Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:19][CH:18]2[CH:16]([CH:17]2[NH:20][C:21]2[N:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][N:22]=2)[CH2:15]1)(=[O:13])=[O:12].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[O:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[O:58][NH2:59]>C(Cl)Cl.C1COCC1.CCN(CC)CC>[O:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[O:58][NH:59][C:27]([C:24]1[CH:23]=[N:22][C:21]([NH:20][CH:17]2[CH:16]3[CH:18]2[CH2:19][N:14]([S:11]([C:2]2[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=2)(=[O:12])=[O:13])[CH2:15]3)=[N:26][CH:25]=1)=[O:28]
Reactant: O=C(O)c1cnc(NC2C3CN(S(=O)(=O)c4ccc5ccccc5c4)CC32)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1cnc(NC2C3CN(S(=O)(=O)c4ccc5ccccc5c4)CC32)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution of 2-{[3-(2-naphthylsulfonyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}pyrimidine-5-carboxylic acid (105 mg, 0.26 mmol) in DCM (5 ml) and THF (5 ml) was added EDCl (59 mg, 0.3 mmol). Et3N (0.08 ml, 0.8 mmol) was added followed by HOBt (42 mg, 0.3 mmol) and O-(tetrahydro-pyran-2-yl)-hydroxylamine (36 mg, 0.3 mmol). The suspension was stirred at r.t. for 3 days. Further EDCl (14 mg), Et3N (0.02 ml), HOBt (11 mg), and O-(tetrahydro-pyran-2-yl)-hydroxylamine (9 mg) were added and stirring at r.t. continued for a further 3 days. The reaction mixture was evaporated to dryness, re-dissolved in EtOAc (20 ml) and washed with sat. aq. NaHCO3 (10 ml) and water (10 ml). The EtOAc layer was dried (Na2SO4), filtered and concentrated to dryness to afford the title compound as a white solid (110 mg, 83%). LCMS purity 90%, m/z 511 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].O[Li].O>O.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2cccc(C#N)c2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2ccnn2-c2cc(C(=O)O)ccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-[5-[(3-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (1.0 eq) and LiOH.H2O (3.0 eq) in a mixture of water (2 mL) and THF (2 mL) was stirred at room temperature for 30 min. Diluted with another 2 mL water, and the mixture was washed with ethyl acetate twice (6 mL×2). The water phase was acidified with 1N HCl (pH=3), filtered and dried the solid to give the title compound. 1H NMR (400 MHz, DMSO-d6): δ 5.36 (2H, s), 6.03 (1H, s), 7.61-7.64 (2H, m), 7.77-7.78 (1H, m), 7.82-7.84 (2H, m), 7.96 (1H, s), 8.09 (1H, s), 8.69 (1H, d, J=4.4 Hz), 13.92 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=2.106 min. [M+H] Calc'd for C17H12N4O3, 321. Found, 321.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].S(Cl)([Cl:16])=O>C1C=CC=CC=1.CN(C)C=O>[ClH:16].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: N=C(N)c1ccc(CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cl
Product: N=C(N)c1ccc(CC(=O)Cl)cc1
Yield: 98.6 %

Procedure:
5.35 g of 4-amidinophenylacetic acid (M.p. 295° to 297° C, decomposition) were suspended in 45 ml of anhydrous benzene. Two drops of dimethylformamide and 17.9 g of thionyl chloride were added and the whole was heated for 11/2 hours under reflux. After cooling, the solid product was filtered off with suction, washed with anhydrous benzene and dried under reduced pressure. 6.9 g of 4-amidino-phenylacetyl chloride-hydrochloride melting at 174° to 177° C (decomposition) were obtained.
Reaction SMILES: C(OC1C=CC([C@@H]2C[C@H]2N)=CC=1)C1C=CC=CC=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[CH2:28][C@H:27]2[N+:29]([O-])=O)=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]2[CH2:28][C@H:27]2[NH2:29])=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Product: N[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 10 %

