Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=3)[OH:18])[C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]=2[CH:14]=1.[OH-:27].[K+]>C(O)(C)(C)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH2:26])=[O:27])=[N:23][CH:24]=3)[OH:18])[C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]=2[CH:14]=1
Reactant: [OH-]
Reactant: Cc1cnc2c(c1)c1c(n2CC(O)c2ccc(C#N)nc2)CCN(C)C1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cnc2c(c1)c1c(n2CC(O)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C
Yield: 15.8 %

Procedure:
5-[2-(3,6-Dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile (600 mg, 1.729 mmol) was dissolved in tert-butanol (12 mL), crushed potassium hydroxide (290 mg, 5.187 mmol) was added, and the mixture heated at 80° C. for 1 h. The reaction was monitored by TLC & LCMS. The reaction mixture was allowed to cool to RT, the solvent was removed under vacuum, and the residue was diluted with water (20 ml) and extracted with EtOAc (2×75 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase chromatography to afford 100 mg of 5-[2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-hydroxy-ethyl]-pyridine-2-carboxylic acid amide. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.62 (s, 1H), 8.1 (s, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.8 (s, 1H), 5.23 (t, 1H), 4.7 (d, 1H), 4.53 (d, 1H), 4.4 (m, 2H), 3.83 (m, 1H), 3.6 (m, 1H), 3.4 (m, 2H), 3.2 (s, 3H), 2.43 (s, 3H). Separation by chiral HPLC provides enantiomers II-111a-b.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[CH:17]=[CH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cn1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
A mixture of 5-nitro-2-pyridinecarbaldehyde (2.85 g prepared according the procedure described in J. Med. Chem. 1992, 35, 3675) and (carbethoxymethylene)triphenylphosphorane (6.0 g) in dry toluene (120 ml) under nitrogen was stirred and heated at reflux for 6 hours. After standing at room temperature overnight the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica gel eluting with dichloromethane to give the title compound (0.8 g) as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].O1[CH:19]=[CH:18][CH2:17][C:16](=[O:20])[NH:15]1.[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH2:18]([CH:17]1[O:24][C:23]2[C:2]([CH:3]=[CH:4][CH3:5])=[CH:1][CH:25]=[CH:21][C:22]=2[N:15]([C:1]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:10])[C:16]1=[O:20])[CH3:19]
Reactant: C1CCOC1
Reactant: O=C1CC=CON1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CC=Cc1cccc2c1OC(CC)C(=O)N2C(=O)c1ccc(OC)cc1
Yield: 62 %

Procedure:
Procedure & NMR Data: 137 mg (2.5 eq, 0.8 mmol) of p-Anisoyl chloride was added to a mixture of 49 mg (4 eq, 1.28 mmol) of NaH and 73 mg (0.32 mmol) of oxazinone P2 in THF (14 mL). 73 mg of P8 were obtained, yield 62%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=[S:23])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.[OH-].[Na+].[CH3:31]I>CCO.O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:7][CH2:8][C:9]([C:14]3[NH:22][C:21]4[C:20]([S:23][CH3:31])=[N:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:12][CH2:13]2
Reactant: CI
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[4-(2-Oxo-3-propyl-6-thioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester (100 mg) was dissolved in 2 mL of EtOH and 1 mL of H2O. NaOH (20 mg) was added as a solution in 1 mL of H2O, followed by MeI (23 uL, 1.5 eq). The resulting reaction mixture was stirred at rt for 30 min. It was then extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford 105 mg of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([NH2:31])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[C:39](Cl)([O:41][CH2:42][CH:43]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]2[C:44]1=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40]>O1CCOCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([NH:31][C:39]([O:41][CH2:42][CH:43]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=2[C:50]2[C:55]1=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:40])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCCCCOc1ccc(-c2ccc(CC[C@@H](N)CC(=O)OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCOc1ccc(-c2ccc(CC[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a stirred suspension of (R)-3-amino-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.14 g) in 50% aqueous 1,4-dioxane (40 ml) were added Na2CO3 (1.19 g, 11.2 mmol) and FmocCl (1.28 g, 4.95 mmol). After being stirred for 1 h, the mixture was diluted with sat. brine (100 ml) and extracted with CH2Cl2 (100 ml×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give (R)-3-(9-fluorenylmethoxycarbonylamino)-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.34 g) which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[CH2:14][CH2:15][CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].C(O)COCCOCCO>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:26][CH:27]=1
Reactant: O=C(CCCN1CCCCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(CCCCN2CCCCCC2Cc2ccc(Cl)cc2)cc1
Yield: 62.2 %

