Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:12]([NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: Clc1nccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CNc2nccc3ccccc23)cc1
Reaction time: 4 h

Procedure:
1-Chloroisoquinoline (1.64 g, 0.01 mol) and benzylamine (2.14 g, 0.02 mol) were mixed at room temperature and heated, with stirring, in an oil-bath at 50° for 4 hours. The mixture was cooled to give a crystalline solid which was equilibrated between methylene chloride (CH2Cl2) and aqueous Na2CO3. The CH2Cl2 fraction was washed with water, dried and evaporated to dryness to give an oil which crystallised on standing (3.0 g). This material was twice re-crystallised from ether/40-60 petroleum ether to give the title compound as buff crystals, m.p. 101°-102°.
Reaction SMILES: [NH2:1][C:2]1(C(OCC)=O)[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]2[C:16]([CH3:20])=[C:17]([CH3:19])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)C.O>[NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:6]2[C:16]([CH3:20])=[C:17]([CH3:19])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12
Reactant: CCOC(=O)C1(N)N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(N)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.5 %

Procedure:
Ethyl (6-amino-4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)- carboxylate (11 g) was dissolved in a mixed solution of ethanol (250 ml) and water (80 ml). Barium hydroxide octahydrate (8.4 g) was added and the mixture was stirred at room temperature for 24 hours. The solvent was distilled away under reduced pressure, and water (100 ml) was added. The pH of the mixture was adjusted to 2 with 1N hydrochloric acid and stirred for 20 minutes. The mixture was neutralized with an aqueous solution of sodium hydrogencarbonate and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel column chromatography. The solvent was distilled away, the resulting residue was crystallized from diisopropyl ether, and the crystals were filtrated to give 7 g of 6-amino-4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, melting point 192°-197° C. with decomposition.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
After heating and refluxing 1.4 g (8.0 mmol) of 4-acetoxybenzoic acid and 6 ml of thionyl chloride, surplus thionyl chloride was removed, and 4-acetoxybenzoic acid chloride was obtained. Then, a mixed solution of 1.7 g of the hydrazide obtained in Step 1, 1 ml of pyridine and 15 ml of dioxane was added to the 4-acetoxybenzoic acid chloride and the mixture was heated and refluxed for two hours. After the reaction was completed, 2.6 g (7.0 mmol) of dihydrazide was obtained by pouring a 50 ml solution of salt, filtering and cleaning the crystals which had deposited, by water and methanol.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28](Cl)[CH:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:18][CH:17]=2)[CH:27]=[N:26]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(OCc2ccc(CCCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a dry 25 mL round bottom flask, fitted with a reflux condenser, was added the product of Example 2D (0.41 g, 1.4 mmol), 2-tert-butyl-4,5-dichloro-2H-pyridazin-3-one (0.93 g, 4.2 mmol), cesium carbonate (1.37 g, 4.2 mmol), and anhydrous dimethylformamide (11 mL). The reaction flask was placed in a 68° C. oil bath and the reaction was stirred for 12 hours. The reaction flask was removed from the oil bath and allowed to cool. The mixture was diluted with ethyl acetate, transferred to a separatory funnel and washed with water (25 mL, 5×). The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.3 g of crude product. Column chromatography [silica gel; eluent hexanes-ethyl acetate (9:1)] provided the desired product (594 mg, 89%). 1H (CDCl3) δ(ppm): 0.05 (s, 6H); 0.90 (s, 9H); 1.64 (s, 9H); 2.65 (t, 2H); 3.64 (t, 2H); 5.23 (s, 2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, 1H). 13C (CDCl3) δ(ppm): 18.57, 26.19, 27.75, 28.09, 32.58, 35.61, 63.14, 66.57, 72.14, 118.46, 125.41, 127.44, 129.23, 132.38, 143.72, 154.02, 159.30.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][O-:16].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([O:16][CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[O-]
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: [Na+]
Solvent: CO
Product: COc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 285 mg, 1.038 mmol), sodium methoxide (1.402 mL, 5.19 mmol) in MeOH (5 mL) was stirred at rt for 3 days. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and concentrated to afford a yellow solid that was chromatographed on a 24 gm silica gel cartridge, eluting with a 0-100% EtOAc/hexanes gradient. Fractions containing the product were concentrated to afford the title compound (112 mg, 0.405 mmol, 39.0% yield) as a yellow solid. HPLC (condition M): retention time=1.70 min.; LCMS (ES+) m/z: 271.9 (bromine pattern); H 1NMR (400 MHz, CDCl3) δ ppm 4.44 (s, 3 H), 5.71 (brs, 1 H), 6.99 (d, J=1.8 Hz, 1 H), 7.22 (brs, 1 H), 7.81 (d, J=1.8 Hz, 1 H), 8.69 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH:10]([F:12])[F:11])=[CH:4][C:3]=1[OH:13].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH:10]([F:11])[F:12])=[CH:4][C:3]=1[O:13][CH2:15][CH:16]1[CH2:18][CH2:17]1
Reactant: BrCC1CC1
Reactant: Oc1cc(OC(F)F)c(F)cc1Br
Product: Fc1cc(Br)c(OCC2CC2)cc1OC(F)F

