18]([O:19][CH3:20])[N:17]=1
Reactant: O=S(=O)(Cl)NCc1ccccc1
Reactant: COC(=N)NC(=O)OC
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(N)=N1
Temperature: 25 °C

Procedure:
A solution of benzylsulfamoyl chloride (168 g) in anhydrous THF (300 ml) is added dropwise to a stirred solution of N-carbomethoxy-O-methylisourea (107 g) and triethylamine (90 g) in anhydrous THF (800 ml) under nitrogen at -70° C. The resulting suspension is warmed to RT, filtered and the filtrate evaporated in vacuo. The residue is partitioned between methylene chloride and 0.5N aqueous HCl. The organic layer is dried, filtered, and concentrated in vacuo affording the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:42][Si](C)(C)C(C)(C)C(C)C)[C:6]2[CH2:19][S:18][CH2:17][C@@H:16]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[N:21]=3)[NH:15][C:14](=[S:26])[CH2:13][CH2:12][C@@H:11]([CH2:27][O:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=3)[CH2:10][O:9][C:8](=[O:39])[C:7]=2[C:40]=1[CH3:41].[F-].[NH4+].[ClH:54]>CO.C(OCC)C>[ClH:54].[OH:42][C:5]1[C:6]2[CH2:19][S:18][CH2:17][C@@H:16]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[N:21]=3)[NH:15][C:14](=[S:26])[CH2:13][CH2:12][C@@H:11]([CH2:27][O:28][C:29](=[O:38])[C:30]3[CH:31]=[CH:32][C:33]([CH2:36][NH2:37])=[CH:34][CH:35]=3)[CH2:10][O:9][C:8](=[O:39])[C:7]=2[C:40]([CH3:41])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](COC(=O)c1ccc(CN)cc1)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: COc1cc(O)c2c(c1C)C(=O)OC[C@H](COC(=O)c1ccc(CN)cc1)CCC(=S)N[C@H](c1nc(C)no1)CSC2

Procedure:
4-Aminomethyl-benzoic acid (4R,9S)-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-16-[dimethyl -(1,1,2-trimethyl-propyl)-silanyloxy]-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-9-ylmethyl ester was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1, and the resulting product was treated in methanol with a 3N solution of hydrochloric acid in diethyl ether to yield 4-aminomethyl-benzoic acid (4R,9S)-16-hydroxy-14-methoxy-13-methyl-4-(3-methyl -1,2,4-oxadiazol-5-yl)-12-oxo-6-thioxo-1,3, 4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-9-ylmethyl ester hydrochloride as white solid.
Reaction SMILES: [OH-:1].[Na+].[C@:3]12([CH3:13])[C:10]([CH3:12])([CH3:11])[CH:7]([CH2:8][CH2:9]1)[CH2:6][C:4]2=O.Cl.[NH2:15]O>C(O)C.O>[C@:3]12([CH3:13])[C:10]([CH3:12])([CH3:11])[CH:7]([CH2:8][CH2:9]1)[CH2:6][C:4]2=[N:15][OH:1]
Reactant: NO
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)C2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)C2CC[C@@]1(C)C(=NO)C2
Reaction time: 7 h

