Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:42])[N:13]([CH3:41])[NH:14][CH:15]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:43])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:42])[N:13]([CH3:41])[NH:14][CH:15]([C:31]([OH:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(NC(CCCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(NC(CCCCN1C(=O)c2ccccc2C1=O)C(=O)O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 96.7 %

Procedure:
A solution of azapeptide ester 24 (0.402 g; 0.679 mmol) in ethyl acetate (5 ml) and acetic acid (0.2 ml) was hydrogenated with 110 mg of 10% Pd C for 18 hours. Filtration of catalyst and removal of solvent gave azapeptide 25 as a white foam (0.330 g). TLC (silica gel; EPAW 20:5:1:1) Rf=0.7. MS m/e 574 (M+, monotrimethylsilyl). NMR (CDCl3): δ1.42 (9H.s); 1.5-2.1 (10H,m); 3.00 (3H,s); 3.4-3.8 (5H,m); 4.3-4.6 (1H,m); 7.6-7.8 (4H,m); 7.8-8.0 (1H, broad).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:20]([CH:28]=O)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:32][CH:33]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[O:36][CH2:35][CH2:34]1>>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:20]([CH2:28][N:40]3[CH2:41][CH2:42][C:37]4([O:36][CH2:35][CH2:34][CH:33]4[OH:32])[CH2:38][CH2:39]3)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:30])([F:31])[F:1])[CH:8]=1
Reactant: OC1CCOC12CCNCC2
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)OCCC3O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This product was prepared according to the procedure described in Example 2 using (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde (WO 0056727) and 4-hydroxy-1-oxa-8-azaspiro[4.5]decane (Description 20).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[C:14]([CH2:18][C:19](Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH:10]3[CH2:12][CH2:11]3)[C:19]([CH2:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:13][C:4]=2[CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[C:4]([NH:13][C:19](=[O:20])[CH2:18][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1cc(Br)ccc1NCC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCC1CC1
Product: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CC1
Reaction time: 1 h
Yield: 49 %
Yield: 36 %

Procedure:
To a solution of 4-bromo-N1-(cyclopropylmethyl)benzene-1,2-diamine (Step B, 1.48 g, 6.15 mmol) in ethyl acetate (30 mL) was added tert-butylacetyl chloride (940 μL, 6.77 mmol) at room temperature. After stirring for 1 h, p-toluenesulfonic acid monohydrate (1.29 g, 6.77 mmol) was added and the mixture was stirred under reflux for 9 h. Water (20 mL) and aqueous ammonia (10 mL) were added and the mixture was extracted with ethyl acetate (30 mL×2) and washed with brine (10 mL). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1 as eluent) to give 5-bromo-1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazole (965 mg, 49%) as a brown oil and N-{5-Bromo-2-[(cyclopropylmethyl)amino]phenyl}-3,3-dimethylbutanamide (761 mg, 36%) as a white solid.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[S:14][C:13]([CH2:15]O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.Cl.[C-:22]#[N:23].[Na+].N>CS(C)=O>[N:1]1([CH:6]([C:10]2[S:14][C:13]([CH2:15][C:22]#[N:23])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [C-]#N
Reactant: CCCC(c1ccc(CO)s1)n1ccnc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=S(Cl)Cl
Product: CCCC(c1ccc(CC#N)s1)n1ccnc1
Reaction time: 20 h

Procedure:
0.2 g of the alcohol of example 8 is converted, with thionyl chloride (2 hours at room temperature, concentration by evaporation, redistillation three times with toluene) into the hydrochloride of the chloromethyl compound, which is dissolved in 2 ml of dimethyl sulfoxide and is mixed with 0.2 g of sodium cyanide. After stirring for 20 hours, it is added to dilute ammonia solution, extracted with ethyl acetate and the ethyl acetate extract is dried and concentrated by evaporation. After distillation on a bulb tube, the title compound is obtained as oil. Boiling point: 210°-230° C./0.03 mbar.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34]S[CH2:32][CH2:31]4)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.O[O:38][S:39]([O-:41])=O.[K+]>CO.O>[O:38]=[S:39]1(=[O:41])[CH2:34][CH2:35][CH:30]([NH:29][C:27]([C:14]2[C:15](=[O:26])[N:16]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:17]3[C:12]([C:13]=2[OH:36])=[N:11][CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=3)=[O:28])[CH2:31][CH2:32]1
Reactant: O=C(NC1CCSCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2cccnc2)c1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(NC1CCS(=O)(=O)CC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2cccnc2)c1=O
Yield: 37.3 %

