Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[C:15]([C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=1)[O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([N+:30]([O-])=O)[CH:22]=1)#[CH:16]>O.CO>[C:15]([C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=1)[O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:30])[CH:22]=1)#[CH:16]
Reactant: C#Cc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cccc(Oc2ccc(N)c(N)c2)c1
Yield: 84.8 %

Procedure:
To a rapidly stirred solution containing 41 g (230 mmoles) of sodium hydrosulfite and 32 g (230 mmoles) of potassium carbonate dissolved in 250 ml of water was added dropwise a solution containing 6.7 g (23.4 mmoles) of 4-(3-ethynylphenoxy)-o-dinitrobenzene dissolved in 50 ml of methanol. The reaction mixture changed from black to white within several minutes after the addition. The white solution was evaporated in vacuo at 50° C to remove the methanol. The remaining aqueous solution was then extracted with several 50 ml portions of methylene chloride. The combined extracts were washed with one 50 ml portion of water, dried over molecular sieves and evaporated to dryness to yield 4.45 g (85%) of 4-(3-ethynylphenoxy)-o-phenylenediamine in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[Si:19]([O:9][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ncccc1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cccnc1N)(c1ccccc1)c1ccccc1
Reaction time: 15 h
Yield: 94.5 %

Procedure:
To a suspension of (2-aminopyridin-3-yl)methanol (2.19 g, 17.6 mmol) and 1H-imidazole (6.00 g, 88.2 mmol) in DMF (10 mL) was added dropwise tert-butylchlorodiphenylsilane (5.49 mL, 21.2 mmol). The reaction was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was diluted with DCM (4 0 mL). The organic layer was washed with 1N HCl (10 mL), water (10 mL) and brine (10 mL) and then concentrated to give crude product (6.03 g, 94.3% yield). MS (apci) m/z=363.1 (M+H).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:17][CH:16]=1)C1C=CC=CC=1.CO[CH:30](OC)[CH2:31][NH2:32]>C(O)C>[NH:32]1[CH:31]=[CH:30][N:26]=[C:25]1[CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:20][CH:19]=1
Reactant: COC(CN)OC
Reactant: N#CCCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Solvent: CCO
Product: NCCCCc1ccc(OCCCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.2 %

Procedure:
Compound 2 (0.156 g, 0.425 mmol) was dissolved in anhydrous ethanol (10 mL). To the solution was bubbled anhydrous HCl gas for 3 min. The reaction vessel was sealed and the mixture was stirred at room temperature for 48 h, and then concentrated to dryness under vacuum. The resulting residue was dissolved in anhydrous methanol (5 mL). To the newly formed solution was added 2,2-dimethoxyethylamine (0.097 mL, 0.891 mmol) in one portion. After stirring at room temperature overnight, temperature was raised to reflux which was maintained for another 3 h before the mixture was cooled to ambient temperature. Solvent was removed under vacuum and the residue was treated with 1.2 N HCl aqueous solution at 80° C. for 2 hours. The mixture was then cooled to ambient temperature again and neutralized to pH ˜9 with powder K2CO3. Water was completely removed under vacuum and the residue was dissolved in methanol. The methanol solution was loaded onto silica gel, and the product was eluted with a mixture of concentrated ammonium hydroxide/MeOH/CH2Cl2 (1.8:18:81.2, v/v), affording the product 21 (27 mg, 23% overall yield) as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 1.60 (m, 4H), 2.14 (m, 2H), 2.56 (t, 2H), 2.76 (t, 2H), 2.86 (t, 2H), 3.94 (t, 2H), 6.79 (d, 2H), 6.91 (s, 2H), 7.08 (d, 2H). m/z (APCI): 274 [C16H23N3O+H]+.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Cl[CH2:28][C:29]1[N:30]=[CH:31][N:32]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1>C1COCC1>[C:34]([N:32]1[CH:33]=[C:29]([CH2:28][C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]2)[N:30]=[CH:31]1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (360 mg, 1.39 mmol) in anhydrous THF (10 mL) at −78° C. was added LDA (1.7 M in THF, 1.07 mL, 1.8 mmol) dropwise over 10 min. The reaction mixture was stirred at −78° C. for 1 hour, and 4-(chloromethyl)-1-trityl-1H-imidazole (500 mg, 13.9 mmol) in THF (5 mL) was added slowly. The reaction mixture was allowed to warm to room temperature over 1 hour, quenched with sat. aq. NH4Cl (10 mL), and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (10-50% EtOAc:Hexanes) afforded the title compound (403 mg, 51%). MS (ES+) [M+H]+=580.3.
Reaction SMILES: [C:1]([CH:3]([CH3:21])[CH2:4][CH:5]1[CH2:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)#[N:2].Br.C(O)(=[O:25])C>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:9]2[CH2:8][CH2:7][C:6]3[NH:2][C:1](=[O:25])[CH:3]([CH3:21])[CH2:4][C:5]=3[CH2:10]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CC2CCC(=O)C(CC(C)C#N)C2)cc1
Reactant: CC(=O)O
Agent: Br
Product: COc1ccc(CC2CCC3=C(C2)CC(C)C(=O)N3)cc1
Reaction time: 2 h