Procedure:
Starting from 2-bromo-5-(1,1-difluoro-methoxy)-4-fluoro-phenol (example A5) and bromomethyl-cyclopropane the title compound is obtained as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH:16]([O:19][CH3:20])[O:17][CH3:18].N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27](=[O:29])[CH3:28])=[C:3]([CH:16]([O:17][CH3:18])[O:19][CH3:20])[CH:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)Cl
Reactant: COC(OC)c1cc(C(=O)c2ccccc2)ccc1N
Solvent: c1ccncc1
Solvent: O
Product: COC(OC)c1cc(C(=O)c2ccccc2)ccc1NC(C)=O
Yield: 100 %

Procedure:
To a stirred and cooled (10° C.) solution of 22.1 parts of intermediate 64, namely [4-amino-3-(dimethoxymethyl)phenyl] phenylmethanone, in 147 parts of pyridine were added dropwise 12.1 parts of acetyl chloride. After stirring for 1/2 hour at 10° C. and overnight at room temperature, the reaction mixture was poured into water. The product was extracted with 2,2'-oxybispropane and dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was dissolved in dichloromethane. This solution was washed successively with HCl 0.1N, ammonia and water and was then dried, filtered and evaporated, yielding 27.5 parts (100%) of N-[4-benzoyl-2-(dimethoxymethyl)phenyl]acetamide (interm. 65).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 71.9 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.10 g, 0.46 mmol), valeryl chloride (0.055 mL, 0.46 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (12 mL) provided N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-ylpentanamide (0.099 g). MS m/z 300 ([M+H]+); HRMS: calcd for C19H25NO2 +H+, 300.19581; found (ESI, [M+H]+), 300.1950.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>C(#N)C>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2ncccn2)c(OC)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
Potassium carbonate (2.97 g, 21.5 mmol) was added to a mixture of 2-chloropyrimidine (2.1 g, 17.9 mmol), 2,4-dimethoxybenzylamine (3.0 g, 17.9 mmol) and acetonitrile (20 mL). The reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and partitioned between ethyl acetate (150 mL) and water (10 mL). The organic phase was washed with water (2 10 mL) and brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in diethyl ether (20 mL), washed with hexanes (20 mL) and purified by column chromatography, eluting with a 0-100% gradient of ethyl acetate in hexanes to afford N-(2,4-dimethoxybenzyl)pyrimidin-2-amine as a pale yellow solid in 84% yield (3.70 g): MS (ES+) m/z 245.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(-c2ccc(F)cc2)cc1Nc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 11.1 %

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 4-fluorophenylboronic acid 45 mg, sodium carbonate 57 mg and polymer-carried bis(acetato)triphenylphosphine palladium (II) 31 mg at room temperature, and it was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. 1.0 mol/L Sodium hydroxide aqueous solution 1.0 mL and ethanol 3.0 mL were added to the obtained residue, and it was stirred at room temperature for 1 hour. 6.0 mol/L Hydrochloric acid was added to the reaction mixture, solid matter was filtrated, and it was refined by silica gel column chromatography [Trikonex company, Flash Tube,2008, eluent; hexane:ethyl acetate:acetic acid=20:10:1] to give 2-(4-fluoroanilino)-4-(4-fluorophenyl)benzoic acid 7.8 mg of pale yellow solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccc(Cl)cc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.45 g of 4-chlorobenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 40 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of 50% ethanol yielded 0.43 g of 4-chloro-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as colorless crystals.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH:6]1[C:11](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[C:8]([OH:17])[CH:7]=1>N1C=CC=CC=1>[CH:6]1[C:11](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[C:8]([O:17][S:2]([OH:5])(=[O:4])=[O:3])[CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: O=S(=O)(O)Cl
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(OS(=O)(=O)O)cc1
Temperature: 0 °C

Procedure:
Chlorosulfonic acid is added to the pyridine solution to form a reaction mixture. Preferably, the chlorosulfonic acid is added dropwise while maintaining the cooled temperature. About 1 mole of chlorosulfonic acid per mole of coumaric acid may be used. A slight excess is acceptable. Due to the reaction's exothermic nature, the reaction mixture is preferably stirred at the cooled temperature, e.g., about 0° C., for a time sufficient to allow the p-coumaric acid and the chlorosulfonic acid to react and form zosteric acid. Preferably, the reaction mixture is stirred for about 2 to about 4 hours at the low temperature, more preferably about 2.5 to about 3 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][N:19]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:21]=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 24 h
Yield: 43.5 %

Procedure:
5-Bromo-2-nitropyridine (1 g, 4.93 mmol) was dissolved in DMF (32 ml) and cooled to 0° C. Cesium carbonate (2.408 g, 7.39 mmol) was added, followed by 2-chloro-4-hydroxypyridine (0.702 g, 5.42 mmol). The mixture was stirred in an 80° C. oil bath for 24 hours. The reaction mixture was then cooled to RT, diluted with ethyl acetate (150 mL), washed with water (2×100 mL) and brine (50 mL), dried (MgSO4), evaporated under reduced pressure and purified via silica gel chromatography (ethyl acetate-hexanes) to yield 2-chloro-4-(6-nitropyridin-3-yloxy)pyridine as a clear oil (0.540 g, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, 1H), 8.41 (m, 2H), 8.06 (d, 1H), 7.37 (d, 1H), 7.23 (dd, 1H); MS (ESI) m/z: 252.0 (M+H+).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]1[CH2:9][CH2:10]2)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:6][CH:7]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]1[CH2:9][CH2:10]2)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COS(C)(=O)=O)C2
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1C(CN=[N+]=[N-])C2
Temperature: 100 °C
Yield: 92.8 %

Procedure:
To the title compound of step A (3.4 g, 11.1 mmol) in DMF (15 mL) was added sodium azide (2.1 g, 33.4 mmol). The mixture was heated at 100° C. overnight, cooled to rt, poured into H2O and extracted with DCM. The combined organics were washed with brine and dried (Na2SO4). Purification via silica gel chromatography (10% EtOAc in petroleum ethers) gave the title compound (2.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: CCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Yield: 43 %

Procedure:
The reaction of 2,5-dihydroxybenzoic acid methyl ester with 1-bromotetradecane under conditions described in Example 58 gave 2-(hydroxy-5-(tetradecyloxy)benzoic acid methyl ester (43% yield, mp 49°-53°). The nmr and mass spectra were compatible with the structure.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:15]1[N:19]=[N:18][C:17]([C:20]([F:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23]CC)=[O:22])=[N:16]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O>[CH2:3]([N:15]1[N:19]=[N:18][C:17]([C:20]([F:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([OH:23])=[O:22])=[N:16]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCn1nnc(C(F)(C(=O)OCC)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCn1nnc(C(F)(C(=O)O)c2ccccc2)n1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
NaOH (0.12 g, 3 mole) was added in one portion to a stirred solution of 2-dodecyl-α-fluoro-α-phenyl-2H-tetrazole-5-acetic acid, ethyl ester (0.59 g, 1.4 mole) dissolved in 6 mL of 5:1 CH30H--H2O at room temperature. After stirring for 3 hours, the mixture was concentrated, diluted with H2O, acidified with 6N HCl (pH 1) and extracted with ethyl acetate (2×150 mL). The combined ethyl acetate extracts were washed with brine (50 mL) and dried. Filtration and concentration afforded 0.5 g (91%) of the title compound as an oil.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=2)[CH2:13][CH2:12][CH:11]([O:26][C:27](=[O:29])[CH3:28])[CH2:10]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=2)[CH2:13][CH2:12][CH:11]([O:26][C:27](=[O:29])[CH3:28])[CH2:10]1
Reactant: CCOc1cc(C2CCC(OC(C)=O)CC2NC(=O)OC(C)(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1cc(C2CCC(OC(C)=O)CC2N)ccc1OC
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
3.0 g (7.36 mmol) of acetic acid (1SR,3RS,4RS)-3-tert-butoxycarbonylamino-4-(3-ethoxy-4-methoxy-phenyl)-cyclohexyl ester (compound F6) are dissolved in 6 ml of 4 M HCl in dioxane and stirred for 30 min. After removal of the solvent the residue is dissolved in dichloromethane and 25 ml of sat. NaHCO3 solution are added carefully. After phase separation, reextraction of the water layer and drying of the combined organic layers (Na2SO4) the solvent is removed to give 2.25 g of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:17]([CH3:20])[CH2:18][OH:19])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:54][C:55]([CH3:60])([CH3:59])[C:56](O)=[O:57]>C1COCC1.O>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:17]([CH3:20])[CH2:18][O:19][C:56](=[O:57])[C:55]([OH:54])([CH3:60])[CH3:59])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(O)C(=O)O
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](COC(=O)C(C)(C)O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 0 °C
Yield: 0.1 %

Procedure:
200 mg (0,612 mmol) of (S)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-ol was dissolved in THF (2 ml). PPh3 (169 mg; 0,643 mmol) was added and the mixture cooled to 0° C. To this, a solution of DEAD (95 mg; 0,612 mmol) and 2-hydroxy-isobutyric acid (64 mg; 0,612 mmol) in THF (2 ml) was added dropwise via cannula. After four hours the reaction mixture was poured in cold water, extracted with ether and dried over Na2SO4. Removal of the solvent and silica gel column chromatography (eluent hexane/ethyl-acetate 85/15) of the residue afforded 232 mg (91%) of 2-hydroxy-2-methyl-propionic acid(S)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propyl ester (K1) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=1[CH3:14])=[O:5])[CH3:2].CC[N:17](C(C)C)[CH:18]([CH3:20])[CH3:19].C(N)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:14][C:7]1[CH:8]=[C:9]([C:11]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:13])[NH:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1[nH]c(C(=O)O)cc1C
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C(=O)NC(C)C)cc1C
Yield: 5.3 %

Procedure:
To a solution of 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.160 g, 0.812 mmol) in DMF (4 ml) was added DIPEA (0.140 mL, 0.790 mmol). The reaction mixture was stirred and the solution was divided into four equal portions, one of which was added to a glass vial with a stir bar. To the vial was added isopropylamine (0.017 mL, 0.2 mmol) and HATU (0.075 g, 0.197 mmol) and the reaction mixture stirred overnight. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were collected and lypholized to afford ethyl 3-methyl-5-{[(1-methylethyl)amino]carbonyl}-1H-pyrrole-2-carboxylate (0.010 g, 47%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.58 (br. s., 1H) 8.07 (s, 1H) 6.60 (s, 1H) 4.26 (q, 2H) 3.97-4.12 (m, 1H) 2.24 (s, 3H) 1.30 (t, 3H) 1.14 (d, 6H). MS: m/z 239.4 (M+1).