Procedure:
Sodium hydroxide (15.03 g; 375.50 mmol) is added carefully to a solution, which is boiling under reflux, of (1R)(+)camphor (10.01 g; 65.86 mmol) and hydroxylamine hydrochloride (10.04 g; 144.46 mmol) in 150 ml of ethanol and 20 ml of water. After 7 hours, the reaction solution is cooled down, diluted with water and filtered. The filtrate is brought to a pH of 5-6 using acetic acid. After renewed filtration, the oxime 19 is obtained (3.81 g, 35% of theory) (m.p. 188°-20° C.).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[NH2:40])[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].CO>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[NH2:40])[N:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3Sc3ccccc3N)ncc2[N+](=O)[O-])CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Nc1ccccc1Sc1ccccc1CNc1ncc([N+](=O)[O-])c(NC[C@H]2CC[C@H](N)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the above [4-({2-[2-(2-amino-phenylsulfanyl)-benzylamino]-5-nitro-pyrimidin-4-ylamino}-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (35 mg, 0.06 mmol) in CH2Cl2 (10 mL) was added TFA (1.2 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then treated with saturated NaHCO3. During the work-up, some MeOH was added to solubilize the product in the organic phase. The organic phase was then dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 10:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 20 mg 70%) of the title compound as an off-white solid, m/z 477.9 (M−1)+.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.[NH2:14][C@@H:15]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:16][N:17]([CH3:27])[C:18](=[O:26])[O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:29]1([CH2:28][C@H:15]([NH:14][C:5]([C:4]2[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=2)[C:1]([O:12][CH3:13])=[O:11])=[O:7])[CH2:16][N:17]([CH3:27])[C:18]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:26])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: CN(C[C@@H](N)CC1CCCCC1)C(=O)OCC[Si](C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of mono-methyl isophthalate (0.3230 g, 1.79 mmol, 1.0 equiv), 2-(trimethylsilyl)ethyl (S)-2-amino-3-cyclohexylpropylmethylcarbamate (0.5573 g, 1.77 mmol, 0.99 equiv), EDC (0.6200 g, 1.8 equiv), HOBT (0.4035 g, 1.66 equiv), and DIEA (3.6 mL, 11 equiv) in CH2Cl2 (20 mL) was stirred at rt for 18 h. The reaction mixture was quenched with 10% aq Na2CO3, extracted with CH2Cl2 and dried over Na2SO4. After the solvent was removed, the crude (S)-methyl 3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)benzoate (1.397 g) was used in the next step without further purification. LC-MS (3 min) tR=2.29 min, m/z 499 (M+Na+), 449, 359.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].ClC[CH:9]1[O:14][C:13](=O)[CH2:12][CH2:11][CH2:10]1.[CH3:16]O>>[O:14]1[CH2:9][CH:13]1[CH2:12][CH2:11][CH2:10][C:1]([O:2][CH3:16])=[O:4]
Reactant: O=C1CCCC(CCl)O1
Reactant: O=C([O-])[O-]
Reactant: CO
Agent: [K+]
Product: COC(=O)CCCC1CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
67.9 mg (0.492 mmol) of potassium carbonate were added to a mixture of 48.7 mg (0.328 mmol) of (-)-6-chloromethyltetrahydropyran-2-one obtained in Example 5 and 1 ml of methanol under water cooling, and the solution was then stirred for 30 minutes and further at room temperature for 5 hours. After distilling off with methanol, 10% hydrochloric acid was added to the resultant residue to neutralize the same, and it was then extracted with dichloromethane, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off to obtain 35.4 mg (yield 75%) of pure (-)-methyl 5,6-epoxyhexanoate [a compound of the formula (6')] as the residue. The values of physical properties of this product were good and comparable to those of literature [M. Suzuki et al., Chem. Pharm. Bull., 38, 2381 (1990)].
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[C:28]([CH:33]=O)=[CH:29][CH:30]=[N:31][CH:32]=1)[CH2:20][CH2:19]2.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(Cl)Cl.CO>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][C:28]=1[CH2:33][N:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)[CH2:20][CH2:19]2
Reactant: CN1CCNCC1
Reactant: O=Cc1ccncc1N1CCc2cc(Cl)ccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccncc2N2CCc3cc(Cl)ccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
NaBH(OAc)3 (84 mg, 0.4 mmol) was added into a solution of 5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-4-carbaldehyde (28.6 mg, 0.1 mmol) and 1-methyl-piperazine (10 mg 0.1 mmol) in DCM and MeOH (10 mL, 1:1). The reaction mixture was stirred at RT overnight before it was poured into ice-water (10 mL) and extracted with EtOAc (2×10 mL). The organic layers were washed with brine, dried over anhy. MgSO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (7.2 mg, 16%) as a white solid. MS: 371.1 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1.C(N(CC)CC)C>O1CCCC1.CN1CCN(C)C1=O>[C:1]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
Butyryl chloride (4.09 g) dissolved in 20 ml of tetrahydrofuran was added dropwise to 7.26 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and 7.05 g of triethylamine suspended in 70 ml of 1,3-dimethyl-2-imidazolidinone. The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration, washed with water and dried. The crystals were recrystallized from ethyl acetate to obtain 7.47 g of 2-butyrylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.CS(C)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH:15]=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: OCCCc1nc(-c2ccc(Cl)cc2)co1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCc1nc(-c2ccc(Cl)cc2)co1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a solution of 3-[4-(4-chlorophenyl)-2-oxazolyl] propanol (1.0 g) in dichloromethane (10 ml) were added dimethylsulfoxide (0.6 ml) and phosphoric anhydride (1.1 g) in that order. After stirring for 10 minutes at room temperature, the resultant was cooled to 0° C., to which triethylamine (2 ml) was added. The mixture was stirred for 40 minutes at room temperature, poured into 2N-HCl and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over MgSO4, and distilled to remove the solvent. The oily residue was subjected to a silica gel column chromatography. Crystals of 3-[4-(4-chlorophenyl)-2-oxazolyl]propanal (0.698 g, 70%) were obtained from the fraction eluted with ethyl acetate-hexane (1:3, V/V). Recrystallization from hexane gave colorless prism crystals of mp 41°-42° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[S:12][C:11]([NH2:13])=[N:10][CH:9]=2)=[CH:5][CH:4]=1.N1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:17]=1.[CH:27]1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[S:12][C:11]([NH:13][C:24](=[O:26])[CH2:23][CH2:22][C:18]3[CH:17]=[CH:27][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(Cc2cnc(N)s2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2cnc(NC(=O)CCc3ccccc3)s2)cc1
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A mixture of 5-(4-methoxy-benzyl)-thiazol-2-ylamine (9d, 1.0 g, 4.54 mmol) and 3-pyridin-3-yl-propionic acid (0.92 g, 5.45 mmol), EDCA (1.74 g, 9.08 mmol), HOBt (1.23 g, 9.08 mmol) and NEt3 (1.38 g, 13.6 mmol) in DMF (15.0 mL) was stirred for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give N-[5-(4-methoxy-benzyl)-thiazol-2-yl]-3-phenyl-propionamide (9, 1.05 g) in 66% yield: 1H NMR (500 MHz, CDCl3) δ 7.27 (d, 2 H), 7.3-7.15 (m, 6 H), 6.86 (d, 2 H), 3.98 (s, 2 H), 3.72 (s, 3 H), 2.87 (m, 2 H), 2.64 (m, 2 H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=4)[CH:22]=[C:21]([C:33]([F:36])([F:35])[F:34])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:32][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([C:33]([F:35])([F:34])[F:36])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[F:31]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.8 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (25 ml) and extracted ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash cromatography on silica gel (MeOH/dichloromethane) and crystallization (dichloromethane/heptane) yielded the title compound as a light yellow solid (0.077 g, 46%). MS (ISP) 487.9 [(M+H)+]; mp 228° C.
Reaction SMILES: OC1C=CC2N=C3CCNCCC3=C(C)C=2C=1.[Cl:18]C(OCC)=O.[CH2:24]([O:26][C:27]([N:29]1[CH2:43][CH2:42][C:41]2[C:32](=[N:33][C:34]3[CH:35]=[CH:36][C:37]([O:45]C(OCC)=O)=[CH:38][C:39]=3[C:40]=2[CH3:44])[CH2:31][CH2:30]1)=[O:28])[CH3:25].[OH-].[K+]>>[ClH:18].[CH2:24]([O:26][C:27]([N:29]1[CH2:43][CH2:42][C:41]2[C:32](=[N:33][C:34]3[CH:35]=[CH:36][C:37]([OH:45])=[CH:38][C:39]=3[C:40]=2[CH3:44])[CH2:31][CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)Oc1ccc2nc3c(c(C)c2c1)CCN(C(=O)OCC)CC3
Agent: Cc1c2c(nc3ccc(O)cc13)CCNCC2
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)N1CCc2nc3ccc(O)cc3c(C)c2CC1
Product: Cl
Yield: 16 %