Procedure:
2-(2-Cyanopropyl)-4-(4-methoxybenzyl)cyclohexanone (1.5 g) was added to glacial acetic acid (20 ml) containing 45% w/v hydrogen bromide in acetic acid (5 ml) and the mixture was left to stir for 21/2 hours. The solvent was removed under reduced pressure, the residue was suspended in water and filtered to give the title compound on recrystallisation (0.5 g) mp 182°-184° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([NH2:11])=O)=[CH:3][CH:2]=1>O=P(Cl)(Cl)Cl>[C:9]([CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)#[N:11]
Reactant: NC(=O)CCc1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCCc1ccncc1
Yield: 76.8 %

Procedure:
A mixture of 3-(4-pyridyl)-propionamide (7.1 g, 0.47M) in POCl3 (25 ml) was heated at about 100° to about 110° C. for 2 hrs. The excess of POCl3 was removed in vacuo from the reaction. Thereafter water was added and the resulting solution was basified with aqueous Na2CO3 sol. and extracted with CHCl3. The combined extracts were dried over Na2SO4 and concentrated and distilled at 1 mmHg/118°-120° C. to give 4(2-cyanoethyl)pyridine as an oil (4.8 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:21][CH2:20][CH2:19][N:9]2[C:10](=[O:18])[C:11]2[N:12]([N:14]=[C:15]([CH3:17])[CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.[N:22]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:23]=[O:24].O>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[N:21]([C:23]([NH:22][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:20][CH2:19][N:9]2[C:10](=[O:18])[C:11]2[N:12]([N:14]=[C:15]([CH3:17])[CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1
Reactant: O=C=NCCc1ccccc1
Reactant: Cc1cc2n(n1)CC1(c3ccc(Cl)cc3)NCCN1C2=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc2n(n1)CC1(c3ccc(Cl)cc3)N(C(=O)NCCc3ccccc3)CCN1C2=O
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 10a-(4-chlorophenyl)-7-methyl-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazin-5-one (40 mg, 0.13 mmol) in a mixture of pyridine (400 μl) and CH2Cl2 (400 μl) was added (2-isocyanatoethyl)benzene (150 μl) at 0° C. The mixture was let to come back to room temperature. After 1 h the reaction was complete (monitored by LCMS). Water was then added and the mixture extracted with CH2Cl2. The organic fractions were then stirred overnight with PS-trisamine resin to remove the excess of isocyanate. Filtration through a cotton wool plug and concentration in vacuo gave a residue that was purified by flash chromatography (Silica gel, gradient 2:3 acetone/hexane) to give 10a-(4-chlorophenyl)-7-methyl-5-oxo-N-(2-phenylethyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazine-1-carboxamide (41) as a white solid (58 mg, yield 99%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:11]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35]([C:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH:11]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(OCc1ccccc1)N1C=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2=CN(C(=O)OCc3ccccc3)CC2)cn1
Yield: 56.5 %