Procedure:
This compound was synthesized using the same methodology described in Intermediate D, using as starting material 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene (intermediate F). Yield: 10%. 1HNMR (CD3OD): 1.45 (m, 2H), 2.61 (m, 1H), 2.86 (m, 1H), 6.98 (d, 2H), 7.11 (d, 2H). MS (M+H): 211.9.
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][N:11]([C:18](=[O:48])[C@H:19]([CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:47])[NH2:46])[N:20]([N+:38]([O-])=O)[S:21]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[CH:30]=2)[CH:25]=1)(=[O:23])=[O:22])[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[N:20]#[N:38].[CH3:35][O:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:36][CH3:37])[CH:25]=[C:24]([S:21]([NH:20][C@H:19]([C:18]([N:11]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:10][C:9]([OH:49])=[O:8])=[O:48])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:46])[NH2:47])(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: [H][H]
Reactant: COc1cc2ccc(S(=O)(=O)N([C@@H](CCCNC(=N)N)C(=O)N(CC(=O)OCc3ccccc3)C3CCCCC3)[N+](=O)[O-])cc2cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)O)C3CCCCC3)cc2cc1OC
Product: N#N
Yield: 68 %

Procedure:
To a solution of 3.00 of NG -nitro-N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylglycine benzyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtred to remove the catalyst and evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.65 g (68%) of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylglycine as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([N+:30]([O-])=O)=[CH:22][CH:21]=1>>[CH3:3][C:2]1([CH3:15])[NH:30][C:23]2[C:24]3[C:29]([C:20]([N:19]=[N:1][C:2]4[C:15]5[C:6](=[CH:7][C:8]6[C:13]([CH:14]=5)=[CH:12][CH:11]=[CH:10][CH:9]=6)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=4)=[CH:21][CH:22]=2)=[CH:28][CH:27]=[CH:26][C:25]=3[NH:1]1
Reactant: Nc1ccc([N+](=O)[O-])c2cc3ccccc3cc12
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Product: CC1(C)Nc2cccc3c(N=Nc4ccc([N+](=O)[O-])c5cc6ccccc6cc45)ccc(c23)N1

Procedure:
In the manner described in Example 8, substituting 12.0 grams of 1-amino-4-nitroanthracene for the 1-amino-4-nitronaphthalene, the desired compound is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.[Ti:12](Cl)(Cl)(Cl)[Cl:13].N1C2C(=CC=CC=2)C=CC=1O>CCCCCCC>[Cl-:13].[Cl-:13].[Cl-:13].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][Ti+3:12])[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2cccnc12
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: Oc1ccc2ccccc2n1
Solvent: CCCCCCC
Product: [Cl-]
Product: [Ti+3]Oc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The reaction is performed under an atmosphere of dry nitrogen. 8-Quinolinol powder (1.45 g, 10.0 mmol) is added to a flask and is stirred at room temperature for 10 min. Heptane (100 mL) is added, and the mixture is stirred at 40° C. for 30 min. The stirring rate is adjusted to prevent solids from depositing on the walls of the flask. Titanium tetrachloride (10 mL of 1.0 M solution in heptane) is added dropwise to the quinolinol, and the reaction mixture is stirred at room temperature for 20 h at a rate effective to prevent solids from depositing on the walls of the flask. The color changes from white to tomato-juice red. The solids are isolated by decanting the liquid portion. Residual solvent is removed from the solids using vacuum and a nitrogen purge for 30 min. The flask containing the red, solid product, 8-quinolinoxytitanium trichloride (3.04 g), is transferred to a dry box. For comparison purposes, a sample of this material is tested in the ethylene polymerization described in Example 6. The results are reported in Table 1 for Example “C1.”
Reaction SMILES: C[C@@H]1O[C@@H](O[C@@H:9]2[C:14]3=[C:15](O)[C:16]4[C:28](=O)[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]=5OC)[C:20](=O)[C:17]=4[C:18](O)=[C:13]3[CH2:12][C@@:11](O)(C(C)=O)[CH2:10]2)C[C@H](N)[C@@H]1O.[ClH:39].C(O)(=O)C.[NH2:44][NH:45][C:46]([NH2:48])=[S:47]>C(O)C>[ClH:39].[N:44](=[C:20]1[C:17]2[C:16](=[CH:15][C:14]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[CH:18]=2)[CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2)[NH:45][C:46]([NH2:48])=[S:47]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=S)NN=C1c2ccccc2Cc2cc3c(cc21)CCCC3
Yield: 187.5 %

