Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:11][N:10]=[C:9]2[S:25][CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[C:29]([F:34])[C:28]=2[F:35])=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][N:10]=[C:9]2[S:25][CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[C:29]([F:34])[C:28]=2[F:35])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
A solution of 2-((1-(4-fluorophenyl)-2-((2,3,6-trifluoro benzyl)thio)-1H-imidazol-5-yl)methyl)isoindoline-1,3-dione (29) (390 mg, 0.78 mmol) and hydrazine hydrate (76 μL, 1.57 mmol) in ethanol (8 mL) was refluxed overnight. The white precipitate was removed by vacuum filtration and washed with ethanol and concentrated in vacuo to obtain (1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazol-5-yl)methanamine (30).
Reaction SMILES: C([NH:20][C@@H:21]1[C:48](=[O:49])[N:23]2[C:24]([C:32]([O:34][CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[S:33])=[C:25]([CH2:28][C:29](=[O:31])[NH2:30])[CH2:26][S:27][C@H:22]12)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.[C:51]1([CH3:61])[CH:56]=[CH:55][C:54]([S:57]([OH:60])(=[O:59])=[O:58])=[CH:53][CH:52]=1>C(OCC)(=O)C>[C:51]1([CH3:61])[CH:52]=[CH:53][C:54]([S:57]([OH:60])(=[O:58])=[O:59])=[CH:55][CH:56]=1.[CH:35]([O:34][C:32]([C:24]1[N:23]2[C:48](=[O:49])[C@@H:21]([NH2:20])[C@H:22]2[S:27][CH2:26][C:25]=1[CH2:28][C:29](=[O:31])[NH2:30])=[S:33])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NC(=O)CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of 0.56 g (0.8 mM) of benzhydryl 7β-tritylamino-3-carbamoylmethylthio-3-cephem-4-carboxylate obtained in Example 2(a) in 10 ml of ethyl acetate, 0.18 g (0.96 mM) of p-toluenesulfonic acid monohydrate was added under ice-cooling, and the mixture was stirred for 4 hours. After the reaction, the white crystals which formed were collected by filtration to give 0.392 g of 7β-amino-3-carbamoylmethylthio-3-cephem-4-carboxylic acid benzhydryl ester p-toluenesulfonate.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([CH2:29][NH:30][CH3:31])[CH:26]=[C:25]([CH2:32][OH:33])[CH:24]=2)[N:20]=[N:19][C:18]=1[O:34]C)=O)(C)(C)C.[I-].[K+].Cl[Si](C)(C)C>C(#N)C>[OH:33][CH2:32][C:25]1[CH:24]=[C:23]([C:21]2[CH:22]=[C:17]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:18](=[O:34])[NH:19][N:20]=2)[CH:28]=[C:27]([CH2:29][NH:30][CH3:31])[CH:26]=1
Reactant: CNCc1cc(CO)cc(-c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(OC)nn2)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CNCc1cc(CO)cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)c1
Temperature: 85 °C

Procedure:
18 mg of 2-[6-(3-hydroxymethyl-5-methylaminomethyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester is dissolved in 3 ml of acetonitrile and 19 mg of potassium iodide and 12 mg of chlorotrimethylsilane are added. The reaction is heated to 85° C. for 5 h. The reaction is quenched by the addition of a drop of water, the solvent is removed under reduced pressure and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 3.5 mg. LC-MS (ES+) 361 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:11]=[C:10]2[S:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:7]=1)C.[H-].C([Al+]CC(C)C)C(C)C.O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[C:15]1([C:14]2[C:9]3[C:10](=[N:11][C:6]([CH2:5][CH2:4][OH:3])=[CH:7][C:8]=3[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[S:12][CH:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-acetic acid ethyl ester (47 mg, 0.12 mmol) was dissolved in dry THF (10 ml) under nitrogen and cooled to 0° C. Diisobutyl Aluminium Hydride (0.466 ml of a 1 M solution in hexanes, 0.466 mmol) was added dropwise over 2 min and the mixture stirred at 0° C. for 1 h, then stirred at room temperature overnight. The reaction was cooled to 0° C. and water (5 ml) was added carefully, followed by 1 M Rochelle's salt (5 ml). The reaction was stirred at room temperature for 15 min, and then extracted with DCM (2×25 ml), the extracts combined, dried over magnesium sulphate, and concentrated. The residue was purified on silica, eluting (Ethyl Acetate/Petroleum ether), 50-100%) to give 2-{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-ethanol as a brown solid. Yield=25.3 mg (60.4%).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([OH:31])[C:29]#[CH:30]>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:30]#[C:29][CH2:28][OH:31])=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#CCO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#CCO)ccc12

