Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: OCCN1CCNCC1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(CCO)CC4)cc3nc21
Yield: 62.9 %

Procedure:
1-Ethyl-7-fluoro-8-[4-(2-hydroxyethyl)-1piperazinyl]-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 2.6 g of 1-(2-hydroxyethyl)-piperazine in 16 cm3 of pyridine. 1.3 g of 1-ethyl-7-fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl] 4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 264°-265° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:22][NH2:23])=[O:21])[CH:4]=1.[CH:24](=O)[CH2:25][CH3:26].C(OCC)C.Cl>C(Cl)(Cl)Cl>[CH:24](=[N:23][NH:22][C:20](=[O:21])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[N:6]=1)[CH2:25][CH3:26]
Reactant: CCC=O
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCC=NNC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.5 g, 0.0015 mol) was mixed with propionaldehyde (0.27 g, 0.0015×3.1 mol), and further with a mixed solution of diethyl ether and chloroform and a small amount of concentrated hydrochloric acid. The resultant solution was heated and refluxed for about 8 hours. The obtained reaction solution was concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [C:1]([C@H:4]1[C@H:9]2[O:10][C@H:6]([CH2:7][CH2:8]2)[C@H:5]1[NH:11]C(=O)OC(C)(C)C)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C@@H:5]1[C@@H:6]2[O:10][C@@H:9]([CH2:8][CH2:7]2)[C@@H:4]1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@@H](C(N)=O)[C@@H]2CC[C@H]1O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1[C@H](N)[C@H]2CC[C@@H]1O2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
tert-butyl(1R,2S,3R,4S)-3-carbamoyl-7-oxabicyclo[2.2.1]heptan-2-ylcarbamate (14) (40 mg, 0.156 mmol) was taken in DCM and cooled to 0° C. when TFA (10 eq) was added and the reaction mixture was then stirred at rt for 3-4 h when TLC confirmed completion of reaction. TFA was removed and afforded the product (40 mg, quantitative) as a yellow oil.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCOCC>C1COCC1>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: N#CCCN1CCC(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCN1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of 3-(4-benzylpiperidin-1-yl)propionitrile (8.20 g, 35.9 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 126 mL, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours, then cooled to room temperature and concentrated to a volume of about 30 mL. Aqueous HCl (6 N, 80 mL) was added and stirring was continued for 2 hours at 55°-60° C. The mixture was basified to pH 9 by addition of 6N aq. NaOH and extracted with CH2Cl2 (3×150 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0M, 75 ml, 2.1 equiv). The solvents were removed, ether (60 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×30 mL). Water (40 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1M NaOH, and the aqueous phase was extracted with CH2 Cl2 (3×80 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 7.59 g (91%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)([CH3:21])[CH3:20])=[CH:15][CH:14]=1>ClCCl>[N:26]1([CH2:25][CH2:24][CH2:23][NH:22][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:15]=2)([CH3:21])[CH3:20])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(CCN)cc1
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(CCNC(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of benzoyl chloride (0.2 g) in dichloromethane (3 ml) was added dropwise to a solution of N-{1-[4-(2-aminoethyl)phenyl]-1-methylethyl}-3-(imidazol-1-yl)propylamine (0.4 g) in dichloromethane (7 ml) with stirring at 0° C. The mixture was treated in a similar manner to Example 55 to give N-[2-(4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl)ethyl]benzamide as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)(=[O:3])[CH3:2].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(#N)C>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)OCCC1CN(Cc2ccccc2)CCO1
Solvent: CC#N
Product: CC(=O)OCCC1CN(C(=O)OCc2ccccc2)CCO1
Yield: 72.1 %

Procedure:
To a solution of 2-(2-acetoxyethyl)-4-benzylmorpholine (29.1 g) in acetonitrile (200 ml) is dropwise added benzyl chloroformate (24.4 g). The reaction mixture is refluxed for 30 minutes, cooled and evaporated under reduced pressure. The residue is chromatographed on silica gel. The eluate with hexane is discarded, and the subsequent eluates with hexane-chloroform (1:1) are pooled and evaporated to give the title compound (24.5 g) as an oil.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)=[CH2:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:23][S:24]([O:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH:1]=[CH2:2])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)(=[O:26])=[O:25]
