Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].[CH3:8][O:9][C:10](=[O:19])[CH2:11][C:12](=O)[CH2:13][C:14](OC)=[O:15].Cl.C(OCC)(=O)C>C[O-].[Na+].CO.C(Cl)Cl>[OH:15][C:14]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:5]=[C:12]([CH2:11][C:10]([O:9][CH3:8])=[O:19])[CH:13]=1
Reactant: N=C(N)C(F)(F)F
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1cc(O)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,2,2-Trifluoroethanimidamide (6.7 g, 50. mmol, Oakwood) was dissolved in 0.5 M sodium methoxide in methanol (120 mL, 60. mmol) and 3-oxo-pentanedioic acid dimethyl ester (8.4 mL, 55 mmol, Aldrich) was added. The reaction solution was stirred at room temperature for 72 hours, followed by heating to 50° C. for 42 hours. The solvent was removed in vacuo. 1N HCl (50 mL) was added, this resulted in pH 5. After stirring overnight, 4M HCl (10 mL) and ethyl acetate were added, and layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, on 120 g silica gel cartridge, eluting with a gradient (solvent A=hexane; solvent B=3% iPrOH/EtOAc) from 0-30% solvent B in A over 40 minutes and hold at 30% for 20 minutes at a flow rate of 60 mL/min. The residue obtained on evaporation of product-containing fractions was mixed with DCM and the resulting white ppt (impurity) was removed by filtration. The filtrate was evaporated and the resulting residue was repurified (A=hexane; solvent B=iPrOH) on a 120 g silica gel cartridge, eluting with a gradient from 0-20% B in A over 25 minutes and hold at 20% B at a flow rate of 60 mL/min. Evaporated to afford an oil which crystallized on standing (5.2 g, 75% pure). A portion of the material was purified via preparative HPLC-MS (C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA) to afford product used in the subsequent step. 1H NMR (300 MHz, CDCl3) δ 6.76 (s, 1H), 3.76 (s, 3H), 3.75 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]([O-])(=O)=O.[K+]>S(=O)(=O)(O)O.O>[Br:14][C:5]1[CH:4]=[C:3]([N+:11]([O-:13])=[O:12])[C:2]([CH3:1])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: [O-][Br+2]([O-])[O-]
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a mixture of 2-methyl-1,3-dinitro-benzene (10 g) and 1:1 concentrated sulfuric acid-water (100 mL) at 80° C. was added potassium bromate (10.1 g) portionwise over 2-21/2 hr. The mixture was stirred at 80° C. for an additional 2 hr and cooled to room temperature. The mixture was poured into 500 g ice and then extracted with diethyl ether (300 mL) . The ether layer was washed with 10% sodium bicarbonate solution (250 mL), brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (4:96) to afford 5-bromo-2-methyl-1,3-dinitro-benzene (5.3 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.N1C=CC=CC=1.[C:64](Cl)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>ClCCl>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:64](=[O:71])[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=C(Cl)c1ccccc1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the FR-900506 substance (9.7 mg) in dichloromethane (0.2 ml) and pyridine (0.1 ml) was added benzoyl chloride (50 μl) at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture under reduced pressure to give a crude oil. This oil was purified on silica gel thin layer chromatography (developing solvent: diethyl ether and hexane, 2:1 v/v) to afford 17-allyl-12-[2-(4-benzoyloxy-3-methoxycyclohexyl)-1-methyvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (8.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2(O)C(=O)Nc3cc(Cl)ccc32)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-hydroxy-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (from Example 6a supra) was suspended in a mixture of triethylsilane (5 mL, 31.3 mmol) (Aldrich) and trifluoroacetic acid (12.5 mL) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate (100 mL) and treated with solid sodium carbonate (10.5 g). After stirring for 30 minutes, mixture was extracted with water (2×100 mL) and brine (100 mL). Aqueous layers were back washed with ethyl acetate (100 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as off-white prisms. (Yield 2.12 g, 77.4% over two steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O.[C:23](=[O:26])(O)[O-:24].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([CH:10]1[CH2:11][CH:3]=[CH:4][O:24][C:23]1=[O:26])=[O:7]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: O=C([O-])O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CC=COC2=O)c1
Reaction time: 2 h

