Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH3:2].[N:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[N:6]([C:12]1[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[N:16]([CH3:29])[C:15]3=[O:30])[CH2:5][CH2:4]2>C1COCC1>[I-:1].[Cl:28][C:24]1[CH:23]=[C:22]([C:17]2[N:16]([CH3:29])[C:15](=[O:30])[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:6]4[CH:7]5[CH2:8][CH2:9][N+:3]([CH3:2])([CH2:11][CH2:10]5)[CH2:4][CH2:5]4)[CH:13]=3)[N:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CI
Reactant: Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CC[N+]4(C)CCC3CC4)cc2c1=O
Product: [I-]
Reaction time: 48 h
Yield: 63.1 %

Procedure:
To a solution of iodomethane (0.18 g, 1.3 mmol) in THF (12 mL) was added 6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-3-methylquinazolin-4(3H)-one (Example 2AL) (0.5 g, 1.3 mmol) and reaction stirred for two days. The resultant precipitate was collected via filtration, triturated with minimum amount of methanol and dried to afford 4-(2-(3-chlorophenyl)-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-1-methyl-4-aza-1-azoniabicyclo[3.2.2]nonane iodide (0.44 g, 0.82 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:16][NH:17][CH3:18])=[CH:4][CH:3]=1.CN1C2C(=CC=CC=2)C=C1CNC.[OH:34][CH2:35][C@@H:36]1[C:42](=[O:43])[N:41]([CH3:44])[CH2:40][C:39]2[CH:45]=[C:46]([C:49](O)=[O:50])[CH:47]=[CH:48][C:38]=2[NH:37]1.C(C[C@@H]1C(=O)N(C)CC2C=C(C(O)=O)C=CC=2N1)(OC)=O>>[CH3:18][N:17]([CH2:16][C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:20][CH:19]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:49]([C:46]1[CH:47]=[CH:48][C:38]2[NH:37][C@H:36]([CH2:35][OH:34])[C:42](=[O:43])[N:41]([CH3:44])[CH2:40][C:39]=2[CH:45]=1)=[O:50]
Reactant: CNCc1cc2ccccc2n1Cc1ccc(O)cc1
Reactant: CN1Cc2cc(C(=O)O)ccc2N[C@H](CO)C1=O
Agent: CNCc1cc2ccccc2n1C
Agent: COC(=O)C[C@H]1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Product: CN(Cc1cc2ccccc2n1Cc1ccc(O)cc1)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](CO)N2
Yield: 92.2 %

Procedure:
According to the procedure of Example 1(a), except substituting 1-(4-hydroxybenzyl)-2-(methylaminomethyl)indole (0.40 g, 1.50 mmole) for the 1-methyl-2-(methylaminomethyl)indole, and substituting (2R)-2-(hydroxymethyl)-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid (0.34 g, 1.37 mmole) for the (2R)-2-[(carbomethoxy)methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid, the title compound (0.63 g, 92%) was prepared as an off-white solid: MS (ES) m/e 499 (M+H)+.
Reaction SMILES: [OH-:1].[K+].C([OH:5])C.[C:6]([CH:8]([C@H:14]1[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]1)[C:9]([O:11]CC)=[O:10])#N>O>[CH:20](/[C@H:17]1[CH2:18][CH2:19][C@H:14]([CH:8]([C:9]([OH:11])=[O:10])[C:6]([OH:5])=[O:1])[CH2:15][CH2:16]1)=[CH:21]\[CH2:22][CH2:23][CH3:24]
Reactant: CCC/C=C/[C@H]1CC[C@H](C(C#N)C(=O)OCC)CC1
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Solvent: O
Product: CCC/C=C/[C@H]1CC[C@H](C(C(=O)O)C(=O)O)CC1
Reaction time: 72 h

Procedure:
A mixture of 36.9 g of potassium hydroxide, 250 ml of water, 250 ml of ethanol and 37.2 g of ethyl cyano-[trans-4-(1E-pentenyl)cyclohexyl]acetate is heated to boiling for 3 days while stirring. After cooling the reaction mixture is diluted with 500 ml of water and washed with two 200 ml portions of diethyl ether. 220 ml of 10 percent (v/v) sulphuric acid are added dropwise to the aqueous phase. The precipitated product is extracted with three 200 ml portions of diethyl ether. The extract is washed with two 50 ml portions of water, dried over sodium sulphate, filtered and concentrated. Repeated recrystallization from benzene/hexane (vol. 1:1) gives pure [trans-4-(1E-pentenyl)cyclohexyl]malonic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=2)([OH:27])[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2cccc(Br)c2)CCN(Cc2ccccc2)CC1
Temperature: -75 °C
Reaction time: 2.5 h
Yield: 81.7 %

