Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH2:10][C:11]#[CH:12])[C:7](=[O:13])[CH2:6]1)(=[O:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH2:20]=O.[OH-].[NH4+]>C(O)(=O)C.O1CCOCC1>[C:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH2:10][C:11]#[C:12][CH2:20][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7](=[O:13])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C#CCN1C[C@@H](OC(C)=O)CC1=O
Reactant: C1CCNCC1
Reactant: C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC(=O)N(CC#CCN2CCCCC2)C1
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g of (S)-4-(acetyloxy)-1-(2-propynyl)-2-pyrrolidinone, 20 ml of dry dioxane, 1.64 ml of piperidine, 0.66 g of paraformaldehyde, 3.0 ml of acetic acid and 42 mg of cupric chloride was stirred for 30 minutes and then heated at reflux for 45 minutes. The mixture was basified to pH 10 with ammonium hydroxide and then extracted with 5×50 ml of dichloromethane The extracts were combined, dried, filtered and concentrated with toluene in vacuo. The residual oil was chromatographed on deactivated alumina, giving 2.3 g of the desired product as a pale yellow oil [α]D26° =-17° (dichloromethane).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:34](=O)[C:35]1[O:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[O:39]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH:34]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=Cc1ccco1
Reactant: O=C(O)CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCC=Cc1ccco1
Yield: 45 %

Procedure:
This compound was synthesized from 10-carboxydecyltriphenylphosphonium bromide (10.50 g, 20 mmol) and furfural (1.92 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization afforded the product (2.38 g, 45%) as pale yellow crystals (mp 38°-39° C.); IR: 3450-2500, 1715, 695 cm-1 ; 1H-NMR: 1.35 (m, 14H), 2.35 (t, 4H), 5.60 (m, 1H), 6.30 (m, 3H), 7.35 (s, 1H), 9.40 (bs, 1H). Anal. Calcd. for C16 H24O3 : C, 72.69, H, 9.15; Found: C, 72.44, H, 9.06%. Z:E=43:57.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>CCOCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1
Reactant: C1=COCCC1
Reactant: COC(=O)C1CCCC(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1CCCC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a solution of methyl 3-hydroxycyclohexanecarboxylate [J. Am. Chem. Soc., 70, 1898 (1948)] (61 g) in ether (500 ml), 2,3-dihydropyran (49 g) and p-toluenesulfonic acid monohydrate (1 g) were added. The mixture was stirred at room temperature for 6 hours and washed with water and dried (MgSO4). The ether was distilled off, and the oily residue was distilled under reduced pressure to give methyl 3-(2-tetrahydropyranyloxy)cyclohexanecarboxylate (61.5 g, 60.2%, b.p. 120°-123° C./0.3 mmHg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCCCCC>[Cl:23][CH2:24][C:25]([O:22][C@@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]1[C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: O[C@@H]1CCCC[C@H]1c1cc(Cl)ccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.7 %

Procedure:
In a 1 L round bottom flask equipped with a magnetic stirrer, thermometer and condenser is placed 50 g (0.15 mol) of trans-2-(2'-benzyloxy-5'-chlorophenyl)cyclohexanol. This is dissolved in 200 ml of methylenechloride, and then 18 g (0.16 mol) of chloracetyl chloride is added followed by 0.14 g (0.001 mol) of 4-dimethylaminopyridine. The mixture is heated to reflux and monitored by TLC (20% ethyl acetate, hexane). After 4 hours TLC shows the reaction to be complete, it is cooled to room temperature and 200 ml of saturated sodium bicarbonate is added. The reaction mixture is stirred rapidly for another 3 hours. The organic phase is then separated, dried with anhydrous potassium carbonate, filtered and evaporated under reduced pressure to yield 70 g of an amber oil. This oil is dissolved in 100 ml of hexane from which it crystallizes to afford 47 g of an off-white solid trans-2-(2'-benzyloxy-5'-chloro-phenyl)cyclohexyl chloroacetate, which is used directly in the next step.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[CH2:19][CH2:20][OH:21])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]([O:4][CH3:5])=[O:3])[CH2:15][CH:14]1[CH2:19][CH2:20][OH:21])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1

