Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:41]4[CH2:42][CH2:43][N:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][CH2:40]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=592.00 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:14]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: N#Cc1ccc2ccccc2c1

Procedure:
2-Cyanonaphthalenes are prepared by refluxing 2-formylnaphthalene with hydroxylamine hydrochloride and sodium acetate in ethanol to furnish the corresponding which is refluxed with acetic anhydride in the presence of an acid catalyst to furnish 2-cyanonaphthalene.
Reaction SMILES: C(NC(N[CH:8]([CH3:10])[CH3:9])=O)(C)C.[C:11](O)(=O)[CH2:12][C:13](O)=O.[CH:18]([N:21]1[C:26](=[O:27])[CH2:25][C:24](=[O:28])[N:23]([CH:29]([CH3:31])[CH3:30])[C:22]1=[O:32])([CH3:20])[CH3:19]>C(OC(=O)C)(=O)C>[CH:29]([N:23]1[C:24](=[O:28])[CH2:25][C:26](=[O:27])[N:21]([CH:18]([CH3:20])[CH3:19])[C:22]1=[O:32])([CH3:31])[CH3:30].[CH2:9]1[CH2:8][CH2:10][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)NC(=O)NC(C)C
Reactant: O=C(O)CC(=O)O
Agent: CC(C)N1C(=O)CC(=O)N(C(C)C)C1=O
Solvent: CC(=O)OC(C)=O
Product: C1CCCCC1
Temperature: 90 °C
Yield: 70 %

Procedure:
1,3-Diisopropyl-2,4,6-(1H,3H,5H)-pyrimidinetrione was prepared by the dropwise addition of acetic anhydride (40 ml) over three hours to a solution of 1,3-diisopropylurea (7.5 g, 0.05 mole) and malonic acid (5.2 g, 0.05 mole) at 65° C. After the addition was completed, the temperature was raised to 90° C. and maintained for three hours. The solvent was evaporated under reduced pressure and the residue solidified upon cooling. 1,3-Diisopropyl-2,4,6-(1H,3H,5H)-pyrimidinetrione recrystallized from cyclohexane as colorless needles (7.3 g, 70% yield), m.p. 79°-82°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[N:6]3[CH2:13][CH2:14][O:15][C:5]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:24]I.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:24])[C:7](=[O:12])[N:6]3[CH2:13][CH2:14][O:15][C:5]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N2CCOC2(c2ccccc2)c2cc(Cl)ccc21
Yield: 76.4 %

Procedure:
To a solution of 1.5 g of 9-chloro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one in 20 ml of dimethylformamide was added 0.21 g of 62.5% sodium hydride. The resultant mixture was stirred with heating at 50° - 55°C for 1 hour, and 1.42 g of methyl iodide was added thereto at room temperature. Then, the mixture was heated at 55° - 60°C for 3 hours. After cooling, the reaction mixture was poured into 100 ml of water and acidified with hydrochloric acid. The resulting mixture was extracted with 50 ml of chloroform and the chloroform layer was washed successively with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 1.2 g of 9-chloro-2,3,6,10b-tetrahydro-6-methyl-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one, having a melting point of 124° - 125°C. Recrystallization from ethanol gave colorless prisms, having a melting point of 136° - 137°C.
Reaction SMILES: [ClH:1].Cl.CN1[CH2:9][CH2:8][N:7]([C:10](=[O:34])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[C:22]([NH:27][C:28]4[S:29][CH:30]=[C:31]([CH3:33])[N:32]=4)=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=2)CC1.C(N(CC)CC)C.[NH:42]1[C:46](CCN)=[CH:45][N:44]=[CH:43]1.Cl>>[ClH:1].[ClH:1].[NH:42]1[C:46]([CH2:9][CH2:8][NH:7][C:10](=[O:34])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[C:22]([NH:27][C:28]4[S:29][CH:30]=[C:31]([CH3:33])[N:32]=4)=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=2)=[CH:45][N:44]=[CH:43]1
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)N3CCN(C)CC3)c2)n1
Reactant: NCCc1cnc[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)NCCc3cnc[nH]3)c2)n1
Yield: 86.9 %