Procedure:
A solution of 23.6 g (100 mmol) of 1,3-dibromobenzene in 250 ml of absolute ether was cooled to -75° C. A solution of 62.5 ml (100 mmol) of n-butyllithium (1.6 M in hexane) was added dropwise within 45 minutes. The resulting suspension was stirred at -75° C. for 2.5 hours. Subsequently, a solution of 19.0 g (100 mmol) of 1-benzyl-4-piperidone in 100 ml of absolute ether was added dropwise within 30 minutes at -70° C. to -75° C. and thereafter the mixture was stirred for 2 hours. Subsequently, the mixture was partitioned between ether and saturated ammonium chloride solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of methylene chloride and hexane as the eluent. There were obtained 28.3 g (82% of theory) of 1-benzyl-4-(3-bromophenyl)-piperidin-4-ol as a yellow oil; MS: 345, 347 (M)+.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:6][C:7](C)([O-])C.[K+].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C1(C2CCCCCC2)CCCCCC1>C(O)(C)(C)C>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH:1]2[CH2:2][CH2:3][CH2:7][CH2:6][CH:5]2[OH:4])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S)cc1
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: C1CCCC(C2CCCCCC2)CC1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(SC2CCCCC2O)cc1
Temperature: 25 °C

Procedure:
A 100 ml flask was flame dried, purged with dry nitrogen and fitted with a magnetic stirrer, heating mantle and condenser. Dry THF (25 ml), t-butanol (25 ml), potassium t-butoxide (0.700 g, 2.5 equiv.) and 4-methylthiophenol (1.0515 g, 3.0 equiv.) were added and the mixture was allowed to stir until all of the added solid had dissolved. 1,(R,S),2,(S,R),4(R,S),4(R,S),5(R,S)-4,5-bis((dipropylcarbamoyl-methoxy)-4-oxa-[4.1.0]-bicycloheptane (1.030 g, 2.50 mmol) was added and the mixture was warmed and allowed to reflux for 72 hours. The reaction vessel was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in diethyl ether and extracted 4 times with saturated sodium carbonate and once with brine. The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo. Pure product F was obtained by column chromatography of the residue with 100% ethyl acetate yielding pure 1,(R,S),2(R,S),4(R,S),5(R,S)-4,5-bis(dipropylcarbamoyl)-methoxy)- 2-(4-methyl thiophenoxy)-cyclohexanol, subreaction product 15, (0.423 g, 31%) as a viscous oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22](N)=[N:23][C:24]=2[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][CH2:34][CH3:35])(=[O:3])[CH3:2].C[Si]([Cl:41])(C)C.N#N>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:41])=[N:23][C:24]=2[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][CH2:34][CH3:35])(=[O:3])[CH3:2]
Reactant: CCCc1nccn1-c1nc(N)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: C[Si](C)(C)Cl
Agent: N#N
Solvent: ClCCl
Product: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-(2-propylimidazol-1-yl)purine (2.37 g, 4.72 mmol) in CH2Cl2 (120 mL) was added TMSCl (5.3 mL, 4.54 g, 42.5 mmol) dropwise under N2, and then BTEANO2 (7.1 g, 29.8 mmol) in CH2Cl2 (40 mL). Evolution of gas was observed, and when this subsided, additional TMSCl (5.3 mL) was added. The mixture was then stirred at ambient temperature for 3 h. The solution was diluted with CH2Cl2 and washed (NaHCO3/H2O, 2×200 mL+100 mL), and the aqueous layer was extracted with CH2Cl2. The combined organic phase was dried (Na2SO4), and volatiles were evaporated in vacuo. The residue was chromatographed (MeOH/CH2Cl2, 1:99-1:90) to give crude product (1.40 g, 57%, contaminated with Ph3PO), which was recrystallized (i-PrOH) to give 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(2-propylimidazol-1-yl)purine: mp 126-127.5° C.; UV (MeOH) max 217, 287 nm (∈ 25 300, 15 000), min 238, 261 nm (∈ 4200, 6200); 1H NMR (500 MHz, CDCl3) δ 8.57 (d, J=1.8 Hz, 1H), 8.25 (s, 1H), 7.11 (d, J=1.5 Hz, 1H), 6.27 (d, J=5.5 Hz, 1H), 5.83 (t, J=5.5 Hz, 1H), 5.60-5.62 (m, 1H), 4.49-4.51 (m, 1H), 4.43-4.44 (m, 2H), 3.29 (t, J=7.7 Hz, 2H), 2.19 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 1.86 (sext, J=7.6 Hz, 2H), 1.07 (t, J=7.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5, 169.9, 169.7, 154.6, 153.8, 151.6, 148.4, 142.5, 129.3, 123.0, 120.5, 86.6, 81.0, 73.5, 70.8, 63.2, 33.2, 21.6, 21.1, 20.8, 20.7, 14.2; HRMS m/z 520.1476 (M+[C22H25ClN6O7]=520.1473). Anal. Calcd For C22H25ClN6O7: C, 50.73; H, 4.84; N, 16.13. Found: C, 50.58; H, 4.87; N, 16.15.
Reaction SMILES: CC([O-])(C)C.[K+:6].[CH3:7][C:8]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])=[O:9].[C:20]([O:25][CH2:26][CH3:27])(=[O:24])[C:21]([O-])=[O:22]>C(O)C>[K+:6].[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[C:8]([O-:9])=[CH:7][C:21](=[O:22])[C:20]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: COc1cccc(OC)c1C(C)=O
Reactant: CCOC(=O)C(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(=O)C=C([O-])c1c(OC)cccc1OC
Reaction time: 1 h

