Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Zn:1].[Li+].[Cl-].I[CH2:5][CH2:6][C:7]#[N:8].[C:9]([O-:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Li+]>C1COCC1>[C:9]([O-:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:7]([CH2:6][CH2:5][Zn+:1])#[N:8]
Reactant: N#CCCI
Reactant: [Zn]
Agent: CC(C)(C)C(=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCC[Zn+]
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Zinc powder (490 mg, 7.5 mmol) and LiCl (318 mg, 7.5 mmol) were placed in a Schlenk-flask, equipped with a magnetic stirrer and a septum, dried for 5 min at 400° C. (heat gun) in high vacuum and then dissolved in 7.0 mL of dry THF. 4 drops of 1,2-dibromoethane were added and the mixture was heated to boiling for the activation of the zinc dust. After cooling to 22° C. 3-iodopropionitrile (905 mg, 5.0 mmol) was added dropwise and the mixture was stirred for 2 h at 22° C. The stirring of the reaction mixture was stopped and the excess zinc dust was sedimented. The supernatant solution was transferred to another Schlenk-flask containing a solution of lithium pivalate (811 mg, 1.50 mmol) prepared as described above in 5.0 mL of dry THF. The mixture was stirred for 15 min at 22° C. and then the solvent was removed in vacuo. (2-cyanoethyl)zinc pivalate was obtained as a yellow solid (2.94 g). The content of active zinc species was determined by titration of 398 mg of the reagent with a stock solution of iodine (1.0 M in THF). A concentration of 1020 mg/mmol was determined which corresponds to a yield of 58%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]=[O:13].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[O:13][C:16]2[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: Cn1cc(C=O)c2cc(F)ccc21
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: Ic1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccc(F)cc34)oc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
In ethanol (25 ml), 5-fluoro-1-methylindole-3-carbaldehyde (989 mg, 5.58 mmol) and methyl 4-amino-3-hydroxyphenylacetate (1.27 g, 6.99 mmol) were stirred at room temperature for 9 hours. Iodobenzene diacetate (2.16 g, 6.69 mmol) was added and the mixture was stirred further at room temperature for 18 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue thus obtained was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (1:2, v/v) eluate fractions, a mixture (933 mg) of methyl (2-(5-fluoro-1-methyl-3-indolyl)-6-benzoxazolyl)acetate and 5-fluoro-1-methylindole-3-carboxaldehyde was obtained as a red solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].O>CO>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CCCCl
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CO
Solvent: O
Product: CN(C)CCCOc1ccc(C(=O)c2ccc(OCCCN(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of bis-(4-hydroxy-phenyl)-methanone (7.00 g) in methanol (130 mL) was added at room temperature t-Bu3OK (14.7 g) followed by (3-chloro-propyl)-dimethyl-amine (10.3 g). The reaction mixture was heated under reflux for 18 h and was allowed to cool down to room temperature. Water (50 mL) was added and the solvent was removed in vacuo. Methylene chloride (650 mL) was added and the organic layer was washed with water (2×150 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The crude products were separated and purified by flash chromatography on silica gel (chloroform/2 M ammonia in methanol) to give the title compound bis-[4-(3-dimethylamino-propoxy)-phenyl]-methanone as a colorless residue (250 mg). 1H NMR (400 MHz, CD3OD): 7.78 (d, 4 H), 7.09 (d, 4 H), 4.22 (t, 4 H), 3.37-3.40 (m, 4 H), 2.96 (s, 12 H), 2.24-2.31 (m, 4 H). And title compound [4-(3-dimethylamino-propoxy)-phenyl]-(4-hydroxy-phenyl)-methanone as a colorless residue (150 mg). 1H NMR (400 MHz, CD3OD): 7.88-7.99 (m, 4 H), 7.25-7.29 (m, 2 H), 7.08-7.13 (m, 2 h), 4.48 (t, 2 H), 2.69-2.76 (m, 2 H), 2.56 (s, 6 H), 2.23-2.30 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:38]([O:40]C)=[O:39])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:34](=[O:37])[CH:35]=[O:36])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:33])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][CH:9]([C:38]([OH:40])=[O:39])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:34](=[O:37])[CH:35]=[O:36])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:33])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3cccs3)C2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3cccs3)C2=O)cc1)C(=O)O
Reaction time: 7 h
Yield: 74.7 %