Procedure:
A solution of methyl chloroformate (0.52 ml, 6.73 mmol) in dichloromethane (5 ml) was added dropwise over 0.1 h to a stirred solution of (RS)-1-(tert-butyloxycarbonyl)-2-(2-hydroxyethyl)piperazine (D6) (1.4 g, 6.09 mmol) and triethylamine (1.7 ml, 12.2 mmol) in dichloromethane (45 ml) at 0° C. under argon. The resultant mixture was stirred at room temperature for 18 h, washed with saturated sodium hydrogen carbonate and the organic layer dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10–100% ethyl acetate in hexane to give the title compound as a colourless gun (1.36 g, 78%). 1H NMR (CDCl3) δ: 1.48 (9H, s), 1.60–1.95 (2H, m), 2.80–3.00 (2H, m), 3.05–3.45 (2H, m), 3.50–3.70 (2H, m), 3.70 (3H, s), 3.75–4.45 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]1[NH:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:25]3[CH2:24][CH2:23][N:22]([CH2:26][C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:28])[CH2:21][CH2:20]3)=[O:17])[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCOCC3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-(4-morpholido)-2-piperazinoethanone to give 4-chloro-N-(4-{2-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide, using general procedure A. Amorphous off-white solid. MS 492.3 ([M+H]+)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@@H:4]([C:17]([O:19][CH3:20])=[O:18])[CH2:3]1.C1N=CN([C:26]([N:28]2[CH:32]=N[CH:30]=[CH:29]2)=[O:27])C=1.C1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)CCN1>C(Cl)Cl>[CH2:32]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:30][CH2:29][N:28]1[C:26]([O:1][C@H:2]1[CH2:3][C@H:4]([C:17]([O:19][CH3:20])=[O:18])[N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6]1)=[O:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1ccc2c(c1)CCNC2
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OC(=O)N2CCc3ccccc3C2)CN1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
Compound 19 (1.28 g, 4.6 mmol) dissolved in DCM (20 ml) is added dropwise into CDI (0.75 g, 4.6 mmol) solution in DCM (30 ml). After stirring for 2 hr, 1,2,3,4-tetrahydroisoquinoline (0.644 ml, 4.6 mmol) is added and the mixture is stirred over night. The solvent is removed and residue applied to flash chromatography on silica gel (Hex/ethyl acetate, 2/1 to 1/1). Compound 20 (1.8 g, 90%) is obtained as pale yellow syrup.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:23])[O:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])(C(C)(C)C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=1F)[C:28]([N:30]1[CH2:33][CH2:32][CH2:31]1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:30]1([C:28]([C:27]2[CH:34]=[CH:35][C:36]([O:22][C:20]3[CH:19]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:23])[CH2:9][OH:8])[CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])=[C:25]([F:24])[CH:26]=2)=[O:29])[CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(O[C@@H](C)CO)c1
Temperature: 160 °C

