Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@:5]1([CH3:33])[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:32]=[C:23]2[CH:24]=[CH:25][C:26]3[C:27](=O)[NH:28][N:29]=[CH:30][C:21]([C:22]=32)=[N:20]1)(=[O:3])[CH3:2].N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:41]>O1CCOCC1>[CH3:33][C@@:5]1([O:4][C:1](=[O:3])[CH3:2])[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:32]=[C:23]2[CH:24]=[CH:25][C:26]3[C:27](=[S:41])[NH:28][N:29]=[CH:30][C:21]([C:22]=32)=[N:20]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc3ccc4c(=O)[nH]ncc(n2)c34)[C@](C)(OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc3ccc4c(=S)[nH]ncc(n2)c34)[C@](C)(OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Compound 18.1 (250 mg, 0.54 mmol) was dissolved in dioxane (5 mL) and pyridine (7 mL) was added, followed by phosphorus pentasulfide (242 mg, 0.5 mmol). The mixture was heated at reflux for 24 hr then the solvent was evaporated and the residue was washed with pyridine (3×4 mL). The combined washings were evaporated and the residue was dissolved in 50 mL CHCl3 and washed with 30 mL 10% aqueous sodium bicarbonate followed by water. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated and the residue (180 mg) containing 23.1 was used immediately in the next step.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8].[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=2)[N:29]=1>C(Cl)Cl>[ClH:14].[CH3:23][N:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[C@@H:4]([NH:3][S:36]([C:33]2[CH:34]=[CH:35][C:30]([C:28]3[N:29]=[C:25]([CH3:24])[S:26][CH:27]=3)=[CH:31][CH:32]=2)(=[O:37])=[O:38])[CH2:5][NH:6][C:7]([C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[O:8])[CH2:22][CH2:21]1
Reactant: CN1CCN(C(=O)[C@@H](N)CNC(=O)c2ccc(Cl)s2)CC1
Reactant: Cc1nc(-c2ccc(S(=O)(=O)Cl)cc2)cs1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(S(=O)(=O)N[C@@H](CNC(=O)c3ccc(Cl)s3)C(=O)N3CCN(C)CC3)cc2)cs1
Reaction time: 16 h

Procedure:
Intermediate 90 (0.2 g, 0.5 mmol) was dissolved in 10 ml DCM and TEA (0.35 ml, 2.5 mmol). Commercially available 4-(2-Methyl-thiazol-4-yl)-benzenesulfonyl chloride (130 mg, 0.47 mmol) in 5 ml DCM was slowly added at 0° C. and the reaction was stirred for 16 h. Then the solution was evaporated to dryness and purified by silica gel chromatography. The compound was dissolved in DCM, HCl (2 M in diethyl ether (500 ml)) was added and the solvents were evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[C:13]([OH:17])(=O)[CH:14]=O.O.[NH2:19][NH2:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH3:11])=[N:20][NH:19][C:13](=[O:17])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: O=CC(=O)O
Reactant: COc1ccc(CC(C)=O)cc1
Solvent: O
Product: COc1ccc(-c2cc(=O)[nH]nc2C)cc1

Procedure:
5-Aryl pyridazinone examples were synthesized as outlined in Schemes 7 and 8. Condensation of 4-methoxyphenyl acetone (R14═Me) with glyoxylic acid (Scheme 7), followed by cyclization with hydrazine hydrate or N-substituted hydrazine derivatives afforded 5-(4-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one, and N—R12 examples (Farmaco, 1987, 43, 539).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1)[CH3:2].BrN1C(=[O:17])CCC1=O.[K].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>C(O)(C)(C)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:17])[CH2:10][O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1ccc(CC)cn1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(O)cc1
Agent: [K]
Solvent: CC(C)(C)O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 5 g (0.03759 mol) 5-ethyl-2-vinyl-pyridine dissolved in 75 mL of 25% aqueous tertiary butanol added 8.02 g (0.045 mol) N-bromosuccinimide at 25-30° C. in 30 min. Reaction mixture was stirred for 2 hr. The progress of reaction was monitored by TLC and after complete consumption of the 5-ethyl-2-vinyl-pyridine, 6.01 g (0.03759 mol) potassium salt of 4-hydroxy benzaldehyde was added. Reaction mixture was stirred for 18 hr. at 75-80° C. Subsequent work-up in water and extraction with ethyl acetate yielded 8.04 g (79%) of the titled product. m.p. 81° C.