Procedure:
To a solution of 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(3-pyridinylmethyl)-N-(tetrahydro-2H-thiopyran-4-yl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (24 mg, 0.05 mmol) in methanol (4 mL) was added Oxone (59.3 mg, 0.10 mmol) as a solution in water (1 mL). The resultant mixture was stirred overnight and then concentrated in vacuo. Ethyl acetate was added followed by water. The organics were washed with brine and the aqueous layer extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase preparative HPLC to give the title compound (10 mg, 38%) as a white solid as a format salt. 1H NMR (400 MHz, CDCl3) δ 10.41 (d, J=6.5 Hz, H), 8.58 (s, 1 H), 8.53 (d, J=4.3 Hz, 1 H), 8.41 (s, 1 H), 8.10 (s, 1 H), 7.36 (d, J=8.0 Hz, 1 H), 7.23 (m, 1 H), 7.16 (s, 1 H), 7.01-6.97 (m, 4 H), 5.37 (s, 2 H), 4.26 (m, 1 H), 4.04 (s, 2 H), 3.14 (m, 4 H), 2.49-2.29 (m, 4 H); HRMS m/z calcd for C27H26N4O5FS (M+H)+ 537.1608, found 537.1601.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([C:16]([NH:18][C@@H:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:21]([C:32]4[N:36]([CH2:37][CH2:38][OH:39])[C:35]5[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=5[N:33]=4)[CH2:20]3)=[O:17])[CH:14]=[CH:15][C:7]1=2.O.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:6]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([C:16]([NH:18][C@@H:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:21]([C:32]4[N:36]([CH2:37][CH2:38][O:39][S:2]([CH3:1])(=[O:4])=[O:3])[C:35]5[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=5[N:33]=4)[CH2:20]3)=[O:17])[CH:14]=[CH:15][C:7]1=2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.1 %

Procedure:
Methanesulfonyl chloride (51.3 mg, 0.448 mmol) was added to a solution of (2R,4R)-tert-butyl 4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (78 mg, 0.15 mmol) and DMAP (3.5 mg) in pyridine (1 mL) at 0° C. and the resulting mixture was stirred at room temperature for 5 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over MgSO4 and concentrated to give a yellow solid, which was purified by Companion (ReadSep, 12 g, silica gel packed) with ethyl acetate/heptane from 30-70% to give title compound as a white solid 65 mg (73%). LC-MS: 601.1 (t=2.6 min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2)([O-])=O.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2Cc2cccnc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc2c(ccn2Cc2cccnc2)c1
Yield: 71.7 %

Procedure:
To a stirred suspension of nitroindole (D46) (0.63 g, 2.5 mmol), and iron powder (0.41 g, 7.2 mmol) in methanol (20 ml) was added a solution of ammonium chloride (0.66 g, 12.4 mmol) in water (13 ml). The mixture was then heated under reflux for 12 h, then filtered while hot and evaporated. The residue was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried and evaporated to give the title compound (0.40 g, 72%) as a gum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:26][OH:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][N:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: Cc1cccnc1CO
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccnc1COc1nc(N)nc(-c2ccccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[C:7]([CH3:11])=[CH:6][C:5]=1[O:12][CH2:13][CH3:14].[C-:16]#[N:17].[Na+].C(OCC)(=O)C.O>C(#N)CC.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:16]#[N:17])[C:7]([CH3:11])=[CH:6][C:5]=1[O:12][CH2:13][CH3:14]
Reactant: CCOc1cc(C)c(Br)cc1C(=O)NC
Reactant: [C-]#N
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCC#N
Product: CCOc1cc(C)c(C#N)cc1C(=O)NC
Yield: 58 %

Procedure:
After dissolving N1,4-dimethyl-5-bromo-2-ethoxybenzamide (200 g) in propionitrile (1.51), sodium cyanide (72 g), copper iodide (14 g) and tetrakis(triphenylphosphine)palladium (42 g) were added under a nitrogen atmosphere and the mixture was heated to reflux for 5 hours. Ethyl acetate and water were added and the reaction mixture was filtered through celite. The precipitated crystals in the filtrate were filtered off (15.4 g). This filtrate was then separated and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and was concentrated after filtering off the insoluble portion. The obtained crystals were filtered off and washed with ethyl acetate (77.64 g). The crystals were combined to yield the title compound (93.04 g) as a white solid.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([C:17](=[O:19])[CH3:18])=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1.[CH:20](OCC)=[O:21]>Cl>[OH:21][CH:20]1[CH2:18][C:17](=[O:19])[C:4]2[C:3](=[CH:12][C:11]3[C:10]([CH3:13])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:16])([CH3:15])[C:6]=3[CH:5]=2)[O:2]1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: CCOC=O
Agent: Cl
Agent: [Na]
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OC(O)CC3=O
Temperature: 35 °C
Reaction time: 4 h

Procedure:
A 200-mL round bottom flask was flame dried under nitrogen and charged with sodium metal (3.2 g, 140 mmol). A solution of 1-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)ethanone (15 g, 61.0 mmol) in ethyl formate (350 mL) was added dropwise over 1 h. The resulting yellow solution was stirred at 35° C. for 4 h. The mixture was cooled to 25° C. solution, diluted with 1N HCl (20 mL) and extracted with ether. The extracts were washed with water, brine, and dried over MgSO4. The extracts were concentrated under vacuum to give 2-hydroxy-6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydrobenzo[g]chromen-4-one: 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H, ArH), 6.9 (s, 1H, ArH), 5,85 (t, 1H, CH), 3.32 (br s, 1H, OH), 2.9 (dd, 2H, CH2), 1.67 (s, 4H, 2CH2), 1.27 (s, 12H, 4CH3).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23]>CC(N(C)C)=O.CCOC(C)=O>[OH:15][CH2:14][C:10]1[CH:9]=[C:8]([S:7][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cccc(S)c1
Reactant: N#Cc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1cncc(Sc2cccc(CO)c2)c1
Temperature: 110 °C
Yield: 99.1 %

Procedure:
Add K2CO3 (6.91 g, 50.0 mmol) to a solution of (3-mercaptophenyl)methanol (2.94 g, 21.0 mmol) and 5-bromonicotinonitrile (3.66 g, 20.0 mmol) in DMA (100 mL). Heat the mixture at 110° C. for 2 h. Cool to room temperature. Dilute with EtOAc. Filter. Wash the residue with EtOAc. Concentrate. Dissolve the residue in EtOAc and filter. Concentrate to afford the title compound (4.80 g, quant.): 1H NMR (CDCl3) δ 2.20 (t, J=5.5 Hz, 1H), 4.74 (d, J=5.5 Hz, 2H), 7.38-7.44 (m, 3H), 7.52-7.53 (m, 1H), 7.62 (dd, J=2.0, 2.3 Hz, 1H), 8.62 (dd, J=2.0, 2.3 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.[OH:18][CH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:22][CH:21]=1>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:18][CH2:19][C:20]3[S:24][C:23]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:22][CH:21]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: C=CCOC(=O)c1ccc(CO)s1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)s1

Procedure:
In a manner similar to Example 1(d), by reaction of 2.5 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride with 1.98 g (10 mmol) of allyl 5-hydroxymethyl-2-thiophene carboxylate, 3.7 g (90%) of allyl ester are obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.O=[C:11]([CH3:26])[CH:12]([C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C(O)C>[CH3:17][O:16][C:14](=[O:15])[CH2:13][CH:12]1[C:18]([OH:19])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:8]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=[C:11]1[CH3:26]
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccccc1
Reactant: NNc1ccc(Cl)nn1
Solvent: CCO
Product: COC(=O)CC1C(C)=NN(c2ccc(Cl)nn2)C1(O)c1ccccc1