Procedure:
Daunorubicin hydrochloride (0.4 g.) is dissolved in ethanol (60 cc.) containing 2.5% of acetic acid, and thiosemicarbazide (0.135 g.) is then added. The resulting mixture is heated for 12 hours to 45° C. with stirring, then evaporated to dryness under reduced pressure, and the residue is taken up in water (50 cc.). The resulting solution is lyophilised to give 4-methoxy-5- (or 12-) oxo-6,9,11-trihydroxy-7-(2,3,6-O-tridesoxy-3-amino-1-L-lyxohexosyl)-9-[1-(thiosemicarbazono)ethyl]-12- (or 5-) (thiosemicarbazono)-5,7,8,9,10,12-hexahydro-naphthacene hydrochloride (0.476 g.) in a yield of 89%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.F[B-](F)(F)F.O=[N+:18]=O>ClCCl>[CH3:8][C:6]1[C:7]([NH2:18])=[C:2]([CH3:1])[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]=1[CH3:9]
Reactant: O=[N+]=O
Reactant: Cc1cc(C)c(C)c(C)c1C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1c(C)c(C)c(N)c(C)c1C
Reaction time: 4 h

Procedure:
To a solution of pentamethylbenzene (5 g, 33.8 mmol) in dichloromethane (250 mL) at 0° C. was quickly added nitronium tetrafluoroborate (5 g). The mixture was stirred for 4 h before it was quenched with cold water. The organic layer was concentrated and the residue was reduced (Example 14, procedure C) to give pentamethylaniline in 52% yleld.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17]CC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[N:13]([S:28]([O-:31])(=[O:30])=[O:29])[C:12]2=[O:32])=[O:9])[N:6]=1.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([OH:17])=[O:16])[N:13]([S:28]([OH:31])(=[O:29])=[O:30])[C:12]2=[O:32])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1C(=O)O)c1csc(N)n1

Procedure:
In a mixture of 10 ml of tetrahydrofuran and 10 ml of water is dissolved 155 mg of sodium cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(4-nitrobenzyloxycarbonyl)-2-oxoazetidine-1-sulfonate (syn-isomer). To the solution is added 145 mg of 10% palladium-on-carbon, and the mixture is subjected to catalytic reduction at ambient temperature under normal pressure with stirring. Three hours later, 10 ml of an aqueous solution of 25 mg of sodium hydrogen carbonate is added to the reaction mixture. The catalyst is removed by filtration, and the filtrate is washed with ethyl acetate, and concentrated under reduced pressure. The concentrate is purified by column chromatograhy on Amberlite XAD-II, followed by lyophilization to give cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-carboxy-1-sulfo-2-oxoazetidine.disodium salt (syn-isomer).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:35][C:36]1[S:37][CH:38]=[C:39]([C:41](=[N:45][O:46]C(C)(OC)C)[C:42]([OH:44])=[O:43])[N:40]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(NC1CCCCC1)(NC1CCCCC1)=O.CC1SC(SCC2CS[C@@H]3C(N)C(=O)N3C=2C(O)=O)=NN=1>[N+](C)([O-])=O.C(N(CC)CC)C.C(Cl)Cl>[C:16]([NH:35][C:36]1[S:37][CH:38]=[C:39]([C:41](=[N:45][OH:46])[C:42]([OH:44])=[O:43])[N:40]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(C)(C)ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: O=C(O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h