Procedure:
A solution of benzyl 4-(trifluoromethylsulfonyloxy)-2,3-dihydro-1H-pyrrole-1-carboxylate (200 mg, 0.57 mmol) in THF (10 mL) was purged with nitrogen for 10 minutes. The mixture was treated with K2CO3 (200 mg, 1.44 mmol), 6-methoxypyridin-3-ylboronic acid (100 mg, 0.66 mmol), tetrakis(triphenyl-phosphine)palladium (10 mg, 0.008 mmol), and water (100 μL). The reaction mixture was then heated to reflux for 16 hours. The reaction was treated with saturated aqueous NaHCO3 (20 mL) and then extracted with ethyl ether (20 mL). The organic layer was washed with saturated aqueous NaCl (20 mL), and then dried over Na2SO4. The crude mixture was filtered, concentrated and purified by flash chromatography (SiO2, 50% ethyl acetate/hexane) to afford the title compound (100 mg, 57%). 1HNMR (500 MHz, CDCl3) δ 8.05 (m, 1H), 7.55 (m, 1H), 7.30 (m, 5H), 6.66 (m, 1H), 5.98 (m, 1H), 5.13 (m, 2H), 4.44 (m, 2H), 4.30 (m, 2H), 3.86 (s, 3H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.Cl.[O:14]([NH2:16])[CH3:15].C(N(CC)CC)C>CCO.O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][O:14][CH3:15])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CONC(=O)c1ccccc1N
Yield: 88 %

Procedure:
A mixture of isatoic anhydride (5.0 g, 31 mmol) and methoxylamine hydrochloride (3.8 g, 46 mmol) in EtOH (100 mL) and H2O (10 mL) was charged with Triethylamine (6.4 mL, 46 mmol) and stirred at reflux for 4 h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The obtained solid was washed with ether and hexanes to afford 4.5 g, 88% yield, of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (br. s., 1H), 7.30 (dd, J=1.14, 7.96 Hz, 1H), 7.09-7.19 (m, 1H), 6.70 (dd, J=0.76, 8.34 Hz, 1H), 6.45-6.52 (m, 1H), 6.30 (br. s., 2H), 3.67 (s, 3H); MS (ES+): m/z: 167.0783 [MH+]. HPLC: tR=0.83 min (UPLC TOF: polar—3 min).
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([CH3:5])=O.[C:10]([CH2:12][C:13]([NH2:15])=O)#[N:11]>>[C:10]([CH:12]1[C:3]([CH3:5])=[CH:2][CH2:1][NH:15][CH2:13]1)#[N:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#CCC(N)=O
Product: CC1=CCNCC1C#N
Reaction time: 2.5 h

Procedure:
reacting ethyl acetoacetate with cyanoacetamide and a base, in the presence of an organic solvent, at a temperature of from 60° C. to 80° C., for 1 to 4 hours, to produce 3-cyano-2,6-dihydro-4-methylpyridine;
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(OC(OCC)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=1)C.O>C(O)CCC.Cl>[ClH:1].[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:17]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:20][CH:21]=1)[CH:27]=[CH2:28]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: C=CCOc1ccc(OCC(OCC)OCC)cc1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: C=CCOc1ccc(OC2NCCc3cc(O)c(O)cc32)cc1
Yield: 98.6 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (3.3 g) and (4-allyloxyphenoxy)acetaldehyde diethyl acetal (5.2 g) in a mixture of n-butanol (45 ml), water (12 ml) and concentrated hydrochloric acid (2 drops) was refluxed for 4 hours. After the reaction, the reaction mixture was concentrated to dryness. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixed solvent of 99% ethanol and ether to give 1-(4-allyloxyphenoxy)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0 g), mp 114° to 116°C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[SH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:15][C:10]1[C:9]([C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[S:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Sc1nccs1
Reactant: O=Cc1cc(-c2cccnc2F)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cc(-c2cccnc2F)c(Sc2nccs2)s1
Yield: 100.1 %

