Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>ClCCl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=1)=[O:10])=[O:2]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C=O)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Publicly known [e.g. E. J. Wayne et al, J. Chem. Soc., 1022(1922)] 5-formyl-2-methoxybenzoic acid (4.05 g, 22.5 mmol) was dissolved in 80 ml of dichloromethane, which was cooled with ice. Triethylamine (7.94 ml, 56.2 mmol) was added under stirring. Next, ethyl chlorocarbonate (2.44 ml, 24.8 mmol) was added and, after stirring for 10 minutes, 4-(trifluoromethyl)benzylamine (3.31 ml, 22.5 mmol) was added dropwise, which was allowed to stand overnight. After washed with water, the reaction mixture was dried over anhydrous sodium sulfate and concentrated. Water was added to the residue, which was made acidic with dilute hydrochloric acid. Then, the precipitates were filtered and dried to quantitatively obtain the title compound as milky white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1)[CH3:2]
Reactant: CCOC(=O)CCBr
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCn1cnc2ccccc21
Yield: 90.9 %

Procedure:
Ethyl-3-bromopropanoate (1.29 g, 7.1 mmol), benzimidazole (0.70 g, 5.9 mmol), and potassium carbonate (2.44 g, 17.7 mmol) were combined in anhydrous acetonitrile (60 mL) and heated to reflux for 3 days. Aqueous work-up gave ethyl-3-(benzimidazol-1-yl)propanoate (1.17 g, 91%). 1H NMR (CDCl3) δ 2.02 (s, 3H), 2.26 (m, 2H), 4.10 (t, 2H, J=6 Hz), 4.30 (t, 2H, J=6 Hz), 7.28 (br, 2H), 7.33 (br, 1H), 7.84 (br, 1H), 7.94 (br, 1H), 7.60 (br, 1H).
Reaction SMILES: [OH:1][CH:2]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][N:28]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:29]=3[C:30]([F:33])([F:32])[F:31])[O:22][N:21]=2)=[CH:16][CH:15]=1)[C:3]([NH:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[OH:1][CH:2]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][N:28]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:29]=3[C:30]([F:31])([F:32])[F:33])[O:22][N:21]=2)=[CH:16][CH:15]=1)[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
(R/S)-tert-Butyl 2-(2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)acetate (Example 56, 30 mg, 0.055 mmol) was dissolved in THF (3 mL) and MeOH (1.50 mL). Next, LiOH (2.64 mg, 0.110 mmol) was added. After 20 min, additional LiOH (2.64 mg, 0.110 mmol) was added. After another 20 min, 1N HCl was used to adjust the pH to 4-5. The reaction mixture was concentrated. EtOAc was added and the resulting mixture was filtered. The filtrate was concentrated to provide (R/S)-2-(2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)acetic acid (15 mg, 0.029 mmol, 52.2% yield): LCMS=488.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.47 (1 H, s), 8.13 (2 H, d, J=8.35 Hz), 7.53-7.75 (7 H, m), 5.17 (1 H, s), 3.99 (2 H, s); HPLC peak RT=7.1 min (Method A).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][NH:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[C:21]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([C:28]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[C:21]3[C:11]4[CH:10]=[N:9][NH:8][C:12]=4[N:13]=[CH:14][C:15]=3[CH2:16][CH2:17]2)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCNc2ccccc2-4)cc1
Product: O=C(c1ccccc1)N1CCc2cnc3[nH]ncc3c2-c2ccccc21
Yield: 19 %

Procedure:
The compound, 8-(phenylcarbonyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine was prepared using 3-(4-methoxybenzyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine and bezoyl chloride using the 2 step conditions described in general procedure R to give the desired product as a white solid (0.028 g, 19%). M.p.>150° C.; 1H NMR (CDCl3, 400 MHz) δ: 11.25 (brs, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.84 (dd, J1=1.2 Hz, J2=8.0 Hz, 1H), 7.41 (m, 1H), 7.21-7.07 (m, 6H), 6.82 (d, J=7.2 Hz, 1H), 4.74 (m, 1H), 3.92 (m, 1H), 3.00 (m, 2H); LCMS [M+H]: 341.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH2:6]([O:13][C:14]([O:16]NC(=O)CCC(N)=O)=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:25][C@@H:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:27]([OH:29])=[O:28]>CC(C)=O.O>[C:7]1([CH2:6][O:13][C:14]([NH:25][C@@H:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:27]([OH:29])=[O:28])=[O:16])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc([C@H](N)C(=O)O)cc1
Reactant: NC(=O)CCC(=O)NOC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1

Procedure:
A suspension of NaHCO3 (184 mg, 2.2 mmol), commercially available N-(benzyloxycarbonyloxy)succinamide (548 mg, 2.2 mmol) and (S)-α-amino-4-methoxybenzeneacetic acid (360 mg, 2 mmol), synthesis described in U.S. Pat. No. 3,517,023, in 1:1 acetone/H2O was stirred for 18 hours at 20° C. After partial concentration and extraction with CH2Cl2, the pH was adjusted to 1.5 and the solution extracted with EtOAc (3×). The EtOAc extracts were washed with brine, dried over MgSO4 and concentrated to yield (S)-α-[N-[(phenylmethoxy)carbonyl]amino]-4-methoxybenzeneacetic acid. A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (608 mg, 3.2 mmol), hydroxybenztriazole (643 mg, 4.76 mmol) and (S)-α-[N-(phenylmethoxy)carbonyl]amino-4-methoxybenzeneacetic acid (1 g, 3.17 mmol) in CH2Cl2 (10 mL) was stirred one hour at 0° C. whereupon N-methylmorpholine (0.7 mL, 6.4 mmol) and t-butylamine (0.5 mL, 4.8 mmol) were added and the reaction stirred at 20° C. for 18 hours. The reaction was diluted with EtOAc, washed with H2O, aq. NaHCO3, brine, dried over MgSO4, and concentrated. Pure (S)-N-(1,1-dimethylethyl)-α-[N-[(phenylmethoxy)carbonyl]amino]-4-methoxybenzeneacetamide was obtained after chromatography on silica gel using 35% EtOAc/hexane as eluant. Hydrogenation of (S)-N-(1,1-dimethylethyl)-α-[N-[(phenylmethoxy)carbonyl]amino]-4-methoxybenzeneacetamide over 10% Pd(OH)2 /C at 1 atom of H2 in 1:1 MeOH/EtOAc generated the title compound which required no further purification following filtration and concentration.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.[CH3:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:35][CH2:34][C:31]3[CH:30]=[N:29][C:28]([CH3:27])=[CH:33][N:32]=3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: Cc1cnc(CN)cn1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2cnc(C)cn2)cc1Cl
Reaction time: 18 h
Yield: 40.5 %

Procedure:
In THF (50 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (202 mg, 0.54 mmol), (5-methylpyrazine-2-yl)methylamine (79 mg, 0.64 mmol) and triethylamine (0.2 mL). The solution was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was then added. The reaction was conducted at ambient temperature for 18 h. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=50/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-((5-methylpyrazine-2-yl)methyl)pyrimidine-5-formamide (105 mg, 40% yield).
Reaction SMILES: [CH3:1][C:2]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([CH2:6][CH2:7][O:8][CH3:9])[CH2:3][C:4]#[CH:5].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:27]([SnH:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>>[CH2:36]([Sn:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])/[CH:5]=[CH:4]/[CH2:3][C:2]([CH3:1])([O:10][Si:11]([CH3:14])([CH3:12])[CH3:13])[CH2:6][CH2:7][O:8][CH3:9])[CH2:37][CH2:38][CH3:39]
Reactant: C#CCC(C)(CCOC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/CC(C)(CCOC)O[Si](C)(C)C)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 15 g. (0.069 moles) of 4-methyl-4-trimethylsilyloxy-7-oxa-1octyne and 75 mg. of azobisisobutyronitrile is added dropwise, under nitrogen atmosphere, 21.1 g. (0.073 moles) of tri-n-butyltin hydride. The solution is stirred at 130°-135° C. for 11/2 hours, then cooled to ambient temperature. Distillation provides 29 g. (86%) of product as a colorless oil; b.p. 165°-167° C. (0.25 mm.).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[N:32]([C@@H:35]([CH:40]([CH3:42])[CH3:41])[C:36]([O:38][CH3:39])=[O:37])=[C:33]=[O:34].O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:26][CH2:27][C@H:28]([O:31][C:33](=[O:34])[NH:32][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH:40]([CH3:42])[CH3:41])[CH2:29][CH2:30]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(NC(=O)O[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1)C(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5-cyclohex-1-enyl-3-{(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino}-thiophene-2-carboxylic acid (20 mg, 0.045 mmol) and methyl (S)-(−)-2-isocyanato-3-methylbutyrate (10 μl, 0.07 mmol) in toluene (1 mL) was stirred at 70° C. for 2 h. It was cooled and water (1 mL) was added. The mixture was stirred at room temperature for one h. It was extracted with EtOAc (50 mL), washed with brine, dried (MgSO4) and evaporated. Pure 5-cyclohex-1-enyl-3-[{trans-4-(1-methoxycarbonyl-2-methyl-propylcarbamoyloxy)-cyclohexyl}-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid was obtained by chromatography over silica gel (hexane-EtOAc mixtures, pure EtOAc and 5% acetone in DCM as eluent) (12.4 mg, 45%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([N:22]=[CH:23][CH:24]=3)[CH:21]=2)=[CH:12][CH:11]=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([N:22]=[CH:23][C:24]=3[I:1])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2ccc3ccnn3c2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ccc3c(I)cnn3c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
N-iodosuccinimide (630 mg, 2.8 mmol) was added in one portion to a stirred solution of 6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine (500 mg, 2.4 mmol) in dry DMF (6 ml) at RT under N2. After 45 minutes, the reaction was quenched with saturated aqueous sodium thiosulphate/saturated NaHCO3 (1:1, 40 ml). The mixture was stirred at RT for 15 minutes then partitioned between EtOAc/H2O. The organic layer was washed with water (×1), brine (×1), then dried (MgSO4), filtered and evaporated. The residue was purified trituration with petrol to give the title compound (635 mg, solid). 1H NMR (400 MHz, CDCl3): 8.61 (1H, s), 7.98 (1H, s), 7.57-7.51 (3H, m), 7.42 (1H, dd), 7.22-7.13 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:19])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:4]>CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:19])[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)COC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)COc1ccc(N)cc1
Reaction time: 2 h
Yield: 73.1 %

Procedure:
(4-Nitrophenoxy)-acetic acid methoxycarbonyl methyl ester 44 (20 g, 74.3 mmol) was dissolved in dimethyl formamide (100 ml) in a pressure vessel. Palladium on carbon (5%, 8 g) was added, and the mixture stirred under an atmosphere of hydrogen (4 kg) for 2 hours. The catalyst was removed by filtration and ice water (400 ml) was added to the filtrate. Crude 45 was extracted into ethyl acetate, dried over Na2SO4 and distilled. Crude 45 was then recrystallised from chloroform:hexane (1:6) to get pure 45 (13 g, 73%) as a light brown shining powder with an m.p. between 76.5-78.5° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[CH2:3]1.[I:20]N1C(=O)CCC1=O.O>C(Cl)Cl>[I:20][C:16]1[NH:15][C:14]([C@@H:4]2[CH2:3][C@H:2]([CH3:1])[CH2:6][N:5]2[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])=[N:18][C:17]=1[CH3:19]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c[nH]c([C@@H]2CC(C)CN2C(=O)OC(C)(C)C)n1
Solvent: O
Solvent: ClCCl
Product: Cc1nc([C@@H]2C[C@H](C)CN2C(=O)OC(C)(C)C)[nH]c1I
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stirred solution of tert-butyl (2S)-4-methyl-2-(4-methyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (307 mg, 1.013 mmol) in CH2Cl2 (15 mL) is added N-iodosuccinimide (240 mg, 1.013 mmol) at 5° C. The reaction mixture is stirred for one hour and water (2 mL) is added. The organic layer is separated, dried over Na2SO4, and evaporated to dryness. The residue is purified by flash column chromatography on silica gel (12 to 100% EtOAc in Hexanes) to give tert-butyl (2S,4S)-2-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (246 mg, 62%).
Reaction SMILES: O.[N+:2]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=4)=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[CH:34][CH:35]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CCc3ccc(Cc4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cc2ccc(CCc3ccc(Cc4ccc(N)cc4)cc3)cc2)cc1
Yield: 62.9 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 2.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 25.1 g of 1,2-bis(4-(4-nitrobenzyl)phenyl)ethane in 400 milliliters of tetrahydrofuran were introduced and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Crystals were dissolved in chloroform, subjected to a column chromatography treatment with active alumina and silica gel, and thereafter the solution was reconcentrated to give a concentrate, which was then recrystallized from a toluene solvent, to obtain 13.7 g of 1,2-bis(4-(4-aminobenzyl)phenyl)ethane. Melting point was from 138.8° to 140.4° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cncc(Br)c2)CC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
To a solution of 3,5-dibromopyridine (XXXVIII) (2.90 g, 12.24 mmol) in dry DMF (20 mL) was added 1-methylpiperazine (2.987 mL, 26.93 mmol) and K2CO3 (5.58 g, 40.39 mmol). The reaction was heated at 120° C. overnight. An additional portion of 1-methylpiperazine (6 mL) was added and heating was continued for another 24 h. The reaction was poured into ice water and filtered. The filtrate was extracted with 66% MeOH/CHCl3. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to yield 1-(5-bromopyridin-3-yl)-4-methylpiperazine (XL) as a brown viscous oil (2.49 g, 9.76 mmol, 79.8% yield). ESIMS found for C10H14BrN3 m/z 256 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:17][C@@H:18]([N:20]1[C:29](=[O:30])[CH2:28][C:23]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][C:21]1=[O:31])[CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:19][C@@H:18]([N:20]2[C:29](=[O:30])[CH2:28][C:23]3([CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:22][C:21]2=[O:31])[CH3:17])[CH2:14][CH2:15]1
Reactant: C[C@@H](CCl)N1C(=O)CC2(CCCC2)CC1=O
Reactant: Fc1cc(F)c(N2CCNCC2)cc1F
Product: C[C@@H](CN1CCN(c2cc(F)c(F)cc2F)CC1)N1C(=O)CC2(CCCC2)CC1=O
Temperature: 160 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
A mixture of 1-(2,4,5-trifluorophenyl)piperazine (20 mg, 0.093 mmol) and (S)-8-(2-chloro-1-methylethyl)-8-azaspiro[4.5]decane-7,9-dione (20 mg, 0.082 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (18.1 mg, 0.043 mmol, 52%): ESI-MS m/z 424 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [O-][n+]1ccccc1SCc1ccc(Cl)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccc(Cl)c(Cl)c1)c1cccc[n+]1[O-]

Procedure:
The procedure employed is identical to that of Example 68 using 8 gm (0.028 mol) 2-(3,4-dichlorophenylmethylthio)pyridine N-oxide in 50 ml of chloroform and 5.6 gm (0.028 mol) MCPBA in 100 ml chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][OH:16])[O:8][C:7]([CH3:18])([CH3:17])[CH:6]=[C:5]2[C:19]([F:22])([F:21])[F:20].O[C:24]1[CH:38]=[CH:37][C:27]([O:28][C@@:29]([CH3:36])([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][O:16][C:24]1[CH:38]=[CH:37][C:27]([O:28][C@@:29]([CH3:36])([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[O:8][C:7]([CH3:18])([CH3:17])[CH:6]=[C:5]2[C:19]([F:20])([F:22])[F:21]