Procedure:
A solution of 13.4 g of 95% potassium tert-butylate in 72 ml of ethanol is added over 6 minutes to a solution, stirred and heated to 50° C., of 18 g of 2,6-dimethoxyacetophenone in 54 ml of ethanol. The mixture is heated to reflux, 16.3 ml of ethyl oxalate are added over 9 minutes and refluxing is continued for 1 hour. 40 ml of ethanol are then distilled off and the mixture is allowed to cool with stirring for two and a half hours. The mixture is filtered, and the precipitate is washed with 40 ml of ethanol and dried under vacuum at 60° C. for 17 hours to obtain 31 g of expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[C:29]([O:31]C)=[O:30])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1COCC1.O[Li].O>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[C:29]([OH:31])=[O:30])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(CCS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)ccc2ccccc12
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(CCS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)ccc2ccccc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 17.2 %

Procedure:
To a solution of Example 8A (0.12 g, 0.26 mmoL) in MeOH (3 mL), H2O (3 mL), and THF (15 mL) was added LiOH.H2O (0.17 g, 3.84 mmoL). The mixture was stirred at 80° C. for 16 hours, poured into H2O, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated. Purification on silica gel with 2% MeOH/CH2Cl2 provided 0.02 g (20%) of the desired compound.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[N:14]([CH2:27][C:28](O)=[O:29])[C:13]3=[O:31])[CH2:3][CH2:2]2.Cl.[CH3:33][NH:34][CH3:35].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>ClCCl>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[N:14]([CH2:27][C:28]([N:34]([CH3:35])[CH3:33])=[O:29])[C:13]3=[O:31])[CH2:3][CH2:2]2
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Reactant: CNC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Reaction time: 2 h
Yield: 10.9 %

Procedure:
2-(6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)acetic acid (Intermediate 11A) (49 mg, 0.11 mmol) and dimethylamine hydrochloride (18.2 mg, 0.22 mmol) were weighed into a round bottomed flask and dichloromethane (1 mL) added to form a suspension. Triethylamine (33.8 mg, 0.33 mmol) was added and the suspension stirred for 5 minutes before dropwise addition of 1-propanephosphonic acid cyclic anhydride as a 50% wt solution in ethyl acetate (107 mg, 0.17 mmol) and the resulting reaction mixture stirred for 2 hours. Reaction mixture was washed with sodium bicarbonate solution and the organics were separated using a hydrophobic frit. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. To afford the title compound 2-(6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)-N,N-dimethylacetamide (5.4 mg, 0.012 mmol).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][CH2:13][N:6]2[C:5](=[O:21])[CH2:4][CH2:3]1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:33](Cl)(=[O:42])[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[Cl-].[Na+].O.O>[C:17]([O:16][C:14]([C@H:10]1[N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:33]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:42])[CH2:3][CH2:4][C:5](=[O:21])[N:6]2[CH2:13][CH2:12][CH2:11]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCc3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
In a 20 mL pear-shaped flask, (1S,9S)-tert-butyl 9-amino-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (0.9 g, 3.03 mmol) was combined with DMF (8 ml) to give a colorless solution and cooled to 0° C. Sodium carbonate (385 mg, 3.63 mmol) and benzyl carbonochloridate (516 mg, 432 μl, 3.03 mmol) were added and stirred at room temperature for 6 hr. It was diluted with brine and H2O, extracted with EtOAc (2×60 ml). The combined organic layer was washed with brine and H2O, dried with MgSO4, filtered and concentrated in vacuo to afford (1S,9S)-tert-butyl-9-(benzyloxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate as an oil (1.3 g, 99.5%). ESI-LRMS m/e calcd for C18H21N3O6 [M+] 431. found 432 [M+H+]. The crude was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[N:12][N:13]2[CH:17]=[N:16][NH:15][C:14]2=[O:18])[CH:6]=1>N1C=CC=CC=1>[C:1]([N:15]1[C:14](=[O:18])[N:13]([N:12]=[CH:11][C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)[CH:17]=[N:16]1)(=[O:3])[CH3:2]
Reactant: O=c1[nH]ncn1N=Cc1cccnc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)n1ncn(N=Cc2cccnc2)c1=O
Reaction time: 14 h