Procedure:
Heat 0.5 g of the title compound of Example 39 with 1 ml of hydrazine hydrate, 0.5 g of potassium hydroxide and 5 ml of triglycol for 2 hours at 165°. Cool the resulting reaction mixture to ambient temperature. Mix the cooled reaction mixture with water and diethyl ether. Dry the ether phase over sodium sulfate and then concentrate it to obtain 0.3 g of the title compound as a viscous oil.
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.CCOCC>COCCOCCOC>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:29][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Oc1cccc(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(F)cc1Oc1cccc(Cl)c1

Procedure:
Ethyl 2,4-difluorobenzoate (6.0 g), K3PO4 (7.5 g) and 3-chlorophenol (4.1 g) were stirred at 110° C. in diglyme (25 mL) for 24 hours. The mixture was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and with brine, and dried. The solution was then concentrated. The concentrate was chromatographed on silica gel with 10% ethyl acetate/hexanes.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8].[C:16]([C:18]1[S:19][C:20]([S:24][CH2:25][CH3:26])=[CH:21][C:22]=1[OH:23])#[N:17]>C(#N)C>[C:16]([C:18]1[S:19][C:20]([S:24][CH2:25][CH3:26])=[CH:21][C:22]=1[O:23][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8])#[N:17]
Reactant: CCOP(=S)(Cl)OCC
Reactant: CCSc1cc(O)c(C#N)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(OCC)Oc1cc(SCC)sc1C#N
Temperature: 20 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
7 g of potassium carbonate and 9.4 g of O,O-diethyl chlorothiophosphate were added to a solution of 9.3 g of 2-cyano-3-hydroxy-5-ethylthio-thiophene in 150 ml of acetonitrile and the mixture was stirred for 24 hours at 20° C. and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 14.6 g of 2-cyano-3-(diethoxythiophosphoryloxy)-5-ethylthio-thiophene with a refractive index of nD20 = 1.5635.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH3:8].[O:16]=[C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[NH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)(=O)C.ClCCCl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([N:9]1[CH2:14][CH2:13][CH:12]([N:25]2[CH2:24][CH2:23][CH:22]([N:21]3[C:20]4[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=4[NH:18][C:17]3=[O:16])[CH2:27][CH2:26]2)[CH2:11][CH2:10]1)[CH3:8]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CC(c1cnccn1)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(c1cnccn1)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.8 %