Procedure:
To a portion of methyl 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-hydroxybenzoate (102 mg, 0.3 mmol) and 1-(3,4-difluorobenzoyl)azetidine (71 mg, 0.36 mmol) in DMF (2.0 mL) was added potassium carbonate (207 mg, 1.5 mmol) and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 120 minutes. The mixture was allowed to reach ambient temperature and pressure then partitioned between ethyl acetate (2×25 mL) and water (25 mL). The organic layer was separated, washed with brine, dried (MgSO4), and evaporated in vacuo to give the crude product which was used without further purification (100 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](O)=[O:14])=[O:4].[CH3:22]O>>[CH3:1][O:2][C:3]([N:5]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([O:14][CH3:22])=[CH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=2)=[O:4]
Reactant: COC(=O)N(c1ccccc1)c1ccccc1CC(=O)O
Reactant: CO
Product: COC(=O)N1c2ccccc2C=C(OC)c2ccccc21
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of [2-(methoxycarbonyl-phenyl-amino)-phenyl]-acetic acid (16 g, 55.5 mmol) and polyphosphoric acid (29 g, 167 mmol in terms of P2O5) is heated to 100° C. for 4 hours. To the reaction mixture, methanol (50 ml) is added dropwise at 65° C. with stirring. The resulting suspension is cooled to room temperature, filtered and washed with methanol (40 ml). The white crystals are dried to yield 12.2 g of pure title compound (80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N+:16]([O-:18])=[O:17])=[C:8]([C:12]([O:14]C)=[O:13])[NH:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.C(OCC)(=O)C>C(O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N+:16]([O-:18])=[O:17])=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1[nH]c2cc(OC)ccc2c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2c([N+](=O)[O-])c(C(=O)O)[nH]c2c1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-methoxy-3-nitroindole-2-carboxylate (step 1) in ethanol (10 ml) and water(5 ml) was added K2CO3 and the mixture was stirred for 4 hr at 40° C. The mixture was acidified with 2N HCl and extracted with ethyl acetate (20 ml×2). The organic layer was washed with brine (10 ml) and dried (MgSO4). Removal of solvent gave product as an oil. tlc: Rf=0.1 (50% ethyl acetate in hexanes)
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8]([OH:19])[CH2:9][CH2:10][CH2:11][CH:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13])[CH:3]=[CH2:4].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C1C=CC=CC=1.CCOCC.[O-2].[O-2].[Mn+4]>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:4][CH2:3][C:2]1([OH:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH2:9][CH2:10][CH2:11][CH:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13])[O:19]1)[CH3:21]
Reactant: CCNCC
Reactant: C=CC(O)CCCC(O)CCCC(C)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCN(CC)CCC1(O)CCCC(CCCC(C)OC(C)(C)C)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
41.3 G. of 3,7-dihydroxy-11-tertiarybutoxy-dodec-1ene produced in Example 121 was dissolved in benzene solution and added to a slurry of 320 g. of activated manganese dioxide in 1600 ml. of benzene containing 120 ml. of diethylamine. The reaction mixture was stirred at room temperature for 20 hours and filtered free of solids. Removal of the solvents in vacuo gave a pale brown oil. The oil was dissolved in ether and extracted with aqueous 1N hydrochloric acid. Sodium hydroxide was added to the acid extract. Extraction into ether and evaporation of the solvent affords 2-[2'-diethylaminoethyl]-6-[4-t-butoxypentyl]-2-tetrahydropyranol.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[C:28]([C:29]#[C:30][C:31]([C:34]2[CH:38]=[C:37]([CH:39]=O)[O:36][N:35]=2)([OH:33])[CH3:32])=[CH:27][C:15]2[C:16]3[N:17]([CH:21]=[C:22]([C:24]([NH2:26])=[O:25])[N:23]=3)[CH2:18][CH2:19][O:20][C:14]=2[CH:13]=1.O.[CH3:42]C#N>C1(C)C=CC=CC=1.O1CCCC1>[F:11][C:12]1[C:28]([C:29]#[C:30][C:31]([OH:33])([C:34]2[CH:38]=[C:37]([CH:39]=[CH2:42])[O:36][N:35]=2)[CH3:32])=[CH:27][C:15]2[C:16]3[N:17]([CH:21]=[C:22]([C:24]([NH2:26])=[O:25])[N:23]=3)[CH2:18][CH2:19][O:20][C:14]=2[CH:13]=1
Reactant: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C=O)on1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of KHMDS (0.9 mL, 3.20 equiv) in toluene (0.5M) was added dropwise to a stirred solution of Ph3PCH3I (180 mg, 3.02 equiv) in tetrahydrofuran (3 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 30 min. To this was added a solution of 9-fluoro-10-(3-(5-formylisoxazole-3-yl)-3-hydroxybut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (60 mg, 0.15 mmol, 1.00 equiv) in tetrahydrofuran (0.2 mL) dropwise at 0° C. The resulting solution was stirred for 3 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mmol NH4HCO3 and CH3CN (25% CH3CN up to 40% in 10 min, up to 95% in 2 min, down to 25% in 2 min); Detector, UV 254/220 nm giving the titled compound (10%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1)=[O:5].[Cl:19]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:17]([OH:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1)=[O:5]
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1c(O)cc(Cl)cc1C(=O)Nc1ccc(Br)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
2-Amino-N-(5-bromo-2-pyridyl)-3-hydroxybenzamide (1.99 g) and 990 mg of N-chlorosuccinimide were dissolved in 30 ml of N,N-dimethylformamide, the solution was stirred at 50° C. for 2 hours and the insoluble matter was filtered off. The solvent was evaporated in vacuo, water was added to the resulting residue and the precipitate was collected by filtration. This was dried in vacuo, purified by means of a silica gel column chromatography, water was added to the resulting crudely purified product and the resulting precipitate was collected by filtration and dried in vacuo to give 1.12 g of 2-amino-N-(5-bromo-2-pyridyl)-5-chloro-3-hydroxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[C:12]([C:16]4[CH:20]=[C:19]([C:21](O)=[O:22])[O:18][N:17]=4)[CH:13]=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1.Cl.[CH3:27][O:28][C:29](=[O:35])[C@@H:30]([NH2:34])[CH2:31][O:32][CH3:33]>>[CH3:27][O:28][C:29](=[O:35])[C@@H:30]([NH:34][C:21]([C:19]1[O:18][N:17]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)[CH:11]=2)[CH:20]=1)=[O:22])[CH2:31][O:32][CH3:33]
Reactant: COC[C@H](N)C(=O)OC
Reactant: O=C(O)c1cc(-c2cccc(Nc3nc4ccc(F)cc4s3)c2)no1
Agent: Cl
Product: COC[C@H](NC(=O)c1cc(-c2cccc(Nc3nc4ccc(F)cc4s3)c2)no1)C(=O)OC
Yield: 68 %