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](CO)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
15.1 g of trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethanol, 8.2 mL of pyridine, and 0.41 g of 4-dimethylaminopyridine were dissolved in 50 mL of dichloromethane. A dichloromethane (6 mL) solution containing 6.3 mL of methanesulfonyl chloride was added dropwise to the above solution on ice for 30 minutes. The solution was heated to room temperature, then stirred for 6 hours, and was left over night. The reaction solution was poured into 10% hydrochloric acid, and the organic layer was fractioned. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silicagel/toluene) and recrystallization (hexane/toluene) 3 times, to thereby obtain 9.8 g of trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethyl methanesulfonate in the form of colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1(O)[CH2:19][CH2:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([O:13][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-2-methylalanine (1.00 g, 4.92 mmol) in DCM (10 ml) at 0° C. was added cyclopentanol (0.83 ml, 9.84 mmol), EDCI (1.06 g, 5.42 mmol) and finally DMAP (60 mg, 0.49 mmol). The reaction mixture was warmed to RT and stirred for 18 hours. The DCM was removed in vacuo to give a clear oil. The crude residue was dissolved in EtOAc (100 ml) and washed with water, 1 M NaHCO3 and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude extract was purified by column chromatography (10% EtOAc in heptane) to yield the desired product as a clear oil (0.254 g, 20% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH:9]([N:11]3[CH2:16][CH2:15][C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:17](O)=[O:18])[CH2:13][CH2:12]3)[NH:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[C:26]([C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])([CH3:29])([CH3:28])[CH3:27].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(CC)CC)C>CN(C=O)C>[C:26]([C:30]1[CH:31]=[C:32]([NH:33][C:17]([C:14]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13][CH2:12][N:11]([C:9]3[C:10]4[C:2]([CH3:1])=[CH:3][NH:4][C:5]=4[N:6]=[CH:7][N:8]=3)[CH2:16][CH2:15]2)=[O:18])[CH:34]=[CH:35][CH:36]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1c[nH]c2c1C(N1CCC(C(=O)O)(c3ccccc3)CC1)NC=N2
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ncnc(N3CCC(C(=O)Nc4cccc(C(C)(C)C)c4)(c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-phenylpiperidine-4-carboxylic acid from step B (33 mg, 0.1 mmol) in DMF (2 mL) was added 3-tert-butylaniline (15 mg, 1.0 mmol), BOP (50 mg, 0.11 mmol) and triethylamine (0.04 mL, 0.3 mmol). The reaction mixture was stirred at room temperature for 20 hours, and the amide product was isolated by prep HPLC to give the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[Br:12])(=[O:3])[CH3:2].C(#N)C.Br[CH2:17][C:18]([CH3:20])=[CH2:19]>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:19][C:18]([CH3:20])=[CH2:17])[C:6]=1[Br:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(O)c1Br
Reactant: C=C(C)CBr
Solvent: CC#N
Product: C=C(C)COc1cccc(OC(C)=O)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of 2-bromo-3-hydroxyphenyl acetate (Intermediate 38, 3028 mg) in acetonitrile (60 ml) potassium carbonate (3623 mg, 26.2 mmol) and 3-bromo-2-methyl-1-propene (2123 mg, 15.73 mmol) were added. The reaction mixture was stirred at room temperature overnight. The mixture was washed with water (3 times 60 ml). The organic phase was separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a 100 g-SNAP column and cyclohexane/ethyl acetate from 100/0 to 80/20 as eluent to afford the title compound as a colourless oil (2.324 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].C(O)CCC.[ClH:27]>C(OCC)(=O)C>[ClH:27].[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: N#Cc1ccc(N2CCNCC2)cc1

Procedure:
A mixture of 27.3 g (0.15 mol) of p-bromobenzonitrile, 38.7 g (0.45 mol) of piperazine and 42.0 g (0.30 mol) of solid potassium carbonate in a total volume of 60 mL of n-butanol was heated at reflux for 6 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and the slurry partitioned between 10% sodium hydroxide and chloroform. The chloroform layer was separated, dried (MgSO4) and concentrated under reduced pressure to give an oil. The oil was eluted through a 400 g silica gel column with a 10% methanol in methylene chloride mixture. The appropriate fractions were concentrated under reduced pressure to give a golden oil. Trituration of this oil with ethyl acetate gave a white powder. The collected white powder was stirred for 15 min in ethereal HCl and recrystallized from methanol-water to give 1.5 g (4.5%)* of white solid, mp>160° C. with decomposition.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(CCc2cc(-c3ccccc3)n(-c3ccccc3)n2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc(CCc2cc(-c3ccccc3)n(-c3ccccc3)n2)c1
Yield: 90.1 %

Procedure:
A mixture of 3-[2-(1,5-diphenyl-1H-pyrazol-3-yl)ethyl]phenol (4.50 g, 13 mmol), methyl bromoacetate (2.23 g, 1.375 mL, 14.5 mmol), potassium carbonate (2.19 g, 16 mmol), potassium iodide (catalytic amount) and acetonitrile (80 mL) was stirred at reflux for 3 hours. The mixture was filtered, concentrated and the residue chromatographed on a column of silica gel prepared in a mixture of hexanes and diethyl ether (9:1). Subsequent elution with a mixture of hexanes and diethyl ether (1:1) furnished methyl [3-[2-(1,5-diphenyl-1H-pyrazol-3-yl)ethyl]phenoxy]acetate (4.83 g, 85% ) as an oil.
Reaction SMILES: C1(C)C=CC=CC=1.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10][CH:9]=1.[N:29]12CC[CH:32]([CH2:33][CH2:34]1)[CH:31](O)[CH2:30]2.[H-].[Na+]>C(O)C>[N:8]1[CH:9]=[CH:10][C:11]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH:27]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[O:25])=[CH:12][CH:13]=1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)N1CCc2ccccc2C1c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(OC1CN2CCC1CC2)N1CCc2ccccc2C1c1ccncc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a 50 ml toluene suspension containing 720 mg of ethyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate and 973 mg of 3-quinuclidinol, 102 mg of sodium hydride (60%) was added at room temperature. The resulting mixture was heated under reflux for 5 hours and 40 minutes while the resulting ethanol was removed together with toluene. The reaction mixture was cooled to room temperature, followed by addition of 20 ml of water. The resulting mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=100:2:1), thereby 827 mg of 3-quinuclidinyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate were obtained as yellow oil. The resulting oil was dissolved in 5 ml of ethyl acetate, 2 ml of a 4N hydrogen chloride in ethyl acetate solution was added. The solvent was then removed under reduced pressure. Ethanol and ether were added to the residue, and the crude crystals thus obtained was recrystallized from ethanol and ether, thereby 402 mg of 3-quinuclidinyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate dihydrochloride was obtained as pale yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:37][C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])[C:10]([C:14]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]3)=[O:15])=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:48]1COCC1>C[Mg]Br.CCOC(C)=O.Cl>[C:32]([O:31][C:30]([NH:29][C@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:22]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:16][C:14]([C:10]2[C:9]([NH:37][C:38](=[O:39])[O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:8][C:7]3[C:12](=[CH:13][C:4]([C:1]([OH:3])([CH3:48])[CH3:2])=[CH:5][CH:6]=3)[N:11]=2)=[O:15])[CH2:24]1)=[O:36])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(=O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C(C)(C)O)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of tert-butyl [(3S)-1-(3-{[(7-acetyl-3-{[(benzyloxy)carbonyl]amino}quinolin-2-yl)carbonyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate (0.100 g, 0.156 mmol) in THF (4.0 mL), methylmagnesium bromide in THF (3.0 M, 0.43 mL, 1.3 mmol) was added slowly at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h and was then allowed to warm to room temperature. The reaction mixture was diluted with EtOAc (10 mL), and 1 M HCl was slowly added to adjust the pH to 7. The aqueous layer was extracted twice with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound (94 mg, 92%). LCMS calc. for C36H43N6O6 (M+H)+: m/z=655.2. Found: 655.1.