Procedure:
A solution of 6-valerolactone (2.0 g, 20 mmol) in anhydrous tetrahydrofuran (100 ml) was cooled to −78° C. under a nitrogen atmosphere, and 3-methoxybenzoyl chloride (3.58 g, 21 mmol) and lithium hexamethyldisilazide (40 ml, 1M tetrahydrofuran solution, 40 mmol) were added sequentially. Stirring was carried out for 2 hours, followed by treatment with saturated sodium bicarbonate water. The reaction mixture was extracted with ethyl acetate (100 ml), followed by washing with brine, and subsequently, the solvent was distilled off under reduced pressure, to obtain a brown crude product. Purification by silica gel column chromatography (hexane/ethyl acetate=1/1) afforded the desired compound as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O.NN>C1COCC1.C(O)C.[Ni]>[F:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)c(F)c1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(CN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrobenzyl)morpholine (240 mg, 1.0 mmol) in THF/ethanol mixture (1:1) (25 mL) was added a catalytical amount of Raney-Ni and hydrazine hydrate (9.0 mmol) and the mixture was stirred at ambient temperature for 15 minutes, filtered through a Celite pad. The filtrate was evaporated to provide the title compound, (197 mg, 94%), which was used in further reactions without purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][S:21]([OH:24])(=O)=[O:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][S:21]([Cl:27])(=[O:24])=[O:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CS(=O)(=O)O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CS(=O)(=O)Cl)CC1
Temperature: 42 °C
Reaction time: 1 h

Procedure:
To a mixture of {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanesulfonic acid (34 mg, 0.092 mmol) in methylene chloride (0.30 mL) was added 1 drop of DMF and thionyl chloride (33 μL, 0.46 mmol). The resulting mixture was stirred at 42° C. for 1 h, then the solvents were evaporated to give the crude {trans-4-[(6-Nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanesulfonyl chloride. To the crude sulfonyl chloride made above was added 2.0 M methylamine in THF (0.30 mL, 0.60 mmol). The mixture was stirred at room temperature for 30 h. LCMS showed a small amount of starting material remaining More 2.0 M methylamine in THF (0.15 mL) was added and stirred for 30 min, to give a complete reaction. The solvents were evaporated and the resultant residue was dried in vacuo to give the crude product which was used in the next step without further purification. LCMS calculated for C15H21N4O4S2 (M+H)+: m/z=385.1. Found: 385.1.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>C(=O)C1C(=CC=CC=1)O.C(N(CCCC)CCCC)CCC>[C:11]([OH:13])(=[O:12])[C:4]1[CH:3]=[CH:2][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Solvent: CCCCN(CCCC)CCCC
Solvent: O=Cc1ccccc1O
Product: O=C(O)c1cccc(C(=O)O)c1

Procedure:
53 g (0.32 mol) of isophthalic acid, 53 g (0.27 mol) of trimellitic anhydride, 3 g (0.01 mol) of an azomethine obtained by reaction of 5-amino-isophthalic acid with salicylaldehyde, 0.85 g of tributylamine as catalyst, 196 g (0.7 mol) of 3.3'-dimethyl-4,4'-di-isocyanato-diphenylmethane and 700 g of N-methylprrolidone are stirred for 6 hours at 80° C. Subsequently, 43 g (0.1 mol) of 4,4'-bis-(ethoxalylamino)-diphenylmethane are stirred into the above mixture. The temperature is then raised to 195°C, and agitation is continued for a further 6 hours at this temperature. The fluorocarbon wax suspension as described in Example 2 is added to the trion resin solution so obtained in the same weight ratio.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to 712. Product was isolated as a tan solid (0.026 g, 26%); Mp 111-117° C.; LCMS (m/e) 498 (M); 1H-NMR (DMSO, 400 MHz) δ 9.35 (s, 1H), 9.11 (s, 1H), 8.53 (d, 1H), 8.16 (s, 1H), 7.45-7.49 (t, 2H, J=7.07 Hz), 7.38-7.40 (q, 1H, J=6.57 Hz), 7.10-7.12 (d, 1H, J=8.33 Hz), 6.95 (s, 1H), 6.79-6.81 (d, 1H, J=8.08 Hz), 3.54 (s, 1H), 2.97-2.98 (q, 2H, J=6.83 Hz), 2.87 (s, 2H), 2.73-2.74 (s, 6H), 2.39 (m, 2H), 1.07-1.11 (t, 3H, J=6.82 Hz), 1.00-1.03 (t, 3H, J=6.82 Hz).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C:17](=[O:18])[N:7]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9](Cl)[CH2:10][S:11][C@H:6]12)(=[O:3])[CH3:2].CN(C=O)C.[N-:24]=[N+:25]=[N-:26].[Na+]>C(OCC)(=O)C>[C:1]([NH:4][C@@H:5]1[C:17](=[O:18])[N:7]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([N:24]=[N+:25]=[N-:26])[CH2:10][S:11][C@H:6]12)(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C(Cl)CS[C@@H]2[C@H](NC(C)=O)C(=O)N12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(N=[N+]=[N-])CS[C@@H]2[C@H](NC(C)=O)C(=O)N12
Reaction time: 0.75 h