Procedure:
2-[3-{4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxyloylamino}-2-oxo-1-azetidinyl]-2-(2-thienyl)acetic acid (0.480 g.) was dissolved in methanol (3 ml.), and to the solution, there was added 1 N aqueous sodium hydroxide (2 ml.) under ice-cooling. The mixture was stirred at the same temperature for 7 hours while adjusting to pH 9.0 to 9.5 with 1 N aqueous sodium hydroxide. After the reaction, the reaction mixture was adjusted to pH 7.0 with dilute hydrochloric acid and evaporated to dryness under reduced pressure on a water bath. The resultant residue was dissolved in a small amount of water, and the aqueous solution was adjusted to pH 5.5 with dilute hyrochloric acid and then washed with ethyl acetate. The aqueous solution was adjusted to pH 4.0 to 4.5 with dilute hydrochloric acid and then extracted with ethyl acetate. This extract was evaporated to dryness under reduced pressure to give 2-[3-{4-(3-tert-butoxycarbonylamino-3-carboxypropoxy) phenylglyoxyloylamino}-2 -oxo-1-azetidinyl]-2-(2-thienyl) acetic acid (0.350 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([CH:7]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]1=O)=O.O.[NH2:21][NH2:22].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]1[C:7]2[CH2:14][C:10]3[S:11][CH:12]=[CH:13][C:9]=3[C:8]=2[NH:22][N:21]=1
Reactant: NN
Reactant: COc1ccccc1C(=O)C1Cc2sccc2C1=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1n[nH]c2c1Cc1sccc1-2
Temperature: 25 °C
Yield: 89.2 %

Procedure:
5-(2-Methoxy-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.53 g, 8.3 mmol), hydrazine monohydrate (0.65 mL, 12 mmol), glacial acetic acid (1.5 mL) and ethanol (20 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(2-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (2 g, 7.4 mmol) as white solid in 89% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14]2>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3nccn3C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 85.1 %

Procedure:
Ethyl 7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (100 mg) was dissolved in a mixed solvent of tetrahydrofuran (2 mL)-ethanol (2 mL), 1M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 50° C. for 50 min. The reaction. solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The obtained crystals were collected by filtration, and washed successively with water and diethyl ether to give the title compound (80 mg, yield 86%) as a white solid. The white solid was recrystallized from N,N-dimethylformamide-water to give colorless crystals. melting point 209-210° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH3:24])=[O:8].O1CCCC1.CO.[BH4-].[Na+]>[Cl-].[Na+].O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[OH:8])=[C:18]([CH3:24])[CH:19]=1
Reactant: Cc1cc(Cl)ccc1OCc1ccccc1C(=O)c1nccn1C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1OCc1ccccc1C(O)c1nccn1C
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a mixture of 1.02 g (3 mmol) of 2-(4-chloro-2-methylphenoxymethyl)phenyl 1-methylimidazol-2-yl ketone, 6 ml of tetrahydrofuran and 3 ml of methanol was added 0.11 g (3 mmol) of sodium borohydride under ice-cooling and stirred at room temperature for an hour. After completion of the reaction, 100 ml of brine was added and extracted twice with 50 ml of dichloromethane. The extract was dried over anhydrous magnesium and concentrated under reduced pressure. The crystal thus obtained was recrystallized from ethyl acetate to give 2-[2-(4-chloro-2-methylphenoxymethyl)-α-hydroxybenzyl]-1-methylimidazole (0.57 g, 55.4%) as colorless crystals. mp. 159-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][N:38]([CH3:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][N:38]([CH3:46])[CH3:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CN(C)CCCCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCCCCN(C)C)c(C)c3C)c2cc1OC
Yield: 86.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 6-(dimethylamino)-1-hexanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (66 mg, yield 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[N:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:7]=2[CH:29]=1.[ClH:30].C(OCC)(=O)C>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:8]2[C:7]3[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N:11]=[N:10][C:9]2=[O:12])[CH2:16][CH2:17]1
Reactant: COc1ccc2nnc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2nnc(=O)n(CCN3CCC(N)CC3)c2c1