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:25][CH2:26][C@@H:27]1[C@@H:31]([CH2:32][O:33][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:30][CH2:29][C@H:28]1[N:51]1[CH:59]=[N:58][C:57]2[C:52]1=[N:53][CH:54]=[N:55][C:56]=2[NH2:60])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO>[OH:25][CH2:26][C@@H:27]1[C@@H:31]([CH2:32][OH:33])[CH2:30][CH2:29][C@H:28]1[N:51]1[CH:59]=[N:58][C:57]2[C:52]1=[N:53][CH:54]=[N:55][C:56]=2[NH2:60]
Reactant: CC(C)(C)[Si](OC[C@H]1CC[C@@H](n2cnc3c(N)ncnc32)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1CC[C@H](CO)[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
4N-Hydrochloric acid/dioxane (0.17 ml, 0.68 mmole) was added to a solution of 9-[(1R,2R,3S)-2,3-bis-(t-butyldiphenylsilyloxymethyl)-1-cyclopentyl]-adenine (129 mg, 0.17 mmole) in methanol (1 ml). After stirring the mixture at room temperature overnight, solvent was distilled off from the reaction mixture under reduced pressure, after which water was added to the residue, ether-soluble material was removed therefrom, the residual solution was neutralized with 0.1N solution of sodium hydroxide, and solvent was distilled off therefrom. The residue was purified by Diaion HP-20 column chromatography (methanol concentration gradient) to obtain 9-[(1R,2R,3S)-2,3-bis(hydroxymethyl)-1-cyclopentyl]-adenine (43 mg, Yield 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](NC(=O)OC(C)(C)C)=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].IC.[OH2:28].C[N:30]([CH3:33])[CH:31]=[O:32]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:33][NH:30][C:31](=[O:28])[O:32][C:2]([CH3:7])([CH3:3])[CH3:1])=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCc2ccccc2)cc1Cl
Reactant: CN(C)C=O
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(C)(C)OC(=O)NCc1ccc(OCc2ccccc2)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [4-(benzyloxy)-2-chlorophenyl]carbamate (3.00 g) in N,N-dimethylformamide (45.0 mL) was added 55% sodium hydride (471 mg) under ice-cooling and a nitrogen flow, followed by stirring for 30 minutes under ice-cooling. Iodomethane (0.673 mL) was added thereto under ice-cooling, followed by stirring for 30 minutes. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl [4-(benzyloxy)-2-chlorophenyl]methylcarbamate (1.42 g).
Reaction SMILES: O[C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].S(Cl)(Cl)=[O:17].N1C=CC=CC=1.Cl.[O:27]1[CH2:32][CH2:31]OCC1>ClCCl>[CH2:10]([C:9]1[CH:14]=[CH:15][C:6]([CH:4]([CH3:5])[C:2](=[O:3])[CH2:31][C:32]([OH:27])=[O:17])=[CH:7][CH:8]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Reactant: C1COCCO1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Cc1ccc(C(C)C(=O)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(−)-ibuprofen (1.2 g, 5.8 mmol) is dissolved in dioxane (5 mL); thionyl chloride (2.36 mL) is added and the solution obtained is refluxed and left to reflux for 3 hours. After cooling to room temperature, the solvent is evaporated at reduced pressure, and the excess of thionyl chloride is eliminated, dissolving the residue twice with dioxane and evaporating the solvents under high vacuum. An oily yellow residue (1.3 g; 5.79 mmol) is obtained, which is dissolved in dry dichloromethane (2 mL) and added, by means of slow dripping and in an inert atmosphere, to a solution of 2,2-dimethyl-1,3-dioxan-2,5-dione (Meldrum's acid) (0.83 g; 5.79 mmol) and pyridine (1.12 mL; 14 mmol) in dry dichloromethane (5 mL) previously cooled to T=+5° C. with a water/ice bath. Once the additions are completed, the mixture is left for one hour at this temperature and then for another hour at room temperature. The mixture, diluted with dichloromethane is repartitioned with a 2N solution of HCl and crushed ice, under vigorous stirring for approximately 30 min. After separation of the phases, the organic phase, washed with 2N HCl (2×10 mL) and with a saturated solution of NaCl, is dried on Na2SO4 after evaporation of the solvent at reduced pressure, the residue of (R) (+)-5-[2-(4-isobutyl-phenyl)-propion-1-yl]-2,2-dimethyl-1,3-dioxan-4,6-dione ([α]D=+62°; c=1.1% CH2Cl2) without further purifications, is dissolved in methanol (14 mL); the solution is reheated to reflux for 3 hours. After cooling and evaporation of the solvent, the residue is purified by means of flash chromatography (eluent: n-hexane/ethyl ether 8:2) to yield pure methyl ester of (R) (−)-4-[(4′-isobutyl)phenyl]-3-oxopentanoic acid as a colourless oil (0.6 g; 2.28 mmol); [α]D=−192.5° (c=1; CH3OH); 1H-NMR (CDCl3): σ 7.1 (s, 4H); 3.88 (q, 1H, J=8 Hz); 3.67 (s, 3H); 3.47-3.28 (q, 2H, J=8 Hz); 2.45 (d, 2H, J=8 Hz); 1.85 (m, 1H); 1.40 (d, 3H, J=8 Hz); 0.95 (d, 6H, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:24])[CH2:20][CH2:21][CH2:22][NH2:23]>>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][NH2:24])=[N:13][CH:12]=1
Reactant: NCCCCN
Reactant: Nc1cc(F)ccc1NC(=O)c1ccc(Cl)nc1
Product: NCCCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Yield: 47 %

Procedure:
N-(2-Amino-4-fluorophenyl)-6-chloronicotinamide (266 mg, 1 mmol) and 7 ml of 1,4-butanediamine were heated to 80° C. for 3 hours. The excess 1,4-butanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (149 mg, 47% yield) as a brown solid. LC-MS (m/z) 318 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1)[CH3:2].[CH3:13]I>CC#N>[CH2:1]([C:3]1[C:8]([CH2:9][O:10][CH3:13])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1)[CH3:2]
Reactant: CCc1nc(SC)ncc1CO
Reactant: CI
Solvent: CC#N
Product: CCc1nc(SC)ncc1COC
Yield: 98 %

Procedure:
A solution of 4-ethyl-5-hydroxymethyl-2-methylthiopyrimidine (0.63 g, 3.42 mmol), Ag2O (1.6 g, 6.9 mmol) and MeI (1.1 mL, 17.1 mmol) in CH3CN (10 mL) was stirred overnight, filtered and concentrated to give 4-ethyl-5-methoxymethyl-2-methylthiopyrimidine in 98% yield (0.66 g); GC/MS calcd. for C9H14N2OS (M+) 198, found 198. The title compound was then prepared by (a) oxidation of 4-ethyl-5-methoxymethyl-2-methylthiopyrimidine (0.66 g, 3.35 mmol) with mCPBA (1.18 g, 6.85 mmol) as described for Example 67, and (b) reaction with methyl hydrazine (0.36 mL, 6.85 mmol) followed by citraconic anhydride (0.77 g, 6.85 mmol) also described in Example 67; resulting in a yield of 41% (0.40 g) from 4-ethyl-5-methoxymethyl-2-methylthiopyrimidine; 1H NMR (CDCl3) δ 8.14 (s, 1H), 6.43 (s, 1H), 4.29 (s, 2H), 3.53 (s, 3H), 3.36 (s, 3H), 2.68 (m, 2H), 2.14 (s, 3H), 1.13 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])=[O:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The commercially available p-chlorophenylsulfonyl isocyanate (15.0 g, 58.6 mmol) is added dropwise to t-butanol (90 ml) and the mixture is allowed to stir at room temperature for 60 hours. The solvent is evaporated and the white solid is recrystallized from hexane and ethylacetate to obtain N-t-butoxycarbonyl-p-chlorophenylsulfonamide, m.p. 98°-99° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][N:15]2[CH2:19][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:16]2=[O:26])=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C.ClCCl>[C:20]1([C@H:18]2[O:17][C:16](=[O:26])[N:15]([CH2:14][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][O:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[CH:28][CH:27]=3)[CH2:19]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1O[C@H](c2ccccc2)CN1Cc1ccc(CBr)cc1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1O[C@H](c2ccccc2)CN1Cc1ccc(COc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A solution of 3-hydroxypyridine (23 mg, 0.24 mmol) in DMF (1 mL) was added to a suspension of 3-(4-bromomethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one (70 mg, 0.20 mmol) (synthesized according to procedure 4) and sodium hydride (60%) (9 mg, 0.22 mmol) in DMF (1.5 mL) and the reaction mixture was stirred overnight at RT. It was diluted with dichloromethane (6 mL), washed with water (2×5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by chromatography on silica gel, eluting with dichloromethane containing 0.25-1% of methyl alcohol, to yield the title compound as a white solid (33 mg, 45%). 1H NMR (300 MHz, CDCl3): δ 8.40 (s, 1H), 8.25 (s, 1H), 7.38 (m, 1H), 5.50 (dd, 1H), 5.11 (s, 2H), 4.59 (d, 1H), 4.43 (d, 1H), 3.80 (t, 1H), 3.34 (dd, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].ClCCl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCc1cccnc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
2-Nitrobenzene sulfonyl chloride(11.64 g) was added to a dichloromethane solution (100 ml) of 3-(2-aminoethyl)pyridine(6.11 g) and triethylamine(9 ml) at 0° C. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound(5.06 g) as a yellow powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([CH2:9][OH:10])[C@H:7]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@@H:4]1[CH2:5][CH2:6]2.CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:10][CH2:9][CH:8]1[CH:3]([CH2:2][O:1][S:30]([CH3:29])(=[O:32])=[O:31])[C@H:4]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[C@@H:7]1[CH2:6][CH2:5]2)(=[O:32])=[O:31]
Reactant: O=C(OCc1ccccc1)N1[C@@H]2CC[C@H]1C(CO)C2CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1C(COS(C)(=O)=O)[C@@H]2CC[C@H]1N2C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of (1R,4S)-benzyl 2,3-bis(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (LI) (1.85 g, 6.35 mmol) and Et3N (2.65 mL, 19.05 mmol) in DCM (70 mL) at −30° C. was added a solution of MsCl (1.47 mL, 19.05 mmol) in DCM (15 mL) dropwise. The reaction mixture was stirred for 15 min at −10° C. then for 1.5 h at 0° C. The reaction mixture was dilluted with DCM, washed with 1 M HCl, 1 M K2CO3, brine and then dried over MgSO4. The solvent was removed under vacuum to give (1R,4S)-benzyl 2,3-bis((methylsulfonyloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (LII) as a very thick, light yellow oil (2.70 g, 6.03 mmol, 95% yield). 1H NMR (CDCl3) δ ppm 1.74 (brs, 4H), 1.88 (brs, 1H), 2.16 (brs, 1H), 2.97 (brs, 2H), 3.03 (brs, 3H), 3.97-4.09 (m, 1H), 4.10-4.18 (m, 1H), 4.22 (brs, 1H), 4.26-4.34 (m, 1H), 4.40 (brs, 1H), 5.11 (brs, 2H), 7.35 (brs, 5H); ESIMS found for C18H25NO8S2 m/z 448 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([C:22]([NH2:24])=[O:23])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]#[N:21]>>[C:20]([C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:22]([NH2:24])=[O:23])[C:14]=1[NH:13][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[O:3][CH2:1][CH3:2])#[N:21]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: N#Cc1ccnc(C(N)=O)c1N
Product: CCOc1ccccc1C(=O)Nc1c(C#N)ccnc1C(N)=O

Procedure:
The title compound was prepared from 2-ethoxybenzoyl chloride and 3-amino-4-cyanopyridine-2-carboxamide (Preparation 12), following the procedure of Preparation 7, and was obtained as a colourless solid (6.2%), m.p. 150-152° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:27][CH:26](C(O)=O)[CH2:25]3)=[CH:20][CH:19]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](Cl)(=[O:35])[C:32](Cl)=O.C[N:38]([CH:40]=[O:41])C>ClCCl>[CH2:31]([O:35][C:40]([NH:38][CH:26]1[CH2:25][CH:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[N:17]=[C:13]([C@@H:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:14][CH:15]=3)=[CH:23][CH:22]=2)[CH2:27]1)=[O:41])[C:32]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CC(C(=O)O)C3)cc2)c[nH]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CC(NC(=O)OCc4ccccc4)C3)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of A7 (14.8 g) in dichloromethane (800 mL) was added oxalyl chloride (5.1 mL) at rt. DMF (209 μL) was added in three portions over 4 h. The reaction was concentrated and re-dissolved in dichloromethane (500 mL). The fresh made diazomethane (0.3M, 500 mL) was added at 0° C. The reaction was slowly warmed up to rt. After overnight stirring, the reaction was concentrated to obtain the crude A8 (17.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH:10]([C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([C@H](N)C)C=CC=CC=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C@H:10]([C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CC(C(=O)O)CN(C(=O)OC(C)(C)C)C1
