Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[C:5](=O)[N:6](C)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.N.[CH3:16][N:17]1[CH2:22]CC(=O)[CH2:19][CH2:18]1>CO>[CH3:16][N:17]1[CH2:18][CH2:19][C:5]2[N:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[CH2:22]1
Reactant: CN1CCC(=O)CC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: CN1CCc2ncc([N+](=O)[O-])cc2C1
Reaction time: 72 h
Yield: 58.7 %

Procedure:
3,5-Dinitro-1-methyl-2-pyridone (5.97 g; 30 mmol) was treated with 1.22M ammonia in methanol (300 ml) then 1-methyl-4-piperidone (3.73 g, 33 mmol) and the mixture heated at 60° for 5 h, then allowed to stand at ambient temp for 72 h. Evaporation in vacuo gave an orange/red residue which was triturated in dichloromethane and diethyl ether, collected by filtration, washed with diethyl ether and dried in air. Chromatography through silica gel, eluting with ethyl acetate, gave the title compound as a red solid (3.4 g, 59%).
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[CH:14]([O:17][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)([CH3:16])[CH3:15]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)Oc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of sodium (290 mg, 12.5 mmol) in isopropanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 25° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic phases were dried and evaporated to yield 540 mg (98%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@H:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCC[C@@H](O)CC(=O)OC(C)(C)C
Reactant: CCCCCCI
Product: CCCCCCC[C@@H](O)[C@@H](CCCCCC)C(=O)OC(C)(C)C

Procedure:
The target compound (1.80 g, 33%) was obtained in the same manner as in Production Example C-1, except that the (R)-3-hydroxydecanoic acid t-butyl ester (4.00 g, 16.4 mmol) obtained in Production Example B-5 and 1-iodohexane (5.20 g, 24.5 mmol) were used.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH2:22])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:30][N:31]1[CH:35]=[C:34]([S:36](Cl)(=[O:38])=[O:37])[N:33]=[CH:32]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH:22][S:36]([C:34]3[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=3)(=[O:38])=[O:37])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cn(C)cn3)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}amine (160 mg, 0.459 mmol) was dissolved in DMF (3 mL) and added pyridine (0.074 mL; 0.917 mmol). The reaction was stirred 5 min and added 1-methylimidazole-4-sulfonyl chloride (83 mg, 0.459 mmol). The reaction mixture was heated at 45° C. for two days. The reaction mixture was cooled to rt, added silica gel, and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 100% EtOAc to obtained the title compound as a white solid (150 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.12 (br. s., 1H), 8.49 (d, J=5.4 Hz, 1H), 7.52-7.83 (m, 2H), 7.51 (d, J=1.8 Hz, 1H), 7.28-7.43 (m, 1H), 7.25 (t, J=9.3 Hz, 1H), 7.05 (d, J=5.3 Hz, 1H), 3.58 (s, 3H), 3.00-3.23 (m, 1H), 1.35 (d, J=6.9 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[N:13]1([CH2:18][CH2:19]O)[CH:17]=[CH:16][N:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[N:13]1([CH2:18][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]3)=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: OCCn1ccnc1
Reactant: O=C1CCOc2cc(O)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCOc2cc(OCCn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.7 %

Procedure:
Under N2, a solution of 2.0 g (0.012 mol) of 7-hydroxy-4-chromanone (J. Org. Chem., 1994;59:1216) in 25 mL of THF was treated with 1.29 g (0.013 mol) of 2-(1H-1-imidazolyl)-1-ethanol and 3.15 g (0.012 mol) of triphenylphosphine. The solution was cooled in ice and treated over 10 minutes with a solution of 1.89 mL (0.012 mol) of diethyl azodicarboxylate in 5.0 mL of THF. After stirring at room temperature for 3 days, the solution was diluted with EtOAc and washed with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with a gradient of CHCl3 to CHCl3 /MeOH (96/4) gave the product which was recrystallized from EtOAc/hexane to give 0.92 g (29.7% yield) of a white solid, mp 128-130° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 259 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].Cl.Cl[CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37]>CC(N(C)C)=O>[CH3:37][N:33]1[CH2:34][CH2:35][CH2:36][CH:32]1[CH2:31][CH2:30][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CCc2ccccc2O)cc(OC)c1OC
Reactant: CN1CCCC1CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(CCc2ccccc2OCCC2CCCN2C)cc(OC)c1OC
Yield: 65 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(3,4,5-trimethoxyphenyl)ethyl]phenol (prepared as described in Preparation 28), 1.18 g of potassium t-butoxide and 0.958 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.900 g (yield 65%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1cc2cc[nH]c(=O)c2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Temperature: 120 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
To a solution of 11.0 g of 7-Fluoro-6-methoxy-2H-isoquinolin-1-one (57 mmol) in DMF (108 mL) was added potassium carbonate (11.8 g), followed by 10.6 g of 1-fluoro-4-nitrobenzene (75 mmol). The reaction mixture was stirred at 120° C. for 6 hr then poured onto ice water. The slurry was extracted with ether to remove excess pFPhNO2. The precipitate was collected by filtration, washed with ether and dried in vacuo to give 12.1 g (68%) of the product asa yellow solid. RP-HPLC: 4.79 min; ES-MS (M+H)+=315.0; 1H-NMR (DMSO-d6) δ (ppm): 4.0 (3H, s), 6.76 (1,d), 7.48 (d, 1), 7.53 (d, 1), 7.83 (d,2), 7.92 (d, 1), 8.38 (d, 2).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10]Cl)[N:6]=1)([CH3:4])[CH3:3].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:2]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1ccn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 37.4 %