Procedure:
2-(3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate (prepared according to Example 27; 70 mg, 0.14 mmol), triethylamine (0.10 mL, 0.72 mmol) ethyl chloroformate (0.035 mL, 0.36 mmol) and 2-(1H-imidazol-5-yl)ethanamine (80 mg, 0.72 mmol) were reacted according to the method of Example 29 to provide N-(2-(1H-imidazol-5-yl)ethyl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetamide dihydrochloride (32.7 mg, 40.0% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.02 (d, 1H), 8.39 (t, 1H), 8.00 (dd, 1H), 7.66 (d, 1H), 7.40 (s, 1H), 7.30 (m, 2H), 7.19 (d, 1H), 7.16 (dd, 1H), 6.93 (s, 1H), 6.88 (dd, 1H), 5.33 (s, 2H), 4.52 (s, 2H), 3.45 (q, 2H), 2.86 (t, 2H), 2.35 (s, 3H). Mass spectrum (apci) m/z=465.2 (M+H-2HCl).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Na].[CH2:17]([O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH3:18]>C(O)C>[CH2:17]([O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:14][CH:13]=1)[CH3:18]
Reactant: Oc1ccc(C2=CCCCCCC2)cc1
Reactant: CCOC(=O)CCCCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCCCOc1ccc(C2=CCCCCCC2)cc1

Procedure:
12 g of p-(1-cyclooctenyl)-phenol are first added to a solution of 1.7 g of sodium in 60 ml of absolute ethanol whilst stirring in an anhydrous atmosphere, and after 30 minutes 18.8 g of 5-bromopentanoic acid ethyl ester are added dropwise. After completion of the addition, the mixture is stirred for 15 hours at 70° C and is evaporated to dryness in vacuo. The evaporation residue is distributed between 3 times 150 ml of ether and twice 100 ml of water. The organic phases are combined, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on silica gel with chloroform as the eluant gives 5-[p-(1-cyclooctenyl)-phenoxy]-pentanoic acid ethyl ester of boiling point 165° -170° C at 0.03 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[Cl:21][CH2:22][CH2:23][CH2:24]I>CN(C=O)C>[Cl:21][CH2:22][CH2:23][CH2:24][S:11]([C:8]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: ClCCCI
Reactant: O=C(O)c1cc(S(=O)O)ccc1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(S(=O)(=O)CCCCl)ccc1O
Temperature: 40 °C

Procedure:
To 16.7 mmol 2-hydroxy-5-sulfino-benzoic acid and 41.7 mmol triethylamine in 40 ml DMF was added 18.3 mmol 1-chloro-3-iodopropane, and the mixture heated at 40° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/methanol/acetic acid gradient) to afford the title compound. MS (m/e): 279.1 ([{37Cl}M−H]−, 33%), 277.0 ([{35Cl}M−H]−, 100%)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@@H:50]1COC(=O)[N:51]1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([C:50]#[N:51])=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 69 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 4-(2-piperazin-1-ylpyrimidin-5-yl)benzonitrile, trifluoroacetic acid salt (0.64 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.75 g), to yield the title compound as a white solid (0.70 g, 69%).
Reaction SMILES: [C:1]1([NH:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[I:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[NH:18]C1C=CC=CC=1>ClC1C=CC=CC=1>[C:1]1([NH:11][C:12]([NH:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[I:15])=[NH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Ic1ccccc1Nc1ccccc1
Reactant: N#CNc1cccc2ccccc12
Agent: Cl
Solvent: Clc1ccccc1
Product: N=C(Nc1ccccc1I)Nc1cccc2ccccc12
Yield: 33.5 %

Procedure:
A solution of 1-naphthylcyanamide (182 mg, 1.08 mmol) and o-iodophenylaniline hydrochloride (279 mg, 1.09 mmol) in chlorobenzene (5 ml) was heated at 135°-140° C. for 14 hours. It was concentrated and the residue was partitioned between dichloromethane and 10% NaOH solution. The organic layer was dried over Na2SO4 and concentrated. The resulting light green residue was recrystallized from 95% EtOH-H2O to give N-(1-naphthyl)-N'-(o-iodophenyl)-guanidine (140 mg, 33%) as off-white needles. mp 154°-155° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:24]1[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)=[N+]=[N-]>C1COCC1.O>[NH2:20][CH:23]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:24]1[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(COc2ccc(C(N=[N+]=[N-])c3ccccc3)cc2)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2ccc(C(N)c3ccccc3)cc2)o1
Temperature: 60 °C
Yield: 110.1 %

Procedure:
To a suspension of triphenylphosphine polymer supported (633 mg, 0.89 mmol) in THF (3 mL) was added a solution of methyl 5-((4-(azido(phenyl)methyl)phenoxy)-methyl)furan-2-carboxylate (293 mg, 0.81 mmol) in THF (6.1 mL) and H2O (0.12 mL). The reaction was stirred very slowly and heated at 60° C. for 18 h. Triphenylphosphine polymer supported (300 mg) and water (62 μL) were added and the heating was maintained at 60° C. for 5 h. The reaction was then allowed to cool to room temperature. The resin was removed by filtration, washed twice with THF and DCM. The combined organic phases were dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound (301 mg) which was taken on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[N:4]=[C:5]2[C:14]3[C:13]([O:15]C)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][C:9]=3[N:8]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:7](=[O:28])[C:6]=12.[Br-].[Mg+2].[Br-].N1C=CC=CC=1>O>[NH2:1][C:2]1[N:3]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[N:4]=[C:5]2[C:14]3[C:13]([OH:15])=[CH:12][C:11]([O:17][CH3:18])=[CH:10][C:9]=3[N:8]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:7](=[O:28])[C:6]=12
Reactant: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccc(Oc5ccccc5)cc4)nc3c3c(OC)cc(OC)cc32)cc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccc(Oc5ccccc5)cc4)nc3c3c(O)cc(OC)cc32)cc1
Yield: 73.9 %