Procedure:
With 5-bromo-4-(2-fluoropyridin-3-yl)thiophene-2-carbaldehyde (250 mg) as a starting material, and using 2-mercaptothiazole (134 mg) and potassium carbonate (193 mg), an operation similar to that of Reference Example 1 was performed to give the title compound as a white powder (yield 282 mg, yield 100%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].II>CCCCCC>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3/[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]/3=[CH2:26])/[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: II
Solvent: CCCCCC
Product: C=C1CC[C@H](O)C/C1=C\C=C1/CCC[C@@]2(C)C1CC[C@@H]2[C@H](C)CCCC(C)C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of Vitamin D3 (750 mgs) in hexane (20 ml) was added iodine (2 mgs). After stirring for 1 hr. at 20° the solution was washed with aqueous sodium thiosulphate, water and dried over sodium sulphate. After removal of the solvent, chromatography afforded trans-vitamin D3 (460mgs).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[O:7][C:6]2[C:13]([CH2:21][C:22](=[O:24])[CH3:23])=[C:14]3[C:19](=[CH:20][C:5]1=2)[CH2:18][CH2:17][CH2:16][CH2:15]3.Cl>[OH-].[Na+]>[OH:24][CH:22]([CH3:23])[CH2:21][C:13]1[C:6]2[O:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4](=[O:3])[C:5]=2[CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18]2
Reactant: CC(=O)Cc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)Cc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of sodium borohydride (0.4 g) in 0.02 N aqueous sodium hydroxide (30 ml) was added dropwise a solution of 4-oxo-10-(2-oxopropyl)-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2carboxylic acid (2.3 g) in 0.02N aqueous sodium hydroxide (100 ml). The resulting solution was stirred at ambient temperature for 20 hours, then cooled in ice and acidified with dilute hydrochloric acid. The precipitate was filtered washed with water and dried giving the title compound as a white solid, mp 235°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[S:14][C:15]([Cl:22])=[CH:16][C:17]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:12][C:13]1[S:14][C:15]([Cl:22])=[CH:16][C:17]=1[S:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: NCCCCCCCC(=O)O
Product: O=C(O)CCCCCCCNS(=O)(=O)c1cc(Cl)sc1Cl

Procedure:
8-Aminocaprylic acid (1.0 g, 0.006 mole) was treated with 2,5-dichloro-3-thiophene sulphonyl chloride (1.58 g, 0.006 mole) according to the method described in Example 4 to give the title compound after recrystallisation from isopropanol/water (1.1 g, m.p. 92°-93° C.).
Reaction SMILES: [C:1](=[O:16])([O:9]C1C=CC=CC=1)[O:2]C1C=CC=CC=1.[CH3:17][C:18]1[C:24]([CH3:25])=[C:23]([OH:26])[C:22]([CH3:27])=[CH:21][C:19]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].N#N.C1(O)C=CC=CC=1>>[C:1](=[O:2])([OH:16])[OH:9].[CH3:27][C:22]1[C:23]([OH:26])=[C:24]([CH3:25])[C:18]([CH3:17])=[C:19]([CH:21]=1)[OH:20]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: Cc1cc(O)c(C)c(C)c1O
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Oc1ccccc1
Product: O=C(O)O