Procedure:
A solution of 0.784 g. of methyl 7β-acetamido-3-chloro-3-cephem-4-carboxylate in 40 ml. of DMF was cooled to 5° C. in an ice bath and 0.193 g. of sodium azide were added. The reaction mixture was stirred in the cold for 45 minutes and then transferred to a separatory funnel with ethyl acetate. The mixture was washed with cold water, with brine, and was dried and evaporated to dryness. There were obtained 0.581 g. of the 3-azido ester product as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(Br)c2)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Br)c2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A solution of 168 mg (0.47 mmol) of tert-butyl (3RS,4RS)-4-(3-bromophenyl)-3-hydroxy-piperidine-1-carboxylate and 157 mg (0.71 mmol) of 2-bromomethyinaphthalene in 2 ml of dimethylformamide was treated with 28 mg (0.7 mmol) of sodium hydride (60% dispersion in refined oil) and the mixture was stirred at room temperature for 3 hours. Subsequently, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:4 mixture of ethyl acetate and hexane as the eluent. There were obtained 173 mg (74% of theory) of tert-butyl (3RS,4RS)-4-(3-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow oil; MS: 439, 441 (M-C4H8)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:9][C:10]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C@H:25]([NH:34][CH3:35])[C@@H:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCCC>[CH3:24][C@H:25]([NH:34][CH3:35])[C@@H:26]([OH:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[C:1]([O:5][C:6]([C@H:8]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:9][C:10]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCCOCC(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Agent: CN[C@@H](C)[C@@H](O)c1ccccc1
Solvent: CCCCCC
Product: COCCOC[C@H](CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 1-[2-(tert-butoxycarbonyl)-3-(2-methoxyethoxy)propyl]-1-cyclopentanecarboxylic acid (110.1 g, 0.333 mole) in hexane (550 ml) was treated with (+) pseudoephedrine (55.1 g, 0.333 mole) and the mixture was heated to reflux. The resulting solution was cooled to induce crystallisation, and stirred at 5° C. for 1 hour to granulate the crystals. After overnight refrigeration at 5° C., filtration, washing with hexane (200 ml) and drying gave the crude (+) pseudoephedrine salt of the (S) acid (89.9 g, 54.4%) as a white solid m.p. 76°-80° C. Recrystallisation of 30 g of this material twice from hexane (225 ml) gave the (+)pseudoephedrine salt of the title compound (21.45 g, 71.5% recovery) as white crystals m.p. 86°-7° C., [α]D +34.9° (c=1, MeOH). Found: C,65.21; H,9.23; N,2.91. C27H45NO 7 requires C,65.42; H,9.15; N,2.82%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][CH2:25][O:24]4)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14]CC)=[O:13].O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC(OCC)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][CH2:25][O:24]4)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Cl)cccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Cl)cccc21
Yield: 92 %