Procedure:
A mixture of 3-amino-7,9-dimethoxy-5-(4-methoxybenzyl)-2-(4-phenoxyphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (500 mg), magnesium bromide (168 mg) and pyridine (10 ml) was heated under reflux for 2 days, added water thereto after cooling. The precipitated solid was collected by filtration, washed with water, and purified with silica gel column chromatography to obtain the target compound (360 mg).
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=2)[C:5]([CH3:20])=[CH:4][C:3]=1[O:21]C.[C:23](OCC)(=O)C>CCCCCC>[CH3:20][C:5]1[CH:4]=[C:3]([OH:21])[CH:2]=[C:7]([CH3:23])[C:6]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1
Reactant: COc1cc(C)c(Sc2ccc(OC)c(C(C)C)c2)cc1C
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(O)cc(C)c1Sc1ccc(O)c(C(C)C)c1

Procedure:
3,5-dimethyl-4-(4′-hydroxy-3′-iso-propyl-phenylsulfanyl)phenol was prepared from 2,5-dimethyl-4-(3′-iso-propyl-4′-methoxy-phenylsulfanyl)anisole according to the procedure described in example 8, step d. 1H NMR (300 MHz, DMSO-d6): δ 9.58 (bs, 1H), 9.21 (bs, 1H), 6.77 (m, 1H), 6.63 (m, 3H), 6.46 (dd, 1H, J=2.7 Hz and J=8.1 Hz), 3.09 (m, 1H), 2.28 (s, 6H), 1.06 (d, 6H, J=7.2 Hz); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate 25% in hexane; Rf=0.12
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:2]2.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.Cl>CO.CC(C)=O>[ClH:17].[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@H:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:2]2
Reactant: O=C(NC1CN2CCC1CC2)c1cccc(Cl)c1
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc(Cl)c1

Procedure:
N-(3-Quinuclidinyl)-3-chlorobenzamide (52.5 g) dissolved in methanol is added to a solution of D-tartaric acid (29.7 g) in methanol. The precipitate obtained is collected by filtration and treated twice with methanol under reflux. The salt thus purified (20 g) is decomposed with aqueous sodium hydroxide solution and the product extracted with chloroform. After the organic phase has been dried and evaporated, the base obtained is treated in acetone with ethanolic hydrogen chloride solution. The hydrochloride which precipitates is collected by filtration and recrystallized in ethanol. 9.4 g of optically pure (S)-(-)-N-(3-quinuclidinyl)-3-chlorobenzamide hydrochloride are obtained.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([NH2:4])=[O:3].CN1CCOCC1.ClC(OCC)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][OH:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[Cl-].[NH4+]>COCCOC>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][N:32]([OH:33])[C:1]([C:2]([NH2:4])=[O:3])=[O:6])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: NC(=O)C(=O)O
Reactant: COc1ccc(CCNO)cc1OC
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: COc1ccc(CCN(O)C(=O)C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-hydroxamide. To a suspension of oxamic acid (195 mg, 2.21 mmol) in 1,2-dimethoxyethane (7 mL) under an argon atmosphere was added dropwise N-methylmorpholine (0.27 mL, 2.42 mmol), followed by ethyl chloroformate (0.23 mL, 2.42 mmol). After stirring for 1 h at room temperature, a solution of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-hydroxyamine (417 mg, 2.10 mmol) in 1,2-dimethoxyethane (5 mL) was added, and the resulting mixture was stirred for 4 h. Saturated aqueous ammonium chloride was added, and the mixture was extracted with methylene chloride (2×). The combined organic extracts were washed successively with 10% hydrochloric acid and water and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 5% methanol/methylene chloride, and recrystallized from methanol/methylene chloride to provide the oxamide (98 mg, 17%): m.p. 143°-144° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=1[CH:29]=[O:30].C(Cl)(Cl)Cl>C(#N)C.O>[CH:29]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:21]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([I:1])=[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[N:9]1)[C:25]#[N:26])=[O:30]
Reactant: CC(C)c1n[nH]c2nccc(I)c12
Reactant: N#Cc1ccc(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CC(C)c1nn(-c2ccc(C#N)cc2C=O)c2nccc(I)c12
Yield: 69 %