Procedure:
A mixture of 1-(1-(2-pyrazinyl)-ethyl)-4-oxopiperidine (37 mg), 4-(2-oxo-1-benzimidazolinyl)piperidine (41 mg), 1,2-dichloroethane (0.75 mL), glacial acetic acid (0.011 mL) and sodium triacetoxyborohydride (60 mg) was stirred at room temperature for 48 h. The reaction mixture was poured into dichloromethane (5 mL) and saturated aqueous Na2CO3 (3 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (2×5 mL) and the combined organic layers dried over Na2SO4 and concentrated under reduced pressure. Purification by preparative TLC, eluting with chloroform; 10% methanol; 1% NH4OH, followed by trituration with diethyl ether gave 35 mg of (±)-1,3-dihydro-1-(1-{1-[1-(2-pyrazinyl)-1-ethyl]piperidin-4-yl}piperidin-4-yl)-2H-benzimidazol-2-one as a colorless solid: 1H NMR (400 MHz, CDCl3) 9.77 (br s, 1H), 8.69 (d, 1H), 8.54 (dd, 1H), 8.46 (d, 1H), 7.35 (m, 1H), 7.11-7.03 (m, 3H), 4.39 (m, 1H), 3.73 (q, 1H), 3.11 (m, 3H), 2.90 (m, 1H), 2.35-2.55 (m, 5H), 2.11 (m, 2H), 1.92-1.61 (m, 6H), 1.44 (d, 3H). Analysis calculated for C23H30N6O.0.1 H2O.0.3 CHCl3 : C: 63.01, H: 6.92, N: 18.92 found C: 63.07, H: 6.96, N: 18.76.
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:23]([CH2:26][CH2:27][C:28]1[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=1[CH3:33])([OH:25])=[O:24].N1CCCCC1>C(O)C>[CH:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([CH2:27][CH2:26][C:23]([OH:25])=[O:24])[C:29]=2[CH3:36])[C:14](=[O:20])[NH:15]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: CC(C)c1ccc(OCCc2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCOc4ccc(C(C)C)cc4)c32)c(C)c1CCC(=O)O
Temperature: 90 °C
Yield: 58.2 %

Procedure:
A mixture of 4-[2-(4-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one (118 mg, 0.4 mmol), 4-carboxyethyl-3,5-dimethyl-2-formylpyrrole (78 mg, 0.4 mmol) and piperidine (0.3 mL) in 1.0 mL of ethanol was heated in a sealed tube at 90° C. for 18 hours and cooled to room temperature. The reaction mixture was concentrated and the residue was dissolved in methylene chloride followed by the addition of diethyl ether. The precipitate was filtered and washed with ethyl acetate to give 110 mg (58%) of 3-(5-{4-[2-(4-isopropyl-phenoxy)-ethyl]-2-oxo-1,2-dihydro-indol-3-ylidenemethyl}-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (piperidine salt).
Reaction SMILES: [NH2:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=2[SH:5](=[O:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:4][C:3]1=[NH:20].[H-].[Na+].Cl[C:24](OCC)=[O:25]>O1CCCC1>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]2[N:2]3[NH:1][C:24]([OH:25])=[N:20][C:3]3=[N:4][SH:5](=[O:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: N=C1N[SH](=O)(c2ccccc2)c2cc(Cl)ccc2N1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[SH]1(c2ccccc2)N=C2N=C(O)NN2c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7.0 g of 4-amino-7-chloro-3,4-dihydro-3-imino-1-phenyl-1,2,4-benzothiadiazine-1-oxide, prepared according to Example 6, in 250 ml tetrahydrofurane are added 0.68 g of sodium hydride (80%) in portions. After stirring for 30 minutes at room temperature 2.4 ml ethyl chloroformate, dissolved in 10 ml tetrahydrofuran, are added dropwise. The mixture is stirred at room temperature for three hours, then separated from the precipitated sodium chloride and concentrated. The residue is dissolved in 150 ml toluene and boiled for 16 hours under reflux. The precipitated product is sucked off and crystallized from dimethylformamide/methanol as colorless crystals, m. pt. 343°-348° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10](Cl)=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN(C)[C@@H]1CCN(CC2C=CC(C(O)=O)=CC=2)C1.[O:40]1[CH2:45][CH2:44][N:43]([CH:46]2[CH2:50][CH2:49][N:48]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)[CH2:47]2)[CH2:42][CH2:41]1>>[O:40]1[CH2:45][CH2:44][N:43]([CH:46]2[CH2:50][CH2:49][N:48]([C:51]3[CH:59]=[CH:58][C:54]([C:55]([NH:1][C:2]4[CH:7]=[C:6]([C:8]5[S:9][CH:10]=[CH:11][CH:12]=5)[CH:5]=[CH:4][C:3]=4[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:56])=[CH:53][CH:52]=3)[CH2:47]2)[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)s2)cc1N
Reactant: O=C(O)c1ccc(N2CCC(N3CCOCC3)C2)cc1
Agent: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N2CCC(N3CCOCC3)C2)cc1
Yield: 40 %