Procedure:
The title compound was prepared according to the procedure as set forth in Example 5, except that 3-[3-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-isoxazole-5-carboxylic acid was used instead of the compound of Example 2 and (S)-2-amino-3-methoxy-propionic acid methyl ester hydrochloride was used instead of (S)-Val-OMe.HCl to yield 68% of the title compound. Mass (ES+): 471 (M++1), 493 (M++Na); IR (KBr): 3319, 2929, 1740, 1670, 1571, 1474; 1H NMR (DMSO-d6) δ: 3.29 (s, 3H), 3.67 (s, 3H), 3.74 (m, 2H), 4.74 (m, 1H), 7.18 (m, 1H), 7.53 (m, 2H), 7.62 (dd, 1H), 7.72 (s, 1H), 7.76 (dd, 1H), 7.95 (m, 1H), 8.32 (s, 1H), 9.39 (d, 1H), 10.70 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].COCCOC.[Li+].[N:29]1[CH:34]=[CH:33][C:32](B([O-])[O-])=[CH:31][CH:30]=1.[Li+].C(=O)([O-])[O-].[Na+].[Na+]>O>[ClH:8].[CH3:1][N:2]1[C:7]([C:32]2[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=2)=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21]
Reactant: [O-]B([O-])c1ccncc1
Reactant: Cn1c(Cl)c(-c2ccccc2)nc(-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cl
Product: Cn1c(-c2ccncc2)c(-c2ccccc2)nc(-c2ccccc2)c1=O
Yield: 31.6 %

Procedure:
To a solution of 1-methyl-3,5-diphenyl-6-chloro-1H-pyrazin-2-one (0.5 g) in 3:1 ethylene glycol dimethylether : water (30 cm3), under nitrogen, was added sequentially 4-pyridyl boronic acid lithium salt (0.42 g), sodium carbonate (0.72 g) and tetrakis-triphenylphosphine palladium (0.07 g). The reaction was heated at reflux, under nitrogen, overnight. The solvents were evaporated and the residue partitioned between water and 5% methanol/dichloromethane. The organic phase was separated, dried over magnesium sulphate and evaporated in vacuo. The residue was subjected to silica gel chromatography using 2% methanol/dichloromethane as eluant. The product was treated with hydrogen chloride in methanol and recrystallised from ethyl acetate/diethyl ether to afford 1-methyl-3,5-diphenyl-6-(4-pyridyl)-1H-pyrazin-2-one hydrochloride(0.2 g ; 32%) as yellow crystals. Found C, 70.50; H, 4.90; N, 11.20% C22H17N3O.HCl requires C, 70.30; H, 4.83; N, 11.18%.m/e (ES+) 340 (M+H)+.
Reaction SMILES: [Ca:1].C(=O)([O-])[O-].[Ca+2].[N+:7]([O-:10])([OH:9])=[O:8]>>[N+:7]([O-:10])([O-:9])=[O:8].[Ca+2:1].[N+:7]([O-:10])([O-:9])=[O:8].[N+:7]([O-:10])([O-:9])=[O:8].[NH4+:7]
Reactant: [Ca]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=[N+]([O-])[O-]
Product: [NH4+]