Procedure:
To a solution of 1,1-dimethylethyl (1-{2-[6-(methyloxy)-3-oxo-1,2,4-benzotriazin-4(3H)-yl]ethyl}-4-piperidinyl)carbamate (48 mg, 0.11 g mmol) in chloroform (2 ml) was added 4M HCl in 1,4-dioxane (2 ml). The reaction was stirred at rt for 1 h before evaporation and trituration with ethyl acetate to provide the desired compound as a yellow oil which was used without further purification (42 mg, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]=[O:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:27].[Na+].Cl([O-])=O.[Na+]>O.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:27])=[O:25])=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: O=CCc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)Cc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Yield: 95.5 %

Procedure:
To a solution of 0.7 g of 4-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetaldehyde and 0.5 g of sodium dihydrogenphosphate in 5 ml of water and 30 ml of dimethyl sulfoxide was added a solution of 0.35 g of sodium chlorite in water (5 ml) and the resulting mixture was reacted at room temperature for 20 minutes. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 0.7 g of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH:10]C(=O)C.O.OS(O)(=O)=O>CO>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10]
Reactant: CC(=O)Nc1nc2c([nH]1)CCCC2
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1nc2c([nH]1)CCCC2
Temperature: 100 °C
Yield: 87.8 %

Procedure:
To a solution of 150 mg (0.83 mmol) of N-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)-acetamide in methanol (3 mL) was added water (3 mL) and conc. H2SO4 (0.3 mL). The mixture was heated at 100° C. under microwave (150 w, 250 psi) for 1 h. After removal of all the solvents, the residue was neutralized with sat. aq. Na2CO3 solution then diluted with methanol (50 mL). After removal of the inorganic salts through filtration, the organic phase was concentrated and dried under vacuum to afford 100 mg (86%) of the 4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylamine, which was used for the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([F:26])([F:25])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.[NH3:27].CO>C1COCC1>[F:25][C:8]1([F:26])[C:7]2[S:6][C:5]([C:3]([NH2:27])=[O:2])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: N
Reactant: COC(=O)c1nc2c(s1)C(F)(F)COc1ccc(C#CC(C)(C)O)cc1-2
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(F)(F)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of 4,4-Difluoro-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (86 mg, 0.227 mmol) in THF (5 mL) at room temperature, NH3/CH3OH (self-made, 5 mL) was added. The mixture was stirred at room temperature for 3 h, then concentrated to give a residue which was purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%) to give 4,4-Difluoro-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as an off-white solid (25 mg, 30%). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.60 (d, J=2.1 Hz, 1H), 8.18 (s, 1H), 7.46 (dd, J1=8.4 Hz, J2=2.2 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 5.49 (s, 1H), 4.75 (t, J=10.7 Hz, 2H), 1.49 (s, 6H); LC-MS (ESI & APCI): 365.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[CH2:14][CH2:13]2)[CH3:11])=[CH:6][CH:7]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](O)CC1
Reactant: BrCCCCBr
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](OCCCCBr)CC1

Procedure:
In analogy to example 11.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester and 1,4-dibrombutane were reacted to yield trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester as yellowish oil, MS: 418 (M, 1Br, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:17]#[N:18].[CH3:19][O-].[Na+].CI>CO>[NH2:1][C:2]1[C:3]([C:17]#[N:18])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:19])[N:7]=1
Reactant: C[O-]
Reactant: N#Cc1c(N)[nH]c(=S)c(C#N)c1-c1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nc(N)c(C#N)c(-c2ccccc2)c1C#N
Temperature: 0 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
To a stirred solution of 0.19 g (0.75 mmol) 6-amino-4-phenyl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile in 25 ml methanol were added 0.14 ml (0.76 mmol) sodium methylate solutiuon (5.4M in methanol) and 0.09 ml (1.5 mmol) methyl iodide and stirring continued for 16 hours at room temperature. The reaction mixture was then cooled to 0° C. and the resulting crystals collected by filtration and washed with ether/methanol (3/1) to afford 0.1 g (50%) 2-amino-6-methylsulfanyl-4-phenyl-pyridine-3,5-dicarbonitrile as a white crystalline solid. EI-MS m/e (%): 266 (M+, 40), 265 ([M—H]+, 100).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16]>C1(C)C=CC=CC=1>[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[C:15]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:16]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.2 %