Procedure:
Compound (100a) (2.0 g), cesium carbonate (3.41 g), and 4-fluoro-3-formylbenzonitrile (1.25 g) were suspended in acetonitrile (23 mL), followed by reflux for 3 hr. The reaction solution was distributed between chloroform and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain compound (125a) (2.00 g, 67%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:9]=1[O:19][CH2:20][CH2:21][CH3:22])[C:3](=[O:6])[CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.Br[C:33]1[CH:46]=[N:45][C:36]2[NH:37][C:38](=[O:44])[C:39]([CH3:43])([CH3:42])[NH:40][CH2:41][C:35]=2[CH:34]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:42][C:39]1([CH3:43])[C:38](=[O:44])[NH:37][C:36]2[N:45]=[CH:46][C:33](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:16])[F:17])[C:9]=3[O:19][CH2:20][CH2:21][CH3:22])=[O:6])=[CH:34][C:35]=2[CH2:41][NH:40]1
Reactant: C=CC(=O)N(C)Cc1cccc(OC(F)(F)F)c1OCCC
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)cccc1OC(F)(F)F
Yield: 44.5 %

Procedure:
A solution of N-methyl-N-(2-propoxy-3-trifluoromethoxybenzyl)acrylamide (0.468 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated sequentially with diisopropylethylamine (0.40 mL, 2.3 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.111 mmol) and P(o-tol)3 (0.067 g, 0.222 mmol) were added and the solution was deoxygenated with Ar for 20 minutes. The mixture was heated to reflux for 18 h, then allowed to cool. The mixture was diluted with EtOAc (30 mL) and then washed with H2O (3×50 mL) and brine (2×100 mL), dried (Na2SO4) and concentrated to a yellow-orange solid. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.25 g, 31%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.78 (m, 1H), 8.41-8.36 (m, 1H), 8.01-7.92 (m, 1H), 7.56-7.49 (m, 1H), 7.36-7.08 (m, 4H), 4.87-4.69 (m, 2H), 3.96-3.83 (m, 4H), 3.16-2.88 (m, 4H), 1.78-1.71 (m, 2H), 1.31-1.29 (m, 6H), 1.03-0.98 (m, 3H); MS (ESI) m/e 507 (M+H)+.
Reaction SMILES: C#C.[CH2:3]([Mg]Cl)[CH2:4]CC.[F:9][C:10]1[CH:19]=[CH:18][C:13]([O:14][CH2:15][CH:16]=[O:17])=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[OH:17][CH:16]([CH2:15][O:14][C:13]1[CH:18]=[CH:19][C:10]([F:9])=[CH:11][CH:12]=1)[C:3]#[CH:4]
Reactant: CCCC[Mg]Cl
Reactant: O=CCOc1ccc(F)cc1
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)COc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 48 %

Procedure:
Acetylene gas, dried by passing through a trap containing sulfuric acid, is bubbled at a moderate rate, through 5 ml of vigorously stirred tetrahydrofuran, for 15 minutes. To this acetylenic solution, is then added dropwise, with continued passage of acetylene, 3.5 ml of a 2.4 M solution of n-butylmagnesium chloride in tetrahydrofuran (8.4 mmoles) over 45 minutes. The mixture is stirred a further 15 minutes, and a solution of 580 mg (3.9 mmoles) of p-fluorophenoxy acetaldehyde (Example 156) in 3 ml of tetrahydrofuran is added dropwise over 15 minutes. This solution is stirred for 2 more hours, with passage of acetylene, poured into 50 ml of a saturated solution of ammonium chloride, extracted twice with 50 ml of ether, washed with 10 ml of ammonium chloride solution, dried with magnesium sulfate, filtered, and evaporated. The crude subject product is purified by sublimation at 75° C. (0.1 mm) for 5 hours to give 330 mg (48%) of white crystals, mp 46°-47° C.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH2:32][NH:33][OH:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[Cl-].[NH4+].ClCCl.CO>O1CCOCC1>[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2([CH2:32][N:33]([OH:34])[C:6]([NH2:5])=[O:7])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: ONCC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCC1
Reactant: C[Si](C)(C)N=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)N(O)CC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCC1
Temperature: 100 °C

Procedure:
0.94 g (8.13 mmol) of trimethylsilyl isocyanate is added dropwise under an argon atmosphere at room temperature to a solution of 2.7 g (7.45 mmol) of N-[4-(quinolin-2-yl-methoxy)phenyl-cyclohexyl]methyl-hydroxylamine in 25 ml of dioxane p.a. The reaction mixture is heated at 100° C. under an argon atmosphere for 2.5 h, cooled to room temperature and treated with saturated ammonium chloride solution. It is extracted several times with ether, and the organic phase is dried over sodium sulphate and concentrated in vacuo. The product is obtained after column chromatography on silica gel using dichloromethane/methanol (9:1).