Procedure:
21.4g (0.1 mole) of diphenyl carbonate, 18.2g (0.12 mole) of 2,3,5-trimethylhydroquinone and 0.1g of potassium carbonate were heated and stirred under the N2 -gas atmosphere at 150° C for 3 hours. After this, phenol was distilled off and the residue solidified to obtain a glassy solid. Distilled phenol was 105% of calculated quantity. M. P.: 97°-103° C, molecular weight: 975 (calculated value 1047).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8]Cl)[N:4]1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOCCOC.C(OCC)C>[CH2:23]([N:30]1[CH2:8][CH:5]2[N:4]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:3]([CH2:7][CH2:6]2)[CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: ClCC1CCC(CCl)N1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: Clc1ccc(N2C3CCC2CN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
2,5-Bis-chloromethyl-1-(4-chloro-phenyl)-pyrrolidine (3.73 g, 13.57 mmol), potassium carbonate (3.75 g, 27.14 mmol), and benzyl amine (4.45 mL, 40.71 mmol) in diglyme (25 mL) was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether (600 mL) and washed with water (6×300 mL). The combined organic layers were dried with magnesium sulfate and concentrated to a brown oil. Silica gel flash chromatography using 50% chloroform/hexanes as eluent yielded 3-Benzyl-8-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]octane (1.0 g, 23.5%) as a golden solid which had the following properties: Mp. 115-117° C.; 1H NMR CDCl3 δ: 7.29 (s, 5H), 7.14 (d, J=8.1 Hz, 2H), 6.67 (d, J=8.3 Hz, 2H), 4.08 (brd s, 2H), 3.38 (s, 2H), 2.54-2.42 (m, 4H), 2.08-2.00 (m,2H), 1.95-1.86 (m,2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][C@@H:14]2[C@@H:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[CH2:9][C@@H:10]2[C@@H:14]([CH2:13][N:12]([C:22]3[CH:21]=[CH:20][C:19]([N+:24]([O-:26])=[O:25])=[CH:18][C:17]=3[F:16])[CH2:11]2)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1ccc(CN2C[C@H]3CNC[C@H]3C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2C[C@H]3CN(Cc4ccccc4)C[C@H]3C2)c(F)c1
Reaction time: 15 h

Procedure:
To a solution of cis-3-benzyl-3,7-diazabicyclo[3.3.0]octane (0.35 g, 1.73 mmol) in acetonitrile (10 mL) is added 3,4-difluoronitrobenzene (0. 19 mL, 1. 73 mmol) and potassium carbonate (0.60 g, 4.33 mmol) under a nitrogen atmosphere at ambient temperature. The reaction is stirred 15 hours, concentrated in vacuo, and diluted with ethyl acetate (100 mL). The organic phase is washed with water (3×20 mL) and saline (20 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (99/1). The appropriate fractions are combined (Rf =0.49, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.94, 7.88, 7.29, 6.62, 3.73, 3.64, 3.44, 2.97, 2.75, 2.55.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7](CC2C=CC(OC)=CC=2)[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2
Reactant: COc1ccc(CN2C(=O)C(N)c3ccccc3-c3ccccc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1C(=O)Nc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.1 g (0.29 mmol) (RS)-7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one in 8 ml of dichloromethane at 0° C. temperature 0.67 ml (8.7 mmol) of trifluoroacetic acid and 0.25 ml of trifluoromethansulfonic acid (2.9 mmol) were added and the mixture was stirred for 4 hours at room temperature. After concentration of the mixture at 40° C. in vacuo an aqueous NaHCO3 solution was added and the mixture extracted two times with ethyl acetate. The combined organic layers were dried (MgSO4). After evaporation of the solvent a light yellow oil was obtained, that was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][N:15]=[N+:16]=[N-:17])(F)[CH2:10][C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:34]C(N1C[C@@](O)(COS(C)(=O)=O)C[C@H]1C(=O)NCC1C=CC=C(Cl)C=1F)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][N:15]=[N+:16]=[N-:17])([OH:34])[CH2:10][C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@](O)(COS(C)(=O)=O)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1C[C@@](F)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F
Product: CC(C)(C)OC(=O)N1C[C@@](O)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F

Procedure:
was obtained using the same protocols as described in Scheme B15 step A for the preparation of (2S,4R)-4-azidomethyl-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester starting from (2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-methanesulfonyloxy methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared from (2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as described scheme B13). MS (UPLC/MS): 450/452 [M+Na]+, 472/474 [M+HCOO]−; tR (HPLC conditions f): 2.08 min.