Procedure:
Following the same procedure as described in Example 1, step 6 (scheme 1), but substituting compound 4 for compound 168 and compound 7 for compound 269, title compound 270 was obtained in 40% yield.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C@H:10]([NH:74]C(OCC1C=CC=CC=1)=O)[C:11]([NH:13][CH:14]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21]([CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([S:34]([NH:37][C@@H:38]([CH2:42][NH:43][C:44]([C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[N:51]([CH2:55][CH2:56][CH2:57][NH:58][C:59]2[NH:60][CH:61]=[CH:62][N:63]=2)[N:50]=[CH:49]3)=[O:45])[C:39]([OH:41])=[O:40])(=[O:36])=[O:35])=[C:29]([CH3:64])[CH:28]=1)=[O:22])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O>CO.[Pd].O.C(#N)C>[NH2:74][C@@H:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:11]([NH:13][CH:14]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21]([CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH3:64])[C:30]([S:34]([NH:37][C@@H:38]([CH2:42][NH:43][C:44]([C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[N:51]([CH2:55][CH2:56][CH2:57][NH:58][C:59]2[NH:60][CH:61]=[CH:62][N:63]=2)[N:50]=[CH:49]3)=[O:45])[C:39]([OH:41])=[O:40])(=[O:35])=[O:36])=[C:31]([CH3:33])[CH:32]=1)=[O:22])=[O:16])=[O:12]
Reactant: Cc1cc(OCCCC(=O)NCCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)N[C@@H](CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: Cc1cc(OCCCC(=O)NCCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)cc(C)c1S(=O)(=O)N[C@@H](CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Reaction time: 3 h
Yield: 114.6 %

Procedure:
The product of step B (25 mg, 24 umol) in methanol (3 mL) was added to 10% palladium on carbon (14 mg) in methanol (3 mL) under nitrogen in a Parr bottle. It was hydrogenolyzed at 50 psi for 180 min, filtered through Celite, rinsed with methanol, and concentrated to afford a viscous oil. This was redissolved in 1:1 water/acetonitrile containing 0.1% TFA (nmL) and lyophilized (1:1 acetontrile/water/0.1% TFA) to afford the product as a white powder (29 mg, 100% yield) which analyzes for 2 equal peaks by HPLC (4.6×150 mm Zorbax C-18, 1 mL/min; Water/90% acetonitrile/0.1% trifluoroacetic acid, 2-100% B over 14 min) Rt=9.78 and 10.14 minutes. LRMS (ES): 1054.5 ([M+H]+, 10%) 527.8 ([M+2H]+2, 100%); identical for each peak. This was not further purified but taken into the next step as a mixture of two diastereomers.
Reaction SMILES: [C:1]([CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1)#[N:2].[CH2:19](N)[CH2:20][NH2:21].S.O>CCOCC>[NH:2]1[CH2:19][CH2:20][N:21]=[C:1]1[CH:3]1[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4]1
Reactant: N#CC1CC2c3ccccc3C1c1ccccc12
Reactant: NCCN
Agent: S
Solvent: O
Solvent: CCOCC
Product: c1ccc2c(c1)C1CC(C3=NCCN3)C2c2ccccc21
Temperature: 130 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g), ethylenediamine (1.5 g) and hydrogen sulfide (about 100 mg) is stirred at 130° C for 20 hours. The reaction mixture is mixed with water and ether to be distributed in two layers. The ether layer is washed with water, dried, and evaporated to remove the ether. The residue is recrystallized from ether to give 11-(2-imidazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (5.0 g) as crude crystals. IR (KBr), 1621 cm-1 (N--C=N).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:48][CH:49]([CH3:51])[CH3:50])[C:22]([NH:24][N:25]([CH2:44][CH:45]([CH3:47])[CH3:46])[S:26]([C:29](=O)[CH2:30][N:31]1C(=O)C2C(=O)C=CC=C2C1=O)(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.NN>C(O)C>[NH2:31][CH2:30][CH2:29][S:26]([N:25]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:48][CH:49]([CH3:51])[CH3:50])(=[O:28])=[O:27]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)C(=O)CN1C(=O)C2=CC=CC(=O)C2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCN)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A solution of 0.46 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(1,3-dioxo-2-phthalimidoethansulphonyl)-4-methylvalerohydrazide in 10 ml of ethanol was treated with 4.5 ml of hydrazine hydrate and stirred at room temperature for 2 hours. Evaporation gave a residue which was triturated with ethyl acetate and filtered. The filtrate was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulphate. The residue was purified by column chromatography on silica gel using methanol/dichloromethane (5:95) for the elution to give 0.26 g of (E)-2′-(2-aminoethanesulphonyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a pale yellow gum.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.O.[NH2:17]N.Cl.Cl.NN>C(O)CO>[NH:1]([C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)[NH2:17]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: OCCO
Product: NNc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 140 °C
Yield: 90.3 %