Procedure:
0.23 g of dicyclohexylcarbodiimide were added under argon at 20° C. to a mixture of 1.002 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetic acid and 3 ml of methylene chloride and the mixture was stirred at 20°-25° C. for one hour to obtain a suspension of dicyclohexylurea. In a second flask, 0.28 ml of triethylamine were added at 20° to 25° C. to a suspension of 0.344 g of 3-[(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-7-amino-ceph-3-eme-4-carboxylic acid in 2 ml of nitromethane to form a brown solution which was added over 5 minutes with stirring at 20°-25° C. to the first suspension. The mixture was rinsed with methylene chloride and was then stirred for 2 hours and was vacuum filtered to remove dicyclohexylurea (0.2 g). The filter was rinsed with methylene chloride and the filtrate and 8 ml of N hydrochloric acid were stirred. The mixture was vacuum filtered and the brown product was rinsed with water and methylene chloride to obtain 0.4 g of mainly the starting product. The filtrate was washed with distilled water until the wash water was neutral, dried and distilled to dryness under reduced pressure. The residue was added to 5 ml of ethyl acetate and the mixture was vacuum filtered at room temperature. The product was rinsed with ethyl acetate to obtain 0.32 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[O:10].ClC1C=C(Cl)[CH:17]=[C:16]([O:21]CC2C=CC=CC=2)[C:13]=1[CH:14]=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C@@H:9]1[O:10][C:14](=[O:15])[CH2:13][C@@H:16]([OH:21])[CH2:17]1
Reactant: O=Cc1c(Cl)cc(Cl)cc1OCc1ccccc1
Reactant: O=CCc1ccccc1Cl
Product: O=C1C[C@@H](O)C[C@H](Cc2ccccc2Cl)O1

Procedure:
By substituting an equimolar amount of o-chlorophenylacetaldehyde for 2,4-dichloro-6-phenylmethoxybenzaldehyde in step C of Example 1 and following Steps C through F there is obtained a corresponding amount of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:10][CH:11]=[CH:12][CH:13]=2)[O:5][N:4]=1.S(Cl)([Cl:24])=O.N1C2C=CC=CC=2N=N1.[OH-].[Na+].C(OC)(C)(C)C>CN(C)C(=O)C>[C:17]([O:16][C:15](=[O:21])[NH:14][C:9]1[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][Cl:24])[CH:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1ncccc1-c1cc(CO)no1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc2[nH]nnc2c1
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1ncccc1-c1cc(CCl)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, tert-butyl {3-[3-(hydroxymethyl)isoxazol-5-yl]pyridin-2-yl}carbamate (781 mg, 2.68 mmol) was dissolved in N,N-dimethylacetamide (2.7 mL). To the solution was added the above solution of thionyl chloride-benzotriazole (1:1.1) in N,N-dimethylacetamide (6 mL, 14.4 mmol) dropwise under an ice water cooling, which was stirred at the same temperature for one hour and then stirred at room temperature. After one hour and 20 minutes, under the ice water cooling, a solution of thionyl chloride-benzotriazole (1:1.1) in N,N-dimethylacetamide (2.2 mL, 5.12 mmol) was added dropwise thereto, and the solution was stirred at room temperature for one hour. Under the ice water cooling, to the reaction solution were added 1N aqueous sodium hydroxide and tert-butylmethylether to adjust basic and then extracted. The organic layer was washed sequentially with 0.5N aqueous sodium hydroxide and 5% sodium chloride water, dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure, so as to obtain a crude body of the title compound (953 mg) as a pale yellow oily product.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:32][CH:31]=2)=[C:21]([CH:25]=1)[C:22](O)=[O:23])=[O:16])[CH3:13].C(N(CC)CC)C.Cl.[NH2:56][C@H:57]1[CH2:62][CH2:61][CH2:60][CH2:59][C@H:58]1[C:63]([O:65][CH2:66][CH3:67])=[O:64]>ClCCl.O>[CH2:66]([O:65][C:63]([C@H:58]1[CH2:59][CH2:60][CH2:61][CH2:62][C@H:57]1[NH:56][C:22]([C:21]1[CH:25]=[C:17]([CH:18]=[CH:19][C:20]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:32][CH:31]=1)[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[O:23])=[O:64])[CH3:67]
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)O)c1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)N[C@@H]2CCCC[C@@H]2C(=O)OCC)c1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
39 mg (0.20 mmol) of N-[(3-dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDC) and 27.4 mg (0.20 mmol) of 1-hydroxy-1H-benzotriazole hydrate (HOBT) are successively added to a suspension of 100 mg (0.20 mmol) of 5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoic acid in 30 ml of dichloromethane at RT. After 30 min, 41 mg (0.41 mmol) of triethylamine and 38 mg (0.18 mmol) of ethyl cis-2-amino-1-cyclohexanecarboxylate hydrochloride are added, and the mixture is stirred overnight. 10 ml of water are then added, the phases are separated, and the aqueous phase is extracted with dichloromethane (three times 25 ml). The combined organic phases are washed with saturated sodium chloride solution, dried, (sodium sulphate) and concentrated in a rotary evaporator. The crude product is purified by column chromatography (silica gel 60, mobile phase gradient cyclohexane-->cyclohexane-ethyl acetate 5:1). 102 mg of product are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[C:5]([CH3:16])[C:4]([C:17]([O:19]CC)=[O:18])=[C:3]1[CH2:22][C:23]([O:25]CC)=[O:24].[OH-].[Na+]>>[C:17]([C:4]1[C:5]([CH3:16])=[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:2]([CH3:1])[C:3]=1[CH2:22][C:23]([OH:25])=[O:24])([OH:19])=[O:18]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2ccc(C)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)c2c(C)c(C(=O)O)c(CC(=O)O)n2C)cc1