Procedure:
0.77 g of 3-i-propyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.64 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 8 ml of N,N-dimethylformamide. 1.54 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from hexane-ethyl acetate to obtain 0.42 g of [(3-i-propyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (2), hereinafter) shown by below formula.
Reaction SMILES: [O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:11])[CH2:9]O.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K]>>[O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[CH2:11][N:35]1[C:31](=[O:41])[C:32]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:33]2[C:34]1=[O:36]
Reactant: C[C@@H](CO)CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: C[C@H](CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O

Procedure:
According to Scheme 2, (25R)-16β-26-dihydroxycholesterol (2) is selectively oxidized at the C-16 position to produce (25R)-16-oxo-26-hydroxycholesterol (9). Compound (9) is then converted to the monotosylate (25R)-16-oxo-26-hydroxycholesterol 26-tosylate (8) directly or by indirect means by solvolysis of (25R)-16-oxo-26-hydroxycholesterol 3β,26-diotsylate (7) derived from Compound 9. The C-26 tosylate of compound (8) is then displaced with potassium phthalimide to produce key compound (5) as described above. ##STR2##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:13].C(=O)([O-])[O-].[K+].[K+].F[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29].O>CN(C=O)C>[Cl:27][C:25]1[CH:26]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([S:13][C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CCS(=O)(=O)c1ccc(S)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from step (i) (1.60 g), potassium carbonate (0.934 g) and 2-fluoro-4-chloro-nitrobenzene (1.18 g) in DMF (20 ml) was stirred at RT overnight. Water (200 ml) was added and the mixture extracted with ethyl acetate. The organics were dried, evaporated under reduced and the residue purified by chromatography on silica eluting with isohexane/diethylether 4:1, yield 0.80 g.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:17]([N:19]([CH2:32][CH3:33])[CH2:20][CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])[CH3:18]>>[CH2:32]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:26])[CH3:33]
Reactant: CCN(CC)CCOc1ccccc1C(=O)Cl
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccccc1C(=O)c1c(-c2ccccc2)oc2ccccc12

Procedure:
Acylation of 2-phenylbenzofuran with 2-(2-diethylaminoethoxy)benzoyl chloride hydrochloride by the procedure described in Example 6 gives the title compound.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.CS([Cl:24])(=O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:24][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH3:9]
Reactant: CCC(O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.7 %

Procedure:
Under ice cooling, to a solution of 1-phenyl-1-propanol (1.0 g, 7.34 mmol) and N-ethyldiisopropylamine (1.42 g, 11.01 mmol) in dichloromethane (10 ml) was added methanesulfonyl chloride (690 μl, 8.81 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent:ethyl acetate/hexane:5/1) to give 1-chloro-1-phenylpropane (610 mg, 54%) as pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[C:5]2[CH2:18][CH2:19][C:20](O)=[O:21].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)=[C:5]2[CH2:18][CH2:19][C:20]([N:34]1[CH2:33][CH2:32][N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])[CH2:36][CH2:35]1)=[O:21]
Reactant: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(Cl)cc23)CC1

Procedure:
Prepared from 5-chloro-2-(4-chlorophenyl)-1H-indole-3-propanoic acid (Description 30) and 1-(2-methoxyphenyl)piperazine according to the method of Description 32. 1H NMR (250 MHz, CDCl3) δ 8.04 (1H, br s), 7.61 (1H, d, J 1.8 Hz), 7.48 (4H, m), 7.29 (1H, d, J 8.5 Hz), 7.17 (1H, dd, J 8.5, 1.8 Hz), 7.02 (1H, m), 7.00-6.82 (3H, m), 3.86 (3H, s), 3.78 (2H, t, J 4.9 Hz), 3.46 (2H, t, J 4.9 Hz), 3.24 (2H, t, J 7.9 Hz), 2.94 (2H, t, J 4.9 Hz), 2.79 (2H, t, J 4.9 Hz), and 2.68 (2H, t, J 7.9 Hz). m/z (ES+) 508, 510 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[N:4]=1
Reactant: COc1cc(OC)nc(N2CCN(Cc3ccccc3)CC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(OC)nc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
In 110 ml of ethanol was dissolved 3.9 g (0.0125 mole) of 4-(4,6-dimethoxy-2-pyrimidinyl)-1-benzylpiperazine obtained as described above, and 2.5 g of 5% palladium carbon was added thereto. While refluxing the mixture under heating, hydrogen gas was passed for 6 hours. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of chloroform:methanol=9:1) to obtain 1.38 g of 1-(4,6-dimethoxy-2-pyrimidinyl)piperazine as pale red crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Li+].[F:20][C:21]([F:37])([F:36])[C:22]1[N:27]=[C:26]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33]([O-])=[O:34])[CH:25]=[CH:24][CH:23]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:37])([F:20])[F:36])[N:27]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C([O-])c1ncoc1-c1cccc(C(F)(F)F)n1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Agent: [Li+]
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C(F)(F)F)n3)cn2)o1