Procedure:
To a suspension of 93.6 g of 2-amino-6-trifluoromethoxybenzothiazole in 420 cm3 of ethylene glycol under a stream of nitrogen are added 48 g of hydrazine hydrate and 42 g of hydrazine dihydrochloride. The mixture is heated for 2 hours at 140° C. After cooling, the precipitate is filtered off and triturated with a water/diethyl ether mixture (1/1 by volume). 89.9 g of 2-hydrazino-6-trifluoromethoxybenzothiazole are thus obtained, melting at 208° C.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH2:13]([O:20][C@:21]1([CH3:44])[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:23][C:22]1=[O:43])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:13]([O:20][C@:21]1([CH3:44])[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:23][CH:22]1[OH:43])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@]1(OCc2ccccc2)C(=O)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C[C@]1(OCc2ccccc2)C(O)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -40 °C

Procedure:
Vitride (22 L, 76.19 mole, 70% wt. in toluene, 3.46M) was diluted with toluene (18 L) and added dropwise to a solution of (3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-3-methyl-dihydrofuran-2(3H)-one (62.5 mole from step 1) in toluene (150 L) maintaining temperature around −40±5° C. during the addition. After the addition was over, TLC was checked to ensure completion of the reaction (if the reaction is not complete, more Vitride is added till reaction is complete). The reaction was quenched with acetone (5.5 L) maintaining temperature between −30° C. and −40° C. and 2.5 N HCl (70 L) was added at 0° C. The toluene layer was separated and the aqueous layer was extracted with ethyl acetate (30 L). The combined organic layers were washed with brine (30 L), dried over magnesium sulfate (10 Kg), filtered and the filtrate was concentrated in vacuo to dryness to furnish 32 kg of crude residue. The crude material was used as such for the next step. An analytical sample was prepared by purification of 1 g of residue by flash column chromatography (silica gel, ethyl acetate in hexane) to furnish (3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-3-methyl-tetrahydrofuran-2-ol. 1HNMR (DMSO-d6): δ 7.35-7.24 (m, 15 H), 6.68 (d, J=5 Hz, 0.6 H), 5.89 (d, J=6.8 Hz, 0.4 H), 5.00 (m, 1 H), 4.73-4.50 (m, 6 H), 4.18-4.13 (m, 0.4 H), 4.06-4.00 (m, 0.6 H), 3.79 (d, J=7.5 Hz, 0.6 H), 3.65 (d, J=6 Hz, 0.4 H), 3.61-3.48 (m, 2 H), 1.33 (s, 2 H), 1.32 (s, 1 H); MS (ES+): 457.38 (100% M+Na). Analysis: Calculated for C27H30O5: C, 74.62; H, 6.96; Found: C, 74.36; H, 7.05.