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl (4′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained in 92% yield as a colorless solid: mp 228-229° C.; 1H NMR (300 MHz, CDCl3) δ 7.26-7.21 (m, 1H), 7.03 (dd, 1H), 6.71 (dd, 1H), 6.52 (s, 1H), 6.36 (s, 1H), 4.93 (dd, 2H), 4.69-4.63 (m, 1H), 4.54-4.51 (m, 3H), 2.95 (t, 2H); 13C NMR (75 MHz, CDCl3) δ 177.8, 170.9, 162.1, 162.1, 143.1, 131.7, 130.0, 128.6, 124.7, 119.6, 118.7, 117.0, 106.7, 92.8, 77.2, 72.3, 58.1, 41.2, 28.9; MS (ES−) m/z 370.4 (M−1).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12.C(N(C(C)C)C(C)C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35](ON1C(=O)CCC1=O)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35]([NH:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Reactant: Nc1cnn2c1NCCC2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.2 %

Procedure:
To a solution of 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (4.44 g) and N-ethyldiisopropylamine (3.88 g) in methylene chloride (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (4.29 g). The mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% methanol/chloroform to give 3-[3-(tert-butoxycarbonylamino)propionyl]amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (3.67 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:32][NH2:33].[CH2:34](O)[CH3:35]>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[CH:16]=[C:4]3[N:3]=[C:2]([NH:32][N:33]=[CH:22][C:17]4[CH:15]=[CH:16][CH:4]=[C:34]([CH3:35])[CH:18]=4)[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]3[N:14]=2)=[CH:18][CH:19]=1
Reactant: CCO
Reactant: NN
Reactant: COc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(-c2cc3nc(NN=Cc4cccc(C)c4)cc(N4CCOCC4)n3n2)cc1
Temperature: 150 °C
Reaction time: 0.42 h

Procedure:
There was suspended, in ethanol (2 mL), 5-chloro-2-(4-methoxy-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (64.8 mg, 0.188 mM) and then potassium carbonate (28.6 mg, 0.198 mM) and hydrazine monohydrate (91.2 μL, 1.88 mM) were added to the suspension. This suspension was stirred at 150° C. for 25 minutes under the irradiation with microwaves. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (22.1 μL, 0.188 mM) were added to the suspension and the mixture was stirred at room temperature for one hour. This reaction mixture was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (54.6 mg, overall yield of these two steps: 66%).
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][N:6]1[CH:11]([CH3:12])[CH2:10][O:9][CH2:8][CH:7]1[CH3:13])C.O.[NH2:16][NH2:17].[CH2:18](O)[CH3:19]>>[CH2:18]([CH:5]([N:6]1[CH:7]([CH3:13])[CH2:8][O:9][CH2:10][CH:11]1[CH3:12])[C:4]([NH:16][NH2:17])=[O:14])[CH3:19]
Reactant: NN
Reactant: CCOC(=O)CN1C(C)COCC1C
Reactant: CCO
Solvent: O
Product: CCC(C(=O)NN)N1C(C)COCC1C
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Ethyl-2-(3,5-dimethylmorpholino)acetate (0.19 g, 0.944 mmol) was dissolved in ethanol (4 mL) and hydrazine hydrate (0.047 g, 0.944 mmol) was added dropwise. The reaction mixture was stirred at 80° C. for 20 h and the reaction mixture was concentrated under reduced pressure to give the crude product, which was used without further purification in the subsequent step. (Crude yield: 97%). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 2H), 8.84 (s, 1H), 3.60-3.63 (m, 2H), 3.25-3.29 (m, 2H), 3.14 (s, 2H), 3.05 (s, 2H), 0.86-0.88 (m, 6H): LCMS m/z 188.12 [M+H]+, tR 4.716 min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1.[CH3:20][S:21][CH2:22][S:23]([CH3:25])=[O:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=[C:22]([S:21][CH3:20])[S:23]([CH3:25])=[O:24])[CH:15]=[N:14]1
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: CSCS(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CSC(=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)S(C)=O

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde (15 g) and methyl methylthiomethyl sulphoxide (6 ml) were heated under reflux in tetrahydrofuran (100 ml) containing Triton B solution (6 ml; 40% in methanol) for 12 hours. The mixture was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-methylthio-2-methylsulphinylvinyl)-2H-1,2,3-triazole, m.p. 122°-123°.