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>C1COCC1>[C:1]1([C:7]2[S:8][C:9]([CH:12]([C:18]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=3)[OH:13])=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cnc(-c2ccccc2)s1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cnc(-c3ccccc3)s2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of 2-phenylthiazole-5-carbaldehyde 38e (0.567 g, 3 mmol.) in 15 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 6.5 mL, 3.25 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 40e (72.9%). 1H NMR (CDCl3) δ 7.90 (m, 2H), 7.64 (s, 1H), 7.41 (m, 3H), 6.69 (s, br, 2H), 6.04 (s, 1H), 3.86 (s, 6H), 3.85 (s, 3H), 1.57 (d, 1H, J=5.5 Hz); MS (ESI) m/z 358.1 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]1[C@@H:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][C:40]([C:42]4[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=4)=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48]1([N:58]=[C:59]=[O:60])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:59](=[O:60])[NH:58][C:48]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]=[CH:50][CH:49]=2)[CH2:13][C@H:12]1[C@@H:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][C:40]([C:42]4[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=4)=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from (S,S)-2-[1-(1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)piperazine-2-yl)-ethylamino]-4-[5-(pyridine-4-yl)benzimidazol-1-yl]pyrimidine (72 m,) and naphthyl isocyanate (23 mg) according to the procedure described in EXAMPLE 14, Step F. Mass spectrum (ESI) 704.2 (M+1).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[C:12]([CH:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2]1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCOc2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)C1COc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A solution of 4-chromanone (11.2 g) and diethyl oxalate (13.3 g) in anhydrous dioxane (75 ml) is added under stirring at room temperature to a suspension of 50% sodium hydride (4 g) in anhydrous dioxane (150 ml). The mixture is allowed to react under stirring at 80° C. for 3.5 hours. After cooling, the reaction mixture is diluted with ice water and acidified to pH 4 with 40% citric acid aqueous solution. The oily precipitate is extracted with ethyl acetate, then the organic solution is washed with 40% citric acid and water until neutral. After evaporation of the solvent in vacuo the residue is purified over a SiO2 column using hexane/ethyl acetate 80:20 as eluent. Crystallization from isopropyl alcohol gives 3-ethoxalylchroman-4-one, m.p. 73°-75° C. (7.7 g), which is reacted with phenylhydrazine (3.68 g) in acetic acid (80 ml) at a temperature varying between 25° C. and about 40° C. for 30 minutes. The reaction mixture is diluted with ice water and then neutralized with 30% ammonium hydroxide. The precipitate is filtered and washed with water. Crystallization from isopropyl alcohol gives 1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazole-3-carboxylic acid, ethyl ester, m.p. 154°-156° C. (7.4 g), which is reacted with acetonitrile (74 ml) in dioxane (45 ml) in the presence of 50% sodium hydride (2.2 g) under stirring at 60° C. for 30 minutes. After cooling the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered and washed with water and purified over a SiO2 column, using chloroform as eluent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH:42]=[C:41](OS(C(F)(F)F)(=O)=O)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH:40]=[C:41]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:30])=[C:9]([N+:27]([O-:29])=[O:28])[CH:10]=2)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Product: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Yield: 51.8 %

Procedure:
Prepared from (2-nitro-4-tributylstannanyl-phenyl)-carbamic acid tert.-butyl ester (Example D2) (3.18 g, 6.06 mmol) and 4-trifluoromethylsulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert.-butyl ester (1.99 g, 6.0 mmol) [prepared from Boc-4-piperidone by treatment with LDA in THF at −78° C. followed by reaction with N-phenyl-bis(trifluoromethanesulfonimide) according to Wustrow et al. Synthesis 1991, 1993] according to the general procedure E. Obtained as an orange solid (1.304 g, 52%).