Procedure:
Following general procedure Z3 followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(6-trifluoromethyl-pyridin-2-yl)-oxazole-4-carboxylic acid lithium salt. LC-MS-conditions 02: tR=0.92 min; [M+H]+=446.24.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][C:8]3[NH:9][N:10]=[C:11](C)[C:7]=3[C:4]=2[NH:5][N:6]=1.[CH3:15]O>>[CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][C:8]3[N:9]([CH3:15])[N:10]=[CH:11][C:7]=3[C:4]=2[NH:5][N:6]=1
Reactant: Cc1n[nH]c2c1ccc1[nH]nc(C)c12
Reactant: CO
Product: Cc1n[nH]c2c1ccc1c2cnn1C
Yield: 70 %

Procedure:
1,6-Dihydro-3,8-dimethylbenzo[1,2-c:3,4-c']dipyrazole as a light-lavender powder melting at above 290° C. The product powder (70% yield) was obtained by trituration of the crude product in hot methanol followed by cooling.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:10]2[C:6]([S:7][C:8]([C:11]3[C@H:12]([CH3:35])[C@@H:13]4[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]4[C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])=[CH:9]2)=[C:5]([S:36][CH3:37])[N:4]=1.ClC1C=CC=C(C(OO)=[O:46])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[OH:33][C@@H:31]([C@H:30]1[C:29](=[O:34])[N:14]2[C:15]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:17])=[C:11]([C:8]3[S:7][C:6]4=[C:5]([S:36]([CH3:37])=[O:46])[N:4]=[C:3]([S:2][CH3:1])[N:10]4[CH:9]=3)[C@H:12]([CH3:35])[C@H:13]12)[CH3:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(SC)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc(S(C)=O)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
4-Nitrobenzyl(1S,5R,6S)-2-[5,7-bis(methylthio)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (140 mg) was dissolved in 2.5 ml of dichloromethane. m-Chloroperbenzoic acid (56 mg) was added to the solution. The mixture was stirred at room temperature for 15 min. An aqueous sodium thiosulfate solution (5 ml) was added thereto, followed by separation. The organic layer was washed with 10 ml of a semisaturated aqueous sodium hydrogencarbonate solution and 10 ml of semisaturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 97 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfinyl-5-methylthioimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].FC(F)(F)C(O)=O.[C:17]1([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(S)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
2-Chloro-4-fluoro-benzenethiol (250 g, 1.54 mol) was dissolved in dichloromethane (1.25 L) and trifluoroacetic acid (120 mL, 1.57 mol) followed by triphenylmethanol (400 g, 1.54 mol) were added at room temperature (ice bath cooling necessary during addition of triphenylmethanol). The mixture was stirred for 1.5 h at room temperature, concentrated and dried in vacuo to yield the title compound as a yellow solid (622 g, 99% purity by HPLC, 99%), that was used without further purification in the next step. 1H NMR (CDCl3, 400 MHz): δ 6.55 (ddd, J=2.9 Hz, 8.0 Hz, 8.9 Hz, 1H), 6.91 (dd, J=6.2 Hz, 8.9 Hz, 1H), 6.97 (dd, J=2.9 Hz, 8.6 Hz, 1H), 7.20-7.27 (m, 9H), 7.34-7.39 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][C:60]([F:64])([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][C:60]([F:64])([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of 1-[9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (110 mg, 0.27 mmol), 1,1′-(azodicarbonyl)dipiperidine (137 mg, 0.54 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.136 mL, 0.54 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.197 mL, 2.70 mmol) was added to the reaction mixture. The mixture was stirred at 60° C. for 6 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (43.3 mg, 0.089 mmol, 33%) as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=[CH:7][C:6]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:3])[CH3:2].[N+:37]([O-])([OH:39])=[O:38]>C(O)(=O)C>[N+:37]([C:8]1[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:7]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCOc1ccc(OCCCCCCCCCCCC)c(NC(C)=O)c1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOc1cc([N+](=O)[O-])c(OCCCCCCCCCCCC)cc1NC(C)=O
Temperature: 25 °C

Procedure:
The product of Stage 3 (22.8 g) is suspended in 250 ml of glacial acetic acid. 4.9 ml of nitric acid of density 1.39 are added dropwise with stirring at room temperature, the mixture becoming pasty. Following the addition of another 50 ml of glacial acetic acid, the mixture is stirred for a few hours and filtered under suction. The filtered residue is suspended twice with acetonitrile, filtered under suction and dried.