Agent: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 14.9 %

Procedure:
A mixture of (3RS,5SR)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (6.16 g), (R)-(+)-1-phenylethylamine (2.60 g) and ethanol (24 ml) was dissolved by heating to 70° C., and recrystallized. The precipitated crystals were collected by filtration, dissolved in ethanol (7 ml) again and recrystallized. The precipitated crystals were collected by filtration, the obtained crystals were suspended in water, acidified by adding saturated aqueous potassium hydrogen sulfate solution, and the mixture was extracted 3 times with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (915 mg) as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([SH:12])[CH:6]=[CH:5]2.Br[CH2:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl>N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][CH2:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(S)ccc2c1
Reactant: COC(=O)CCCC(=O)CBr
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CCCC(=O)CSc1ccc2cc(O)ccc2c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Into 205 ml (1.16 mmol) of 6-hydroxynaphthalene-2-thiol was charged 5 ml of pyridine, and the mixture was stirred under an ice bath. A solution of 315 mg of methyl 6-bromo-5-oxohexanoate in 2 ml of pyridine was added, and the mixture was stirred under an ice bath for 1 hour. Further, the reaction was carried out at room temperature for 4 hours, by heating to 90° C. for 4 hours, and subsequently stirring was continued at room temperature overnight. The reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate.
Reaction SMILES: S(OCC)(O[CH2:5][CH3:6])(=O)=O.[NH2:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:20][CH2:21][CH2:22][O:23][CH3:24].N>C1(C)C=CC=CC=1>[CH2:5]([NH:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:6]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1N
Reactant: CCOS(=O)(=O)OCC
Agent: N
Solvent: Cc1ccccc1
Product: CCNc1cc([N+](=O)[O-])ccc1OCCOC
Temperature: 80 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
185 g of diethyl sulfate (1.2 mole) are added dropwise to a mixture of 577 g of toluene and 212 g of 2-amino-4-nitro-β-methoxyethoxybenzene (1 mole). The mixture is stirred at 80° C. for 5 hours and then neutralized with 169 g of 14% strength aqueous ammonia. The toluene is removed by azeotropic distillation and the aqueous residue is adjusted to pH 0.4 with 165 g of concentrated hydrochloric acid. 10 g of keiselguhr and 0.5 g of zinc dust are added to the mixture. It is then boiled under reflux for 30 minutes and finally filtered hot. The filtrate is adjusted to pH 2 with 120 ml of concentrated sodium hydroxide solution. The precipitate is filtered off with suction and dried in vacuo. 215 g of 2-ethylamino-4-nitro-β-methoxyethoxybenzene are obtained, which corresponds to a yield of 76% of theory.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:22]([O:24][CH:25]([Cl:27])[CH3:26])=[O:23].CN1CCOCC1>ClCCl>[Cl:27][CH:25]([O:24][C:22]([NH:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:23])[CH3:26]
Reactant: CC(Cl)OC(=O)Cl
Reactant: NCC1(CC(=O)OCc2ccccc2)CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 15 °C
Yield: 100.6 %

Procedure:
In a 5-liter, 3-neck, round bottom flask, stirred mechanically and under nitrogen, was added dichloromethane (1.5 L), compound (6) (1.85 mol) and l-chloroethyl chloroformate (258 g, 1.81 mol). The resulting solution was cooled to 15° C. and N-methylmorpholine (396 mL, 3.60 mol) was added slowly, with cooling, over a one hour period. The resulting turbid solution was stirred for 30 min, after which 1H-NMR analysis showed the reaction to be complete. The reaction mixture was washed with water (2×2 L) and brine (1 L) and dried over sodium sulfate. Evaporation of the solvent afforded the title compound (9) as an orange oil (670 g, 98% yield). 1HNMR (CDCl3, 400 MHz): 1.33–1.53 (m, 10H), 1.75 (d, 3H), 2.33 (s, 2H), 3.18 (d, 2H), 5.09 (s, 2H), 5.58 (t, 1H), 6.53 (q, 1H), 7.29–7.33 (m, 5H).