Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:19](O)(=O)CC(O)=O.C([O-])(=O)C.[Na+].C1(=O)OC(=O)C2=CC=CC=C12>C(O)(=O)C>[CH3:18][C:11]1[CH:10]=[C:4]2[C:3](=[C:2]([CH3:1])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:9])[O:7][C:5]2([OH:6])[CH3:19]
Reactant: O=C(O)CC(=O)O
Reactant: CCOC(=O)c1c(C)cc2c(c1C)C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: O=C1OC(=O)c2ccccc21
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)cc2c(c1C)C(=O)OC2(C)O
Yield: 77 %

Procedure:
A 500 ml. three-necked glass flask equipped with a reflux condenser, a thermometer and a stirrer was charged with a mixture consisting of 50 g of 3,5-dimethyl-4-ethoxycarbonyl-phthalic anhydride, 42 g of well-dried malonic acid, 30 g of sodium acetate and 200 g of acetic acid, and the flask was heated in an oil bath. The phthalic anhydride derivative was reacted with malonic acid at 90° to 95° C. for 15 hours with stirring. After the reaction, the reaction mixture was analyzed by high-speed liquid chromatography. It was found that the conversion was 90%, and the desired 5,7-dimethyl-6-ethoxycarbonyl-3-hydroxy-3-methylphthalide was obtained in a yield of 77%.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23]C3CCCCO3)=[CH:19][CH:18]=2)[C@H:10]([NH:31][C:32](=[O:46])[C:33]2[CH:38]=[CH:37][C:36]([O:39]C3CCCCO3)=[CH:35][CH:34]=2)[CH2:9]1)=O)(C)(C)C.[ClH:47]>C(COC)OC.C(O)(C)C>[ClH:47].[OH:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([NH:31][C@H:10]2[C@H:11]([O:15][C:16](=[O:30])[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9]2)=[O:46])=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(OC3CCCCO3)cc2)[C@H](NC(=O)c2ccc(OC3CCCCO3)cc2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: COCCOC
Product: O=C(N[C@@H]1CNCCC[C@H]1OC(=O)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
108.9 g (3R,4R)-3-[4-(Tetrahydro-pyran-2-yloxy)-benzoylamino]-4-[4-(tetrahydro-pyran-2-yloxy)-benzoyloxy]-azepane-1-carboxylic acid tert-butyl ester (mixture of 4 diast.) was dissolved in 200 ml of a 2N dimethoxyethane and i-Pr-OH (1:1) HCl solution at 0° C. The solution was kept at room temperature for 24 h. The deprotected azepine crystallized, and the reaction mixture was cooled to 0° C. before filtration. The white crystals were washed with dry ether then dissolved in pure water. The water solution was extracted twice with ether before being yand lyophilised. 66.4 g (95% yield) 4-Hydroxy-benzoic acid (3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester hydrochloride (1:1) was obtained as a white powder
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18]O)=[CH:12][CH:11]=1)([O-:3])=[O:2].C(N(S(F)(F)[F:26])CC)C>C(Cl)Cl>[F:26][CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:11][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=[N+]([O-])c1ccncc1-c1ccc(CCCO)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccncc1-c1ccc(CCCF)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To 3-(4-(4-nitropyridin-3-yl)phenyl)propan-1-ol (60 mg, 0.23 mmol) in 2 mL of dry DCM at 0° C. was added (Diethylamino)sulfur trifluoride (111 mg, 0.69 mmol) dropwise. The reaction was warmed to rt and stirred for 1 h and quenched onto ice (20 g) in saturated Na2CO3 (20 mL). The mixture was extracted with EtOAc (2×30 mL) and the organic phase was dried over MgSO4 and concentrated. The residue was purified by silica chromatography (EtOAc in hexane, 5% to 30%) to afford 3-(4-(3-fluoropropyl)phenyl)-4-nitropyridine as a pale-yellow oil (12 mg, 20%). 1H NMR (400 MHz, CDCl3): δ 8.82-8.80 (m, 2H), 7.64 (d, J=5.2, 1H), 7.33-7.27 (m, 2H), 4.55 (t, J=5.6 Hz, 1H), 4.43 (t, J=5.6 Hz, 1H), 2.82 (t, J=7.6 Hz, 2H), 2.12-1.99 (m, 2H); MS (ESI) m/z [M+H]+261.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:17]([O:19]C)=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].[H-].[Na+]>O1CCOCC1>[O:19]=[C:17]1[CH:4]([C:3]([O:2][CH3:1])=[O:21])[CH2:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)CCC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)C1CC(=O)NC(Cc2ccccc2)C1=O
Reaction time: 8 h

Procedure:
N-(4-Methoxy-1,4-dioxobutyl)-L-phenylalanine, methyl ester, 6.74 g (0.023 mole), was dissolved in 200 ml of dioxane, and 2.2 g (0.055 mole) of 60% sodium hydride in mineral oil dispersion slowly added. The mixture was refluxed for four hours, stirred, and allowed to reach room temperature overnight. The solvent was evaporated in vacuo and the residue dissolved in 100 ml of water, acidified with concentrated hydrochloric acid to pH 8.5 and extracted with 200 ml ethyl acetate. The ethyl acetate layer was separated, dried over sodium sulfate, evaporated in vacuo, and the residue chromatographed using 150 g of silica gel and eluting with 500 ml of dichloromethane-methanol (98:2) to give 3,6-dioxo-2-(phenylmethyl)-4-piperidinecarboxylic acid, methyl ester: (DL-mixture at 2 position), 5.1 g; mp 146°-147.5°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10]1([C:16](O)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:16]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:17])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(O)C1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Product: O=C(NNc1ccc(F)cn1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010 022076, which is incorporated herein by reference in its entirety; 1.00 g, 7.87 mmol), cyclohexane carboxylic acid (1.21 g, 9.44 mmol), and HOBt.H2O (166 mg, 0.787 mmol) at 0° C. under N2 was added EDC (1.81 g, 9.44 mmol), then the mixture stirred at 0° C. for 15 min, and at RT for 17 h. Water was added, then the organics isolated, cooled to 0° C., then the resulting suspension filtered to leave the title compound as a white solid (1.16 g, 62%). 1H NMR (400 MHz, CDCl3): 1.21-1.38 (3H, m), 1.45-1.55 (2H, m), 1.66-1.73 (1H, m), 1.80-1.96 (4H, m), 2.22 (1H, tt, J 11.6, 3.5 Hz), 6.62-6.66 (2H, m), 7.29 (1H, ddd, J 9.2, 7.9, 3.1 Hz), 7.55 (1H, d, J=4.2 Hz), 8.03 (1H, d, J=2.9 Hz).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH:9]=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>>[N+:23]([C:22]1[C:17]([N:13]2[CH2:12][CH2:11][C:10](=[CH:9]/[CH:8]=[CH:7]/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][CH2:14]2)=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C(/C=C/c1ccccc1)=C1CCNCC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1N1CCC(=C/C=C/c2ccccc2)CC1
Yield: 95.7 %

Procedure:
A well homogenised mixture of Compound 255b (175 mg, 0.878 mmol), 2-chloro-3-nitropyridine (153 mg, 0.966 mmol) and triethylamine (0.139 mL, 0.97 mmol) was stirred at 25° C. for 24 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether 8:2) affording the title product (270 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C([NH:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])=O.O.C(=O)(O)[O-].[Na+]>CO>[NH2:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(NC=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(N)c1
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
Phosphoryl chloride (7.8 ml) was added dropwise to a stirred solution of (E)-methyl 2-[2-(3-formamidophenoxy)phenyl]-3-methoxypropenoate (13.67 g) in methanol (100 ml), the temperature during the addition being kept below 50° C. with the aid of a cooling bath. After stirring for 20 minutes, the reaction mixture was poured into water (500 ml), neutralized with sodium bicarbonate and extracted with ether. The extracts were dried and concentrated to give a yellow oil which was chromatographed using ether as the eluant to give (E)-methyl 2-[2-(3-aminophenoxy)phenyl]-3-methoxypropenoate (8.57 g, 68% yield) as a yellow solid, m.p. 83°-85° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N+:12]([O-:14])=[O:13].[C:15]1(OB(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:11]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2cc(Br)cnc12
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc2cc(-c3ccccc3)cnc12
Yield: 41.6 %

Procedure:
A mixture of 3-bromo-8-nitroquinoline (253 mg), phenylboric acid (159 mg), tetrakis(triphenylphosphine)palladium(0) (23 mg) and aqueous 2M sodium carbonate solution (2.5 ml) in 1,2-dimethoxyethane (3.5 ml) was refluxed for 4 hours. To the mixture was added phenylboric acid (122 mg), and the mixture was additionally refluxed for 3 hours. The resulting mixture, after diluted with ethyl acetate, was washed with aqueous 3° sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate) and the obtained oil was crystallized from diethyl ether to give 8-nitro-3-phenylquinoline (104 mg).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C(OCC)C>[C:24]([C:23]1[CH:22]=[C:21]([NH:20][C:14](=[O:16])[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:17])[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: N#Cc1cccc(N)c1
Solvent: CCOCC
Product: N#Cc1cccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)c1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 3-aminobenzonitrile (Aldrich) according to the method described in Example 1c. Melting Point: 135-138° C. (diethylether)
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]5[CH2:31][CH2:30]5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[CH3:32][N:33]([CH3:62])[CH2:34][CH2:35][O:36][C:37]1C=CC(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)=[CH:39][CH:38]=1>>[CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:17])[CH3:18])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][N:33]([CH3:62])[CH3:32])=[CH:31][CH:30]=5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Reactant: CN(C)CCOc1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(-c3nc(CN(C)C)cc(N4C5CCC4COC5)n3)cc2)cc1

Procedure:
A procedure analogous to that used for the preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea was used, using 1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as the boronic ester component. Yield=0.034 g, 18%. MS; 546.5, M+H.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:31])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)[C:18]([F:21])([F:20])[F:19]>>[Cl:9][C:10]1[CH:11]=[C:12]([O:31][CH2:2][C:3]2[CH:7]=[C:6]([CH3:8])[O:5][N:4]=2)[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)([OH:29])[C:18]([F:19])([F:21])[F:20]
Reactant: Cc1cc(CCl)no1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3cc(C)on3)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 3-chloromethyl-5-methylisoxazole and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=442.3 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([C@H:9]3[CH2:13][CH2:12][CH2:11][O:10]3)[CH2:7][S:8][C@H:3]12.C1(N=C=NC2CCCCC2)CCCCC1.[C:43]([O:47][C:48]([NH:50][C@H:51]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([O:47][C:48]([NH:50][C@H:51]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:52]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([C@H:9]3[CH2:13][CH2:12][CH2:11][O:10]3)[CH2:7][S:8][C@H:3]12)=[O:53])=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c4ccc(O)cc4)C(=O)N23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Methoxybenzyl (6R,7R)-7-amino-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (136 mg, 0.35 mmol)(See example 6] in THF (10 ml) was stirred in an ice bath with dicyclohexylcarbodiimide (108 mg, 0.52 mmol) then (R)-2-t-butoxycarbonylamino-2-(4-hydroxyphenyl)acetic acid (139 mg, 0.52 mmol) in THF (3 ml) was added dropwise over 2 min. The mixture was stirred at 0° C. for 30 min then at room temperature for 30 min. It was filtered and evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/hexane mixtures. The title compound was obtained as a white solid (212 mg, 95%); δH (CDCl3) 1.10-2.0 (4H,m), 1.42 (9H,s), 3.18 and 3.43 (2H,ABq, J 17 Hz), 3.80 (3H,s), 3.77-3.88 (2H,m), 4.89 (1H,d, J 5 Hz), 5.10 (1H,t, J 7 Hz), 5.11 (1H,d, J 5 Hz), 5.19 (2H, s), 5.65 (1H,d, J 5 Hz exch), 5.69 (1H,dd, J 4.9 Hz), 6.72 (2H,d, J 8 Hz), 6.81 (1H,d, J 9 Hz exch), 6.88 (2H,d, J 9 Hz), 7.10 (2H,d, J 8 Hz) and 7.33 (2H,d,J 9 Hz). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (938)].
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([CH:11]([C@@H:21]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:22]([NH:24][N:25]([S:32]([CH3:35])(=[O:34])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:7][NH:8][C:9]([CH:11]([C@@H:21]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:22]([NH:24][N:25]([S:32]([CH3:35])(=[O:34])=[O:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)C(C/C=C/c1cccnc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)C(C/C=C/c1cccnc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.4 %

Procedure:
A solution of 0.21 g of (E)-2(R)-[1(RS)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-(3-pyridyl)-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in 5 ml of methanol was treated with 0.097 g of 4-toluenesulphonic acid. The mixture was stirred for 2.5 hours at room temperature and then diluted with water. The solid was filtered off, washed with water and diethyl ether and dried in vacuum to yield 0.138 g of (E)-2(R)-[1(RS)-(hydroxycarbamoyl)-4-(3-pyridyl)-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Li]CCCC.[CH2:20]1[O:22][CH2:21]1>C1COCC1>[CH3:1][C:2]1([CH2:20][CH2:21][OH:22])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC1c2ccccc2-c2ccccc21
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(CCO)c2ccccc2-c2ccccc21
Temperature: -20 °C

Procedure:
To a solution of 9-methylfluorene (10.0 g, 55.5 mmol) in 100 mL of THF was added n-BuLi (61.0 mmol) at -10° C., then a solution of ethylene oxide (61.0 mmol) in THF was added in one portion. The reaction mixture was stirred at -20° C., then allowed to warm to room temperature, quenched with NH4Cl solution and evaporated to a residue. This was then partitioned between ethyl acetate and water, the organic layer was washed with brine, dried with MgSO4 and evaporated to get the product which was purified by chromatography using 10% ethyl acetate/hexane mixture to provide a pure sample of 9-methylfluorene-9-ethanol, m.p. 84°-85° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(=O)[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.S(=O)(=O)(O)O>>[C:14]1(=[O:19])[N:1]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[C:5]([OH:7])=[O:6])[C:17](=[O:18])[CH2:16][CH2:15]1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)O1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(N2C(=O)CCC2=O)cc([N+](=O)[O-])c1

Procedure:
3-Succinimido-5-nitrobenzoic Acid [D; Y is CH2CH2, Z is OH] was prepared by heating 3-amino-5-nitrobenzoic acid with succinic anhydride in the presence of sulfuric acid. It had the m.p. 285°-290° C. when recrystallized from aqueous dimethylformamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
A 250-mL round-bottomed flask was purged with nitrogen and charged with 197a (4.0 g, 13.0 mmol), 10% palladium on carbon (10% wet, 500 mg), and methanol (130 mL). The flask was evacuated, charged with hydrogen gas, and stirred at room temperature for 15 h. Hydrogen was then evacuated and nitrogen was charged to the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 197b (3.3 g, 91%). MS-ESI: [M+H]+ 279
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[CH:16]([C:13]1[N:12]([CH3:18])[C:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:15][CH:14]=1)=[O:17]
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(C=O)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (from the preparation of Intermediate 18) (400 mg, 1.75 mmol) in DMF (10 mL) is added cesium carbonate (853 mg, 2.62 mmol) and MeI (297 mg, 2.09 mmol). The mixture is stirred at room temperature for 2 hours then water is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give benzyl 5-formyl-1-methyl-1H-pyrrole-2-carboxylate; HPLC Retention time 1.26 minutes (condition C): MS 244.3 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]([Mg]Cl)([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH:11]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=1)[OH:12]
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Reactant: CC(C)[Mg]Cl
Product: CC(C)C(O)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43b (283 mg, 1.55 mmol) and isopropylmagnesium chloride (1.55 mL, 3.10 mmol, 2 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (4:1) as eluent. Orange solid. Yield: 138 mg, 40%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.82-0.93 (m, 3H), 1.02 (d, J=6.6 Hz, 3H), 1.95-2.08 (m, 1H), 4.46 (d, J=6.6 Hz, 1H), 7.39-7.44 (m, 1H), 7.45-7.50 (m, 2H), 7.68-7.75 (m, 2H), 7.96-8.01 (m, 2H), 8.57 (d, J=1.9 Hz, H); MS (ESI): m/z=228.26 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:17]=2)[CH:8]=[C:9]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:33].[Na+]>CCO.O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:12])[C:14]([NH2:15])=[O:33])[CH:8]=[C:7]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:19]([CH3:28])=[C:18]([S:29](=[O:31])(=[O:30])[NH2:32])[CH:17]=2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C#N)c2)n1CC1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C(N)=O)c2)n1CC1CCCCC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of compound 45 (455 mg, 1.0 mmol) and NaOH (3.2 g, 80 mmol) in EtOH (10 mL) and water (10 mL) was stirred at reflux overnight, cooled to rt, concentrated and redissolved in H2O (30 mL), acidified with 1N HCl solution to pH=6. The formed solid was collected by filtration, washed with water and dried under vacuum. The residue was purified by CC (DCM/MeOH=50/1) to give compound 47 (400 mg, 85%) of as a white solid.