Procedure:
A suspension of 54 g. (0.145 mole) of ethyl 1,4-dimethyl-3-ethoxycarbonyl-5-(p-toluoyl)-pyrrole-2-acetate in 500 g. of 25% sodium hydroxide is heated at just below reflux for 3 hrs. The yellow suspension is then poured into ice-hydrochloric acid and the precipitated solid is collected, air dried and recrystallized from acetone-water to give 3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid as a white solid, m.p. 229°-230° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH3:25][NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:26]([CH3:25])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CCOC(=O)CCNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(C)c1nc2cc(F)c(F)cc2cc1C(=O)OCC
Temperature: 90 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
56.2 g of sodium carbonate are added to a solution of 72 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 45.1 g of N-methyl-N-(β-ethoxycarbonylethyl)amine in 750 cm3 of toluene. The suspension obtained is heated to approximately 90° C. and then stirred for 4 hours at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 400 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 94 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-ethoxycarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].C([NH:22][CH2:23][CH2:24]O)(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl.C(O)(C(F)(F)F)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:24][CH2:23][NH2:22])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCCN)c([N+](=O)[O-])c1
Yield: 38.6 %

Procedure:
To a stirred solution of methyl 3-nitro-4-hydroxybenzoate (1.98 g, 10.04 mmol), N-Boc ethanolamine (1.63 g, 10.11 mmol) and PPh3 (3.43 g, 13.08 mmol) in THF (40 mL) was added DIAD (2.57 mL, 13.05 mmol), and the reaction mixture was then heated under reflux overnight. The resulting mixture was evaporated to give a gum. The residual crude gum was dissolved in CH2Cl2 (30 mL) and TFA (30 mL), and the mixture was stirred for 1 hr at room temp. The mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, and dried over Na2SO4. The solvent was evaporated in vacuo to give the oily residue, which was purified by column chromatography on silica -gel with CHCl3 then CHCl3-MeOH (20:1, v/v) as eluent to give 930 mg (27% for 2 steps ) methyl 3-nitro4-(2-aminoethoxy)benzoate as gum. 1H-NMR (CDCl3) δ 3.16–3.19 (m, 1 H), 3.53–3.57 (m, 1 H), 3.90 and 3.94 (s, 3 H), 3.95–3.98 (m, 1 H), 4.21–4.24 (m, 1 H), 6.89–6.91 and 7.11–7.13 (m, 1 H), 8.03–8.19 and 8.21 (m, 1 H), 8.52 and 8.86 (m, 1 H).