Procedure:
7-(3-hydroxy-prop-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl-oxime was prepared in 58% overall yield using the method described in example 23A, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 2-propyn-1-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[CH3:8]>[Fe]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([NH2:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Br)cncc1[N+](=O)[O-]
Agent: [Fe]
Product: Cc1c(N)cncc1Br

Procedure:
This compound is obtained by reducing 3-bromo-4-methyl-5-nitropyridine (Intermediate 29.5) with iron in a manner similar to the synthesis of Intermediate 29.7, on the scale of 10 mmol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH:14][C:15]1[CH:32]=[CH:31][C:18]2[NH:19][C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=3)=[N:21][C:17]=2[CH:16]=1>>[OH:14][C:15]1[CH:32]=[CH:31][C:18]2[NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:27])=[CH:29][CH:30]=3)=[N:21][C:17]=2[CH:16]=1
Reactant: O=C([O-])c1ccc(-c2nc3cc(O)ccc3[nH]2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(O)ccc3[nH]2)cc1

Procedure:
Compound 459 was prepared from 4-morpholinoaniline and 4-(5-hydroxy-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C24H22N4O3: 415.17; found: 415.05.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25].C(N(CC)CC)C.O>C(#N)C>[C:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[O:25])=[CH:3][CH:4]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added 3-(trifluoromethyl)benzoyl chloride (126 mg) and triethylamine (84 μL). The mixture was stirred at room temperature for 30 min and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized (hexane/ethyl acetate) to give the title compound (161 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: Fc1cccc(CBr)c1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 84 %

Procedure:
Prepared in analogy to example 8 from 2-chloro-4-nitrophenol and 3-fluoro-benzylbromide. Colorless solid. Yield=84%. MS: m/e=281.0 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]=[CH:19][NH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[C:1]([C:5]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:20]=[CH:19][N:18]([S:27]([CH3:26])(=[O:29])=[O:28])[N:17]=2)=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)c2nc[nH]n2)CC1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)c2ncn(S(C)(=O)=O)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of 4-(2-tert-butyl-4-fluorophenoxy)-1-(1H-1,2,4-triazol-3-ylcarbonyl)piperidine (200 mg, 0.58 mmol) obtained in Example 274 in pyridine (3 mL) was added methanesulfonyl chloride (99 mg, 0.87 mmol), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate-water. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (245 mg, 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:35][CH3:36])=[C:18]([CH:24]4[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]4)[C:19]([CH3:23])=[C:20](Cl)[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[CH3:37][N:38]1CCCC1=O>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[C-]#N.[Zn+2].[C-]#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:35][CH3:36])=[C:18]([CH:24]4[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]4)[C:19]([CH3:23])=[C:20]([C:37]#[N:38])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12
Reactant: CN1CCCC1=O
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 130 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
Zinc (11 mg, 0.17 mmol) and bis(tri-t-butylphosphine)palladium (71 mg, 0.14 mmol) were weighed into a microwave vial then a solution of tert-butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (182 mg, 0.348 mmol, racemic intermediate from Examples 127/128, step 4) in N-methylpyrrolidinone (2.0 mL) was added. The mixture was degassed with N2 for a few minutes before adding zinc cyanide (82 mg, 0.70 mmol). The resulting mixture was stirred at 130° C. for 3 h. After cooling, the mixture was filtered through a pad of Celite and concentrated. The crude was purified on silica gel, eluted with 0-5% MeOH in dichloromethane. The product eluted right away, along with NMP. The fractions were combined and concentrated then taken up in EtOAc and washed with brine (3×). The organic was dried, filtered, and concentrated to give 0.17 g (96%) of the desired product. LCMS calculated for C25H30F2N7O3 (M+H)+: m/z=514.2; Found: 514.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:16](Cl)=[O:17].Cl>N1C=CC=CC=1>[Br:11][C:4]1[S:3][C:2]([NH:1][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:13]([Cl:12])[CH:14]=2)=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(C(F)(F)F)c(Br)s1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 75.9 %