Procedure:
2.4 g of acetyl chloride are added to a suspension of 3.8 g of 4-(pyridin-3-ylmethyleneamino)-1,2,4-triazol-3-one in 50 ml of pyridine. The resulting solution is stirred for 14 hours at 20° and then concentrated by evaporation. Water is added to the residue and extraction is carried out with chloroform. The organic phase is concentrated by evaporation and the residue is stirred with ether. The crystals are filtered off with suction and then dried under a high vacuum. 4 g of the title compound having a melting point of 164°-166° are thus obtained.
Reaction SMILES: [O-2].[Al+3].[O-2].[O-2].[Al+3].C(OCC)C.[CH2:11]([N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][O:22]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:26]([O:30][C:31]1[CH:38]=[CH:37][C:34]([NH:35][CH3:36])=[CH:33][CH:32]=1)[CH2:27][CH2:28][CH3:29]>CO>[CH2:11]([N:18]1[CH2:25][CH2:24][C:21]([CH2:23][N:35]([C:34]2[CH:37]=[CH:38][C:31]([O:30][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)[CH3:36])([OH:22])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Reactant: CCCCOc1ccc(NC)cc1
Agent: [Al+3]
Agent: [O-2]
Solvent: CO
Solvent: CCOCC
Product: CCCCOc1ccc(N(C)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
Activated neutral aluminum oxide 90 (activity I, made by Merck Co.) (5 g) was added to a diethyl ether solution (10 mL) of 1-benzylpiperidin-4-spiro-2′-oxirane (0.50 g) and 4-butoxy-N-methylaniline (0.53 g) and stirred at room temperature overnight. Methanol (20 mL) was added to the reaction solution and stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (elution solvent; ethyl acetate) to obtain the titled compound (0.71 g).
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@@H:4]1[NH2:5].C(N([CH2:19][CH3:20])CC)C>CN(C=O)C>[C:3]([NH:5][C@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])(=[O:2])[CH2:4][CH2:6][C:19]#[CH:20]
Reactant: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Product: C#CCCC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of D-mannosamine hydrochloride (863 mg, 4.0 mmol), N-succinimidyl 4-pentynoate 9 (Salmain M, Vessieres A, Butler I S, Jaouen G (1991) Bioconjug Chem 2:13-15.) (781 mg, 4.0 mmol), triethylamine (1.67 ml, 12.0 mmol) in DMF (31 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (CHCl3/MeOH 8:1) to give N-4-Pentynoylmannosamine, 10 (898 mg, 87%); 1H-NMR (500 MHz, D2O)□ 2.37 (t, 2.63H, J=2.5 Hz), 2.48-2.63 (m, 10.5H), 3.38-3.42 (m, 1H), 3.52 (t, 1H, J=10 Hz), 3.63 (t, 1.63H, J=10 Hz), 3.69-3.91 (m, 7.89H), 4.05 (dd, 1.63H, J=4.5 and 10 Hz), 4.35 (dd, 1.63H, J=1.5 and 4.5 Hz), 4.47 (dd, 1H, J=1.5 and 4.5 Hz), 5.03 (d, 1H, J=1.5 Hz), 5.13 (d, 1.63H, J=1.5 Hz); 13C-NMR (125 MHz, D2O)□ 14.78, 14.91, 34.62, 34.79, 53.67, 54.50, 60.91, 60.93, 67.01, 67.28, 69.25, 70.56, 70.71, 72.47, 72.50, 76.80, 84.04, 84.45, 93.36, 93.67, 175.68, 176.41; ESI-TOF-HRMS m/e calculated for (M+H)+ C11H17NO6 260.1129; found 260.1120.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:54]#[N:55].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][C:54]#[N:55])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCC#N)CCC3)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 71.4 %

Procedure:
To a well stirred solution of 0.200 g (0.266 mmol) of crude (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 10(a)] in 1.8 ml of absolute N,N-dimethylformamide was added 0.026 (0.399 mmol, 1.5 equiv.) of potassium cyanide. After stirring for 45 min at 50° C., the reaction was allowed to warm to room temperature, poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent to yield 0.130 g (0.190 mmol, 71.4% of theory) of (3R,4R)-3-[1-(3-cyano-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 684 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CO>[NH:10]([C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1)[NH2:11]
Reactant: Clc1cc(Cl)ncn1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12 g of 4,6-dichloropyrimidine were dissolved in 100 ml of methanol, mixed dropwise with 12 ml of hydrazine hydrate (80%) and stirred for 1 hour at room temperature. After sucking off the precipitate and washing with H2O, 10 g of 4-hydrazino-6-chloropyrimidine were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1cccc(F)c1
Yield: 73.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.051 g (74%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide as a white solid.