Procedure:
A liquid calcium nitrate solution 32 is produced by reacting a calcium source, for example calcium carbonate with nitric acid. In this embodiment of the invention a 60% nitric acid solution is neutralised with lime stone (CaCO3). A slight excess of nitric acid is used to convert all of the lime. Undissolved impurities are then removed by filtration and excess nitric acid in the solution is neutralised with ammonia. The filtered solution thus contains an amount of ammonium nitrate. Conditions are operated to give a typical mole ratio of 5 moles calcium nitrate and 1 mole ammonium nitrate in solution.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:10][C:11](=O)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:8][CH3:9]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][NH:10][CH2:7][CH2:8][CH3:9])=[CH:15][CH:16]=1
Reactant: CCCNC(=O)CCc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCNCCCc1ccc(OC)cc1
Temperature: 50 °C

Procedure:
To a stirred mixture of LiAlH4 (8.0 g, 200 mmol) in tetrahydrofuran (100 mL) was added dropwise a solution of 3-(4-methoxyphenyl)-propionic acid n-propyl amid (10.7 g, 49 mmol) (from a) above) in tetrahydrofuran (100 mL). After refluxing for 12 h the mixture was cooled to 50° C. and excess hydride was destroyed by careful addition of water (10 mL), 5% aqueous NaOH (40 mL) and water (20 mL) allowing reflux conditions. The hot slurry was filtered and the white precipitate was washed thoroughly with ethanol. Volatiles were evaporated and the resulting oil dissolved in ethyl acetate (50 mL) what was extracted with 0.5 N aqueous HCl (4×50 mL). The acidic phase was made alkaline (pH=9) by addition of 30% aqueous NaOH and extracted with ethyl acetate (4×50 mL). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to dryness to give an oil that partially crystallized in diethyl ether as the hydrochloride salt. Recrystallization from acetone/diethyl ether gave white flacky crystalline material. Total yield (as free base): 9.9 g, 48 mmol, 98%, mp 176–177° C. IR (neat) cm−1 2960, 2772, 1611, 1514; 1H-NMR (CDCl3) δ 9.46 (br s, 1H), 7.16 (d, 2H), 6.90 (d, 2H), 3.72 (s, 3H), 2.82 (br s, 4H), 2.59 (t, 2H), 2.15 (p, 2H), 1.83 (h, 2H), 0.89 (t, 3H) ppm; 13C-NMR (CDCl3) δ 156.6, 130.3, 127.7, 112.4, 53.7, 47.9, 45.66, 30.3, 25.9, 17.8, 9.7 ppm; MS (EI) m/z 207 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH:28]1([CH2:31]Br)[CH2:30][CH2:29]1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][CH2:31][CH:28]1[CH2:30][CH2:29]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(OCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
A solution of ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (4.1 g, 11.26 mmol) was taken in 50 ml of DMSO and to it added Cs2CO3 (3.02 g, 12.39 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then added cyclopropylmethyl bromide (1.67 g, 12.39 mmol) dropwise. After completion of addition, the reaction mixture was stirred at 70° C. for 4 h. After completion of the reaction, it was poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:3) as eluent provided 3 g of ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.20 (s, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45(d,2H),1.95-2.00(m,1H), 1.75-1.80(m,1H), 1.45-1.50(m,1H), 1.20 (t,3H), 1.00 (m, 6H), 0.35-0.25 (m,5H). Mass: (414, M+1, 100%).
Reaction SMILES: N1NN=NC=1C1NN=C2C=1C[C@@H]1C[C@@H]12.[CH2:15]1[C@H:17]2[CH2:18][C:19]3[C:23]([C@@H:16]12)=[N:22][NH:21][C:20]=3[C:24]([OH:26])=[O:25]>>[N:22]1[NH:21][C:20]([C:24]([OH:26])=[O:25])=[C:19]2[C@H:18]3[CH2:15][C@H:17]3[CH2:16][C:23]=12
Reactant: O=C(O)c1[nH]nc2c1C[C@@H]1C[C@H]21
Agent: C1c2c(n[nH]c2-c2nn[nH]n2)[C@H]2C[C@@H]12
Product: O=C(O)c1[nH]nc2c1[C@H]1C[C@H]1C2

Procedure:
(1aS,5aS)-4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; and (1aS,5aS)-1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid.