Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20](O)=[O:21].Cl.CN(C)CCCN=C=NCC.Cl.[CH3:36][O:37][C:38](=[O:45])[C@H:39]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH2:40].CN1CCOCC1.NN>C(Cl)Cl.[Ni]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:20]([NH:40][C@H:39]([C:38]([O:37][CH3:36])=[O:45])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:21])=[C:4]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cn1c(C(=O)O)c(-c2ccccc2)c2cc([N+](=O)[O-])ccc21
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: [Ni]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A mixture of 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylic acid (0.56 g, 1.9 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.47 g, 2.5 mmol), and L-leucine methyl ester hydrochloride (0.40 g, 2.2 mmol) was stirred in CH2Cl2 (20 mL). N-methylmorpholine (1.01 g, 10 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then washed with 0.05 N HCl and water. The resulting solution was dried with MgSO4 and concentrated. The residue was dissolved in 30 mL of ethanol and a large excess of Raney® nickel and hydrazine (0.6 mL, 19 mmol) were added. After stirring at room temperature for 2 h the catalyst was then removed by filtering through a short pad of Celite®521. The filtrate was concentrated to give 0.65 g (87%) of crude methyl N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-leucinate as a pale yellow solid: MS (ESI) m/z 394 (MH+); HRMS calcd for C23H28N3O3: 394.2128; found (ESI+): 394.2121.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]([CH2:13][CH2:14][CH3:15])C(=O)OC(C)(C)C.Cl>CO>[CH2:13]([NH:5][CH2:4][C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[OH:1])[CH2:14][CH3:15]
Reactant: CCCN(Cc1ccccc1O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCCNCc1ccccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 108.6 %

Procedure:
A solution of tert-butyl 2-hydroxybenzyl(propyl)carbamate (89 g, 0.34 mol) in MeOH (400 mL) was bubbled with HCl gas. After stirring for 5 h at room temperature, the reaction mixture was concentrated under reduced pressure to afford 61 g (90%) of 2-((propylamino)methyl)phenol as HCl salt.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][OH:21])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH:20]=[O:21])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
A solution of oxalyl chloride (0.27 ml, 3.15 mmole) in dry dichloromethane (8 ml) was cooled to −78° C. Dimethyl sulfoxide (0.45 ml, 6.29 mmole) in dichloromethane (1 ml) was added dropwise maintaining the reaction temperature at −40° C. The reaction mixture was stirred for 5 minutes and a solution of (3-hydroxy-propyl)-carbamic acid tert-butyl ester (0.50 g, 2.86 mmole) in dichloromethane (3 ml) was added dropwise. After stirring for 15 minutes, triethylamine (1.99 ml, 14.3 mmole) was added and the mixture allowed to warm to ambient temperature. The reaction was quenched by adding water (10 ml), extracted with dichloromethane and the organic extracts were washed with aqueous hydrochloric acid solution (2M), saturated sodium bicarbonate solution and water. The organic layer was dried under magnesium sulfate and the solvent removed in vacuo to afford the title compound (0.45 g). 1H NMR (CDCl3) δ 9.81 (1H, s), 3.45-3.40 (2H, t, J=5 Hz), 2.72-2.69 (2H, t, J=5 Hz), 1.43 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C.[Pt]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2cccc(F)c2)cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(C=Cc2cccc(F)c2)cc1
Reaction time: 4 h
Yield: 61.9 %

Procedure:
2.41 g (10 mmol) of 4-[2-(3-fluoro-phenyl)-vinyl]-1-nitro-benzene is dissolved in 25 ml of ethyl acetate and treated with 240 mg of platinum 5% on charcoal. Hydrogenation is performed at room temperature and normal pressure for 4 h. The catalyst is filtered off and the filtrate concentrated. The residue is crystallised from diethyl ether/heptane to yield 1.32 g (62%) of an orange solid. MS: m/e=213.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]2[C:17]=1[C:16]([CH3:18])=[C:15]1[C:7](=[N:8][C:9]3[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=2.[C:22]([C:29]1NC=CN=1)([C:24]1[NH:25]C=C[N:28]=1)=O.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([C:19]2[O:21][N:28]=[C:24]([CH2:22][CH3:29])[N:25]=2)=[N:4][C:5]2[C:17]=1[C:16]([CH3:18])=[C:15]1[C:7](=[N:8][C:9]3[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC1=c2c(cc3c(c2C)-c2ccccc2N=3)N=C1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1noc(C2=Nc3cc4c(c(C)c3=C2C)-c2ccccc2N=4)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
3,4-Dimethylpyrrolo[2,3-b]carbazole-2-carboxylic acid (0.49 g, 1.76 mmol) and carbonyl diimidazole (0.33 g, 1.94 mmol) were dissolved in freshly distilled tetrahydrofuran (10 ml) in an oven-dried flask under a nitrogen atmosphere and this solution was stirred at room temperature for three hours. Meanwhile, in a second oven-dried flask, ethylamidoxime (0.39 g 4.43 mmol) was dissolved in THF (5 ml). To this was added crushed 3 Å sieves and the mixture was stirred at room temp for 45 min. Sodium hydride (60% dispersion in mineral oil, 0.142 g, 3.5 mmol) was added and the mixture stirred for a further 2.5 hours. The contents of the two flasks were combined (with further 10 ml THF) and stirred at room temp for 18 hours, by which time TLC showed complete consumption of the imidazolide intermediate. The solvent was removed in vacuo to give a yellow solid. Chromatography on silica (eluting with 25% ethyl acetate/hexane) gave the title compound as a yellow solid (0.150 g, 26%) with m.p. 258°-260° C. (decomp.). (Found: C, 72.03; H, 5.28; N, 16.42. C20H18N4O 0.08EtOAC requires: C, 72.33; H, 5.57; N, 16.60%); δH [2H6 ]-DMSO 11.55 (1H, s, 1-NH), 10.94 (1H, s, 9NH), 8.19 (1H, d, J 7.5, 5-H), 7.29-7.43 (2H, m, 7-H, 8-H), 7.22 (1H, s, 10-H), 7.13 (1H, ddd, J 8, 5.5, 2, 6-H), 3.20 and 3.03 (2×3H, 2×s, 3--CH3 and 4--CH3), 2.83 (2H, q, 7.5, CH2 CH3), 1.37 (3H, t, 7.5, CH2CH3); m/z (%) 330 (100, M+), 260 (34), 232 (29); νmax (KBr disk)/cm-1 3394, 1599, 1259.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH2:17]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:21])=[CH:5][N:6]=2)=[CH:16][O:15][N:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: NC1CCOCC1
Reactant: CCCCc1nocc1COc1ccc(C(=O)OC)cn1
Product: CCCCc1nocc1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 73 %

Procedure:
As described for example 25e, 6-(3-butyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.69 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (180 mg, 73%) which was obtained as a white solid after purification by chromatography (silica, 40 to 60% ethyl acetate in heptane). MS: m/e=360.2 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[OH-].[Na+].[O:19]([CH2:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:19]([CH2:26][C:27]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:11][N:12]=[N:13][N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(Cl)COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred slurry of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam (480 mg.) inwater (10 ml.) is cooled to 0° C., and then the pH is adjusted to 8.0 using 1N sodium hydroxide. To this solution is then added phenoxyacetyl chloride, (0.25 ml.) in portions, with the pH of the solution being maintained between 7 and 8 during the addition, using 0.1N sodium hydroxide. The solution is stirred a further 30 minutes at 0° C. at pH 8. It is then extracted with chloroform, and the extracts are discarded. The aqueous phase is acidified to pH 2 with dilutehydrochloric acid, and then it is further extracted with chloroform. The latter extracts are dried using calcium sulfate and then evaporated in vacuo to give the crude product as a gummy solid. This is purified by dissolving it in chloroform (20 ml.), and adding the resultant solution dropwise to hexane (250 ml.). The precipitate which forms is filtered off,giving 385 mg. of 6-(2-phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamas a white amorphous solid. The infrared spectrum (KBr disc) of the productshows absorption bands at 1785 cm-1 (β-lactam carbonyl), 1670 cm-1 (amide I band) and 1540 cm-1 (amide II band). The NMR spectrum (in DMSO-d6) shows absorption bands at 7.50- 6.70 ppm (multiplet, aromatic hydrogens), 5.70 ppm (multiplet, C-5 and C-6hydrogens), 5.35 ppm (singlet, C-3 methyl hydrogens), 4.66 ppm (s, 2, φ-OCH2) and 1.66 + 1.16 (s, 3H, each, C-2 methyls)ppm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:22]2[O:26][C:25]([CH3:28])(C)C(C)(C)[O:23]2)=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31](C)([O-:33])=[O:32].[OH-].[Na+].C1COCC1>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:22]([OH:23])[O:26][CH:25]([CH2:28][N+:31]([O-:33])=[O:32])[C:15]=2[CH:18]=[CH:19][C:20]=1[F:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: CC1(C)OB(c2c(C=O)ccc(F)c2OCCCOCc2ccccc2)OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])CC1OB(O)c2c1ccc(F)c2OCCCOCc1ccccc1
Yield: 93.8 %

Procedure:
Synthesized according to the methods of general procedure 8 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-benzyloxy-propoxy)-4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (0.40 g, 0.966 mmol), nitromethane (0.15 mL, 2.89 mmol), NaOH (0.038 g, 0.96 mmol), THF (10 mL), water (10 mL). This generated 0.34 g (94% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.83 (s, 1H), 7.32-7.02 (m, 7H), 5.78-5.75 (m, 1H), 5.28-5.23 (m, 1H), 4.60-4.56 (m, 1H), 4.42 (s, 2H), 4.37 (brs, 2H), 3.57 (brs, 2H), 1.92 (brs, 2H). 19F NMR (376 MHz, DMSO-d6 with D2O) δ (ppm): −132.3 (1F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])(=[O:17])=[O:16])=[O:13])[N:4]=1.[Cl-].Cl[CH:27]=[N+:28]([CH3:30])[CH3:29]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]=[CH:27][N:28]([CH3:30])[CH3:29])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: C[N+](C)=CCl
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2N=CN(C)C)n1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
A mixture of 0.80 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-aminobenzenesulfonamide, 0.29 g of [chloromethylene]dimethylammonium chloride and 8 ml of DMF is stirred at room temperature until the reaction has ended. The volatile components are distilled off under reduced pressure and the residue is washed with water and methyl acetate, affording 0.28 g of the desired product. Melting point: 209-210° C. (decomp.)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH:8]=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH:8]=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1c(F)cccc1F
Agent: O=S(=O)(O)O
Product: O=Cc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
To stirring 69% nitric acid (6.48 ml, 93.59 mmol) cooled to 5° C. was added concentrated sulfuric acid (4.16 ml, 78.11 mmol) dropwise, keeping the internal temperature below 8° C. After complete addition stirring was continued for 15 minutes. This mixture was added to a solution of 2,6-difluorobenzaldehyde (10 g, 70.37 mmol) in concentrated sulfuric acid (50 ml) dropwise keeping the internal temperature below 10° C. After complete addition the mixture was stirred at 5° C. for 15 minutes then allowed to warm to room temperature over 90 minutes. The reaction mixture was poured onto ice-water (400 ml) and the resulting solid stirred for 1 hour. The solid was collected by filtration, washed with water and dried under vacuum to yield the title compound (9.27 g, 70%). 1H NMR (DMSO-d6, 300 MHz): 10.21 (1 H, t, J=1.02 Hz), 8.52 (1 H, ddd, J=9.38, 8.60, 5.51 Hz), 7.51 (1 H, td, J=9.53, 1.76 Hz).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9](=[O:17])[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:1]([C:19]1[CH:20]=[CH:21][C:7]2[N:6]([CH3:5])[CH2:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=[O:17])[C:8]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: CN1Cc2ccccc2C(=O)c2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(=O)c1ccccc1CN2C
Temperature: 0 °C
Yield: 92.6 %

Procedure:
Acetyl chloride (8.5 g) was gradually added dropwise to a mixed liquid of 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine (12 g), anhydrous aluminum chloride (21.5 g) and dried methylene chloride (200 ml) while stirring and cooling the liquid with ice. After the dropwise addition, the mixture was stirred for 30 minutes at room temperature, and was heated under refluxing for one hour. Immediately after the reaction, the reaction mixture was poured into a solution containing ice-water (1 kg) and conc. hydrochloric acid (50 ml) while stirring to separate the methylene chloride layer. This layer was washed with a 5% sodium hydrogencarbonate solution, then with water, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the residue was recrystallized from methanol to afford the desired compound (13.2 g).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH2:25][CH3:26]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:31][C:30]4[CH:32]=[CH:33][C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCCc1ccc(N)cc1
Product: CCCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 28 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-propylaniline (46.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-propylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (19.1 mg).
Reaction SMILES: C1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[N:12][N:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:10](=[O:18])[C:9]=1[OH:19].C(=O)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[C:14]([N:11]1[C:10](=[O:18])[CH:9]([OH:19])[C:8](=[N:7][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:13]=[N:12]1)([CH3:16])([CH3:15])[CH3:17]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)n1ncc(N)c(O)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)N1N=CC(=Nc2ccncc2)C(O)C1=O
Yield: 74.9 %

Procedure:
50 ml of a dry benzene solution of 3.1 g of 5-amino-2-tert-butyl-4-hydroxypyridazin-3-(2H)-one, 1.9 g of isonicotinaldehyde and 0.17 g of p-toluene sulfonic acid, was reacted for 1.5 hours under heating and refluxing by means of a Dean Stark trap. After cooling, 100 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed with water and then with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3.3 g of 2-tert-butyl-4-hydroxy-5-(4-pyridylimino)pyridazin-3-(2H)-one as a powder.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][CH2:14][CH:15]1[CH2:23][CH:22]2[CH:18]([CH2:19][NH:20][CH2:21]2)[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])([OH:24])[CH2:16]1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42](O)=[O:43]>ClCCl>[OH:13][CH2:14][CH:15]1[CH2:23][CH:22]2[CH:18]([CH2:19][N:20]([C:42](=[O:43])[CH2:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][CH3:33])[CH2:21]2)[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])([OH:24])[CH2:16]1
Reactant: COc1ccccc1CC(=O)O
Reactant: COc1ccccc1C1(O)CC(CO)CC2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 45.6 %

Procedure:
2.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to a solution of 3 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol and 1.8 g of (2-methoxyphenyl)acetic acid in 60 cm3 of dichloromethane. The reaction mixture is stirred at 20° C. for 20 hours and then washed with 30 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, height [lacuna]cm) in ethyl acetate and then in a mixture of ethyl acetate and methanol (95:5 by volume). Drying under reduced pressure gives a white solid which, after recrystallization from a mixture of ethyl ether and acetonitrile, gives 2.1 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol in the form of white crystals. M.p.=162° C.
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:4]=1[C:15]([OH:17])=[O:16])C.[OH-].[Na+]>C(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([C:15]([OH:17])=[O:16])=[CH:3]2)([O-:14])=[O:13]
Reactant: CCc1c(C(=O)O)[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of commercial ethyl 5-Nitro-2-carboxy-indole (10.21 g, 43.6 mmol) in ethanol (220 mL) was added 110 mL of 2 M NaOH. The reaction was stirred at 60° C. for 18 hours. The reaction was then cooled and the ethanol removed in vacuo and then an additional 200 mL water was added. To the vigourously stirring aqueous solution was added 5 M HCl followed by 1 M HCl until pH 4 was attained and the acid product was precipitated. The product was collected by filtration on a Buchner funnel and washed once with dilute HCl (1:40 v/v) and twice with water. The filtrate was dried over P2O5 in a dessicator in vacuo to afford 8.83 g (42.8, 98%) of acid 97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([O:35][CH2:36][C:37](O)=[O:38])=[O:34].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:37](=[O:38])[CH2:36][O:35][C:33]([C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)=[O:34]
Reactant: O=C(O)COC(=O)c1cccs1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(COC(=O)c1cccs1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (150 mg, 0.357 mmol), 2-(thiophene-2-carbonyloxy)acetic acid (80 mg, 0.428 mmol), EDC (205 mg, 1.071 mmol), and DMAP (43.6 mg, 0.357 mmol) were dissolved in DCM (15 ml), and the solution was stirred at room temperature overnight. The solution was diluted with DCM, washed with 1N HCl and 5% NaHCO3, then with brine. The organic phase was dried over Na2SO4, and the solvent was evaporated. The crude so obtained (233 mg of a pale yellow solid) was triturated with MeOH and sonicated; the fine solid so obtained was filtered and dried in vacuum oven overnight. The desired product was obtained as a white powder (133 mg, 0.226 mmol, 63.3% yield, LC-MS/ESI+ 588.04 [MH]+, [αD]=−24.78, c=0.51, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:23]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:24]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:23]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cn1
Temperature: 25 °C

Procedure:
A mixture of ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionate (1.03 g), 1N aqueous sodium hydroxide solution (8 ml), ethanol (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature. The reaction mixture was poured into water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain crystals of 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionic acid from the fraction eluted with acetone-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane to obtain colorless prisms (740 mg, yield: 74%). Melting point: 123–124° C.