Procedure:
2-Amino-5-bromo-4-trifluoromethylthiazole (1.0 g) was dissolved in pyridine (5 ml) and 3,4-dichlorobenzoylchloride (0.85 g) was added at room temperature with stirring. The mixture was stirred for 5 hr at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-bromo-4-trifluoromethylthiazol-2-yl)-3,4-dicloro-benzamide (1.29 g), m. p. 191-192° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[C:31]2[C:26](=[CH:27][C:28]([CH:32]=O)=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:32][C:28]5[CH:27]=[C:26]6[C:31](=[CH:30][CH:29]=5)[N:22]=[CH:23][CH:24]=[N:25]6)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2nccnc2c1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Product: C[C@@H]1CN(Cc2ccc3nccnc3c2)C[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and quinoxaline-6-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.82 (s, 2H), 8.14 (d, J=8.3 Hz, 1H), 8.07-7.93 (m, 3H), 5.15-5.08 (m, 1H), 4.00-3.87 (m, 2H), 3.37 (t, J=8.7 Hz, 1H), 3.04 (d, J=9.5 Hz, 1H), 2.85-2.84 (m, 1H), 2.66-2.62 (m, 1H), 2.46-2.42 (m, 1H), 2.11-1.92 (m, 7H), 1.71-1.63 (m, 2H), 1.20 (d, J=7.05 Hz, 3H), MS: (M+H m/z=430.1).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[C@@H:8]([OH:9])[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][C:12]23[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]2)[NH:14][O:13]3)[CH2:4]1>CO.[Pd]>[NH2:14][CH:15]1[CH2:16][CH2:17][C:12]([CH2:11][CH2:10][N:5]2[CH2:6][CH2:7][C@H:8]([OH:9])[C@@H:3]([CH3:2])[CH2:4]2)([OH:13])[CH2:19][CH2:18]1
Reactant: C[C@H]1CN(CCC23CCC(CC2)NO3)CC[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reaction time: 2 h

Procedure:
10% Pd—C (240 mg) is placed into a round-bottom flask under an argon atmosphere and covered with methanol. A solution of (3S,4S)-3-Methyl-1-[2-(2-oxa-3-aza-bicyclo[2.2.2]oct-1-yl)-ethyl]-piperidin-4-ol (13) (584 mg, 2.3 mmol) in 20 ml of methanol is added and the mixture is hydrogenated for 2 h at room temperature. Then the mixture is filtrated over celite and evaporated under reduced pressure. The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17](O)=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH2:27]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]([NH:27][CH3:26])=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN
Reactant: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(=O)O
Product: CNC(=O)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 87 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazole (0.2 g) and methylamine (30% methanol solution, 0.12 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 20(a) to obtain the title compound (0.18 g, 87%) as a colorless powder.
Reaction SMILES: [CH2:1]([OH:11])[C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][CH2:9][C@@H:7]2[O:8][C@H:2]([CH2:1][O:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:3]([OH:4])[C@@H:5]2[OH:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: O[C@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In accordance with Flowchart C, 2,5-anhydro-D-glucitol 19 is reacted with trityl chloride in pyridine, giving 2,5-anhydro-1,6-bis-O-(triphenylmethyl)-D-glucitol 20, which is then reacted with sodium hydride and benzyl bromide in dimethylformamide, giving 2,5-anhydro-3,4-bis-O-(phenylmethyl)-1,6-bis-O-(triphenylmethyl)-D-glucitol 21. Compound 21 is then reacted with acetic acid at about 80° C., giving 2,5-anhydro-3,4-bis-O-(phenylmethyl)-D-glucitol 22, which is then reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving 2,5-anhydro-3,4-bis-O-(phenylmethyl)-D-glucitol, 1,6-bis(diphenyl phosphate) 23. Substitution of other esterifying agents as described in Flowchart A will result in the corresponding tetraesters. Compound 23 is then hydrogenated in methanol/acetic acid over palladium on carbon, giving the product of Formula I where R', R", R'" and R"are phenyl, 2,5-anhydro-D-glucitol, 1,6-bis(diphenyl phosphate) 24. which may then be hydrogenated in methanol over platinum oxide, giving the product of Formula I where R', R", R'" and R"" are hydrogen, 2,5-anhydro-D-glucitol, 1,6-bis(dihydrogen phosphate) 25. Compounds 24 and 25 are disclosed in Voll et al., Carbohydrate Research, 95, 145-154 (1981), but are prepared by a different process. ##STR16##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:15]=1.C[O-].[Na+].[C:21](=O)([O:24]C)[O:22]C>>[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[C:13](=[O:14])[CH:12]([C:21]([OH:24])=[O:22])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:15]=1
Reactant: COc1cc2c(cc1OC)C(=O)CCCCC2
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)C(=O)C(C(=O)O)CCCC2
Temperature: 0 °C

Procedure:
A mixture of 2,3-dimethoxy-5,6,7,8,9,10-hexahydrobenzocycloocten-5-one [R. Legros and P. Cangiant, Compt. Rend., 250, 147 (1960)] (0.8 g), sodium methoxide (0.34 g) and dimethyl carbonate (3.6 ml) is heated for two hours under reflux in a stream of nitrogen. The reaction mixture is cooled, and then poured into ice-water containing 1N HCl (20 ml), and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and then concentrated under reduced pressure to afford methyl ester of 2,3-dimethoxy-5-oxo-5,6,7,8,9,10-hexahydrobenzocyclooctene-6-carboxylic acid as a pale yellow oily product (0.85 g). This product is dissolved in methanol (25 ml) and methylene chloride (15 ml). To the solution is added sodium borohydride (0.4 g) in limited amounts with stirring. The mixture is stirred for 1.5 hours. After addition of water (50 ml), the reaction mixture is shaken thoroughly. The organic layer is separated, and the aqueous layer is extracted with methylene chloride. The organic layers are combined and concentrated under reduced pressure. The residue is dissolved in a mixture of methanol (3 ml) and acetone (10 ml). To the solution is added a 1N aqueous solution of sodium hydroxide (10 ml), and the mixture is stirred at 60° C. for 10 minutes. The reaction mixture is cooled and then made acid with hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic layer is concentrated under reduced pressure. To the residue is added dioxane (8 ml) and concentrated hydrochloric acid (3 ml), and the mixture is stirred at 90° C. for 30 minutes. After cooling, water (50 ml) is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and then concentrated under reduced pressure. Precipitating crystals are collected by filtration to give 2,3-dimethoxy-5,6,7,8-tetrahydrobenzocyclooctene-9-carboxylic acid (0.6 g). This product is recrystallized from ethyl acetate to give colorless needles, m.p. 200°-201° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3]1.II>>[CH3:1][CH:2]1[CH2:16][CH:15]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:3]1
Reactant: CC1CC2=C(CCCCCCCCCC2)C1
Agent: II
Product: CC1C=C2CCCCCCCCCCC2C1
Yield: 92 %

Procedure:
Pure 14-methyl-bicyclo[10.3.0]pentadec-1(12)-ene (C) was also prepared as follows: 0.53 g of the above 10:1 mixture of compounds C and D were heated during 4 h 1/2 in the presence of 0.02 g of iodine, under argon atmosphere. After distillation of the reaction mixture (b.p. 100°-110° /0.01 Torr) there were isolated 0.48 g (92% yield) of the desired compound.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:13](#[N:16])[CH:14]=[CH2:15]>>[C:13]([C:14]1[CH2:15][O:12][C:3]2[C:4]([CH:5]=1)=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=2[F:1])#[N:16]
Reactant: C=CC#N
Reactant: COc1ccc(F)c(O)c1C=O
Product: COc1ccc(F)c2c1C=C(C#N)CO2
Yield: 13.6 %

Procedure:
Crude 3-fluoro-hydroxy-6-methoxybenzaldehyde (8.0 g) from above, acrylonitrile (13 mL; 193 mmol) and 1,4. diazadicyclo [2,2,2]octane (0.66 g; 5.9 mmol) were refluxed in a three-necked round-bottom flask (50 mL) under nitrogen for 4 h. Rotary-evaporation of the volatiles left a thick, red oil which was flash-chromatographed on a silica column eluted with methylene chloride/n-hexane (4:5). Concentration of relevant fractions gave an impure product (91% GC) which was crystallized form EtOAc to give 1.31 g of the title compound as colourless bars. Mp. 133°-135° C.