Procedure:
0.296 g (2.049 mmol) of 3-chloro-6-hydrazinylpyridazine in 5.00 ml of ethanol was added to 0.400 g (1.708 mmol) of methyl 4-oxo-3-(phenylcarbonyl)pentanoate, and the mixture was stirred at reflux for 8 h. The solvent was removed under reduced pressure which gave, after chromatography of the residue, 0.300 g (48% of theory) of a viscous yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1([CH3:23])[N:18]2[C:19](=[O:22])[CH2:20][CH2:21][C@@H:17]2[CH2:16][O:15]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:34])(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[F:34][C@H:20]1[C:19](=[O:22])[N:18]2[C:14]([CH3:23])([CH3:13])[O:15][CH2:16][CH:17]2[CH2:21]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1(C)OC[C@H]2CCC(=O)N21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC1(C)OCC2C[C@@H](F)C(=O)N21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture consisting of diisopropylamine (6.5 mL, 46 mmol) and THF (75 mL) at −78° C. was added dropwise a solution of nBuLi (2.5 M in hexanes, 18 mL, 44 mmol), and the resulting solution stirred for one hour. A solution consisting of (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (intermediate 4, 3.6 g, 23 mmol) in THF (25 mL) was added dropwise, and the resulting solution stirred for one hour. A solution consisting of N-fluorobenzenesulfonimide (9.5 g, 30 mmol) in THF (50 mL) was added dropwise, and the resulting solution was allowed to stir for 75 minutes below −55° C., and was subsequently quenched with the addition of a saturated aqueous ammonium chloride solution and warmed to room temperature. The organic material was extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in ethyl acetate, filtered, and the filtrate was concentrated to a gold oil, which was purified by silica gel chromatography. Elution with ethyl acetate:heptanes (1:3 v/v) afforded an approximately 1:1 mixture of the diastereomers of the title intermediate (1.54 g) as a clear oil; TLC Rf 0.40 (solvent system 50:50 v/v heptanes:ethyl acetate); 1H-NMR (CDCl3) δ 5.4-5.2 (m, 1H), 5.2-5.0 (m, 1H), 4.5-4.4 (m, 1H), 4.2-4.1 (m, 2H), 4.0-3.9 (m, 1H), 3.5 (t, 1H), 3.4 (t, 1H), 2.8-2.7 (m, 1H), 2.5-2.3 (m, 1H), 2.1-1.8 (m, 2H), 1.7 (s, 3H), 1.7 (s, 3H), 1.5 (s, 3H) 1.5 (s, 3H); 19F-NMR (CDCl3, 376 MHz) δ −102.2 (dd, ˜0.5F, J=264.2, 13.2 Hz), ˜103.5 (ddd, ˜0.5F, J=264.3, 26.5, 14.6 Hz); MS (ESI+) m/z 174.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[O:13][CH3:14].[CH3:15][C:16]([CH3:18])=[O:17].[OH-].[Na+].O>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16](=[O:17])[CH3:18])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: COCOc1ccc(C=O)cc1OC
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCOc1ccc(C=CC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
4-Methoxymethyloxy-3-methoxybenzaldehyde (1j, 2.30 g, 11.7 mmol) and acetone (19, 8.75 ml, 118.4 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.80 g, 20.0 mmol) and water (20 ml) was added and the mixture stirred for 1 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from hexane to give 2.70 g (97%) of a white solid: mp 73-75° C.; 1H NMR: δ 2.34 (s, 3H), 3.48 (s, 3H), 3.89 (s, 3H), 5.24 (s, 2H), 6.58 (d, 1H, J=16.1 Hz), 7.07 (m, 2H), 7.13 (d, 1H, J=8.7 Hz), 7.43 (d, 1H, J=16.1 Hz); 13C NMR: δ 27.4, 55.9, 56.3, 95.2, 110.4, 115.9, 122.5, 125.7, 128.7, 143.1, 148.7, 149.8, 198.0.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]([NH2:15])=[S:14]>CO>[ClH:1].[C:10]([CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][S:14][C:13](=[NH:12])[NH2:15])#[N:11]
Reactant: NC(N)=S
Reactant: N#CCc1ccccc1CCl
Solvent: CO
Product: Cl
Product: N#CCc1ccccc1CSC(=N)N
Reaction time: 1 h
Yield: 78.5 %

Procedure:
The 2-chlormethylphenylacetonitrile (200 mg, 1.21 mmol) and thiourea (101 mg, 1.33 mmol) were mixed in 1 ml of methanol. The mixture was heated to reflux for 3 to 4 hours. The reaction mixture was evaporated. After that, 1 ml of methanol and 4 ml of acetone were added and the mixture was stirred for one hour. The crystalline material was filtered and the product was dried under high vacuum overnight to yield 231 mg (0.95 mmol, yield 79%) of product as off white crystals, with purity greater than 95%. 1H NMR (300 MHz, d6-DMSO) δ 4.14 (s, 2H), 4.56 (s, 2H), 7.37 (m, 2H), 7.45 (m, 2H), 9.23 (s, 4H). (M+H) 205.97
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[OH:12][CH2:13][C@@H:14]1[O:20][C@@H:19]2[N:16]([C:17](=[O:21])[CH2:18]2)[CH2:15]1.C(N(CC)CC)C.[Cl:29]CCl>>[Cl:29][C:6]1[CH:5]=[CH:4][C:3]([S:8]([O:12][CH2:13][C@@H:14]2[O:20][C@@H:19]3[N:16]([C:17](=[O:21])[CH2:18]3)[CH2:15]2)(=[O:10])=[O:9])=[CH:2][CH:7]=1
Reactant: ClCCl
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: O=C1C[C@@H]2O[C@@H](CO)CN12
Solvent: CCN(CC)CC
Product: O=C1C[C@@H]2O[C@@H](COS(=O)(=O)c3ccc(Cl)cc3)CN12
Temperature: 25 °C
Yield: 76 %

Procedure:
Chlorobenzenesulfonyl chloride (478 mg, 2.27 mmol) was added to an ice-cooled solution of (3R,5S)-3-hydroxymethyl-4-oxa-1-azabicyclo[3,2,0]heptan-7-one (ref. compound 2) (250 mg, 1.75 mmol) and triethylamine (230 mg, 2.27 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature over night. After removal of solvent, the residue was purified by silica gel column chromatography using chloroform-ethyl acetate (5:1) as eluent and 420 mg of (3R,5S)-3-(4-chlorobenzenesulfonyl)oxymethyl-4-oxa-1-azabicyclo[3,2,0] heptan-7-one was obtained as white solid.
Reaction SMILES: [CH3:1][C:2](C)([CH:4]=[CH2:5])[OH:3].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH:25]([Cl:28])([Cl:27])[Cl:26]>>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:5][CH2:4][CH:2]([OH:3])[CH3:1]
Reactant: ClC(Cl)Cl
Reactant: C=CC(C)(C)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(O)CCC(Cl)(Cl)Cl
Yield: 69 %

Procedure:
To a solution of 17.2 g of dimethyl vinyl carbinol in 150 ml of chloroform was added 0.8 g of benzoyl peroxide and, in an autoclave, the mixture was reacted at 135° C. and in a nitrogen atmosphere for 18 hours. Then, the unreacted dimethyl vinyl carbinol and chloroform were removed by distillation under reduced pressure. As the residue was obtained 30.1 g of a dark-reddish viscous fluid. This residue was subjected to vacuum distillation to obtain 28.2 g (yield 69%) of 1,1,1-trichloro-4-pentanol. Gas-chromatographic analysis of this product showed its purity to be 95.4%. Mass spectrometric data suggested that the impurity comprised 1,1,3-trichloro-4-methyl-4-pentanol. The following procedures were used for structural identification of 1,1,1-trichloro-4-methyl-4-pentanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[N+:16]([O-])([OH:18])=[O:17].O.[K+].[Br-]>C(O)(=O)C>[OH:1][C:2]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(=O)OC)c(O)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 88 %

Procedure:
Into a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, a condenser, and nitrogen inlet, dimethyl 4-hydroxyisophthalate (15.0 g, 71.4 mmol) was dissolved in acetic acid (150 mL). Nitric acid (10 ml) was then added dropwise. The mixture was warmed at 60° C. for 12 h. Then, the cool mixture was poured into water. The light yellow precipitate was collected, air-dried and recrystallized from ethanol to give 16.0 g (88% yield) of light yellow crystals: mp=74-76° C. Anal. Calcd. for C10H9NO7: C, 47.07%; H, 3.55%; N, 5.49%; O, 43.89%. Found: C, 47.75%; H, 4.01%; N, 5.44%; O, 43.51%: FT-IR (KBr, cm−1): 3076, 2992, 1722, 1690. Mass spectrum (m/e): 255 (M+, 100% relative abundance), 241, 237. 1H-NMR (DMSO-d6, ppm) δ 3.89 (s, 3H, CH3), 3.97 (s, 3H, CH3), 8.46-8.47 (d, 1H, Ar), 8.55-8.56 (d, 1H, Ar). 13C-NMR (CDCl3, ppm) δ 52.72, 53.38, 117.60, 120.19, 130.61, 135.31, 138.50, 156.13, 163.70, 166.87.