Procedure:
9-Hydroxy-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 9-hydroxy-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63, followed by hydrolysis of the intermediate 9-(ethoxy-carbonyloxy)-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester with dilute potassium hydroxide at 30° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9]O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.S([O-])(=O)(=O)C.CS(Cl)(=O)=O.[C-:21]#[N:22].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O.C(N(CC)CC)C>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][C:21]#[N:22])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: OCC12CCN(CC1)CC2
Reactant: [C-]#N
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC12CCN(CC1)CC2
Yield: 71.3 %

Procedure:
Quinuclidin-4-ylmethanol (1.94 g, 0.014 moles) was converted to the corresponding mesylate by treatment with methane sulphonyl chloride and triethylamine in chloroform. The mesylate was dissolved in dimethylformamide (50 ml) and treated with sodium cyanide (1.4 g, 0.028 moles) at 120° C. for 18 hours. The mixture was cooled and concentrated in vacuo. The residue was partitioned between saturated potassium carbonate and chloroform. The organic layer was separated and dried (Na2SO4), filtered and evaporated to dryness. Chromatography on silica gel eluting with 0-10% methanol/chloroform gave the title compound 1.5 g (72%). M.S. (+ve electrospray) m/z 151 (MH+, 100%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.CCOCC>C(Cl)Cl>[C:5]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]([CH3:17])[CH3:8])=[CH:11][CH:12]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Nc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a solution of acetic anhydride (11.5 mL, 12.45 g, 0.122 mol) in anhydrous CH2Cl2 (100 mL) was added N,N-dimethyl-1,4-phenylenediamine (11.37 g; 83.5 mmol) portion-wise over 30 min at 0° C. The mixture was allowed to gradually warm to room temperature and stirred for 24 hours. The solvent was removed under high vacuum to obtain a black residue which was stirred with Et2O (20 mL) at room temperature. The suspension was filtered and the solid washed with Et2O (3×20 mL). The solid residue was dried under high vacuum to obtain the intermediate N-acetyl-N′,N′-dimethyl-1,4-phenylenediamine as a black solid (12.8 g, 86%) which was used in the next step without further purification.