Procedure:
Trimethylaluminium (2M in toluene) (8.97 ml, 17.94 mmol) was added to 5-methylpyridin-2-amine (1.940 g, 17.94 mmol) in toluene (70 ml) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (3.0 g, 8.97 mmol) in toluene (20 ml) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 5 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organics were dried (MgSO4) filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (2.40 g, 65.2%). 1H NMR (400 MHz, CDCl3) δ 1.03-1.15 (24H, m), 2.29 (3H, s), 3.60-3.68 (3H, m), 3.82-3.86 (1H, m), 3.98-4.02 (1H, m), 4.14-4.15 (1H, m), 4.30-4.34 (1H, m), 7.49-7.52 (1H, m), 8.11-8.13 (2H, m), 9.14 (1H, s); m/z (ES+) (M+H)+=411.44; HPLC tR=3.46 min.
Reaction SMILES: [CH:1]1([NH:4][CH:5]([P:14](=[O:21])([O:18]CC)[O:15]CC)[P:6](=[O:13])([O:10]CC)[O:7]CC)[CH2:3][CH2:2]1.CO.CC(C)=O>C(O)(=O)C.Br>[CH:1]1([NH:4][CH:5]([P:14](=[O:15])([OH:18])[OH:21])[P:6](=[O:7])([OH:13])[OH:10])[CH2:2][CH2:3]1
Reactant: CCOP(=O)(OCC)C(NC1CC1)P(=O)(OCC)OCC
Agent: Br
Solvent: CC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: O=P(O)(O)C(NC1CC1)P(=O)(O)O
Temperature: 45 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
1.28 g of tetraethyl (cyclopropylamino)methylenebis(phosphonate) was dissolved in 13 ml of 25% hydrogen bromide acetic acid solution and the mixture was stirred at 45° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and 20 ml of purified water was added to the residue. Then, the mixture was again concentrated under reduced pressure. The oily product thus obtained was solidified by methanol and acetone and subjected to the filtration. The solid was washed with acetone to give 0.42 g of (cyclopropylamino)methylenebis(phosphonic acid) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[NH4+:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: COc1ccc(S(N)(=O)=O)cc1

Procedure:
Proceeding in a manner similar to that described in Example 1, part B above, 100.42 g (0.486 m) of 4-methoxybenzenesulfonyl chloride from part A above was interacted with ammonium hydroxide and acidified to obtain 69.25 g of 4-methoxybenzenesulfonamide, a white solid which melted at 111.5°-112.5° C. The nuclear magnetic resonance spectrum was in accord with the assigned structure.
Reaction SMILES: C(O[C:9]1([C:17]2C(O)=C[CH:20]=[C:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:22]=2[F:23])[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]1O)C1C=CC=CC=1.[C:36]([OH:39])(=O)[CH3:37]>[Pd]>[F:23][C:22]1[CH:17]=[C:9]([C:14]2[C:36]([OH:39])=[CH:37][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:10]=[CH:20][C:21]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:25])=[O:26]
Reactant: COc1ccc(S(=O)(=O)c2ccc(O)c(C3(OCc4ccccc4)C=CC(F)=CC3O)c2F)cc1
Reactant: CC(=O)O
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)c2ccc(-c3cc(F)ccc3O)cc2F)cc1

Procedure:
The subtitle compound was prepared by the method of example 12 step (iii) using the product of step (ii) and 10% Pd/C in acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[NH2:13][CH2:14][CH:15]([OH:17])[CH3:16].S([O-])([O-])(=O)=O.[Mg+2].[CH2:24]1COCC1>>[CH2:1]([O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:13][CH2:14][CH:15]([OH:17])[CH3:16])=[CH:6][CH:5]=1)[CH3:24]
Reactant: CC(O)CN
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCOC(=O)c1ccc(CNCC(C)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution (100 ml) of 4-formylbenzoic acid methyl ester (10.0 g) and (±)-1-amino-2-propanol (4.6 g) in THF was added anhydrous magnesium sulfate (11.2 g) at room temperature and the mixture was stirred for 3 hrs. The reaction mixture was filtered, and methanol (100 ml) was added to the filtrate under ice-cooling. Sodium borohydride (4.6 g) was added and the mixture was stirred for 1 hr. The reaction mixture was allowed to warm to room temperature and stirred for 12 hrs. and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crystal was washed with diisopropyl ether to give the title compound (8.5 g).