Reactant: CC[C@](C)(Oc1ccc(O)cc1)C(=O)OC
Reactant: CC1(C)C=C(C(F)(F)F)c2cc(Cl)c(OCCCO)cc2O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@](C)(Oc1ccc(OCCCOc2cc3c(cc2Cl)C(C(F)(F)F)=CC(C)(C)O3)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of 3-((6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propan-1-ol (0.5 g, 1.48 mmol), (2S)-Methyl 2-(4-hydroxyphenoxy)-2-methylbutanoate (0.35 g, 1.56 mmol), and triphenylphosphine (0.42 g, 1.6 mmol) in THF (20 mL) was added diethyl azodicarboxylate (0.28 g, 1.6 mmol) and the solution stirred at ambient temperature for 16 h. After concentrating under reduced pressure, the residue thus obtained was chromatographed over silica gel using AcOEt/hexanes to furnish the desired compound (0.49 g).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[C:19]([NH:29][CH2:30][C:31](O)=[O:32])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CN(C=O)C>[CH2:22]([O:21][C:19]([NH:29][CH2:30][C:31]([C@@:7]1([N:6]2[CH:16]=[C:2]([F:1])[C:3](=[O:18])[NH:4][C:5]2=[O:17])[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])=[O:32])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCC(=O)[C@@]1(n2cc(F)c(=O)[nH]c2=O)O[C@H](CO)[C@@H](O)[C@H]1O)OCc1ccccc1
Reaction time: 48 h
Yield: 26.5 %

Procedure:
5-Fluorouridine (0.300 g, 1.144 mmol, Sigma) was suspended in 4.0 mL of anhydrous tetrahydrofuran under nitrogen. Dry DMF (0.25 mL) was added. Slowly, the solid dissolved. Cbz glycine (0.239 g, 1.142 mmol, Aldrich), triphenylphosphine (0.300 g, 1.144 mmol), and DIAD (0.220 g, 1.088 mmol) were added. The yellow solution was stirred for 48 h. The solution was concentrated under reduced pressure and chromatographed eluting successively with 1:20 MeOH:CHCl3, 1:10 MeOH:CHCl3, then 1:5 MeOH:CHCl3 to provide 0.137 g (27%) of the title compound as a colorless oil. (The same reaction without the DMF as a cosolvent resulted in an isolated yield of only 13%): IR (TF) 3300 (br), 1710, 1670 cm-1 ; 1H NMR (300 MHz, methanol-d4) δ3.95 (s, 2H, NHCH2 CO), 4.05-4.20 (m, 3H, ribose H-2',3', 4'), 4.35-4.50 (m, 2H, ribose H-5'), 5.09 (s, 2H, benzylic H), 5.81 (m, 1 H, ribose H-1'), 7.25-7.40 (m, 5H, aromatic H), 7.83 (m, 1 H, vinylic H); 13C NMR (75 MHz, methanol-d4) δ43.41, 64.90, 67.82, 70.65, 74.99, 82.85, 91.43, 125.95 (d, J=34.7 Hz, C 4), 128.77, 128.97, 129.40, 137.86, 141.74 (d, J=234.3 Hz, C5), 150.74, 158.96, 159.24 (d, J=26.2, C4), 171.55; TLC (methanol-chloroform, 1:5) Rf =0.35; exact MS (El) calcd for C19H20N3O9F: m/z 453.1184. Found: m/z 453.1174.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH3:12].C([Li])(C)(C)C.CCCCC.CN(C)[CH:25]=[O:26]>C1COCC1>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:25]=[O:26])[CH:3]=2)[NH:7][N:6]=1)[CH3:12]
Reactant: CCc1n[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCc1n[nH]c2ccc(C=O)cc12

Procedure:
A solution of 6.90 g (30.7 mmol) 5-bromo-3-ethyl-1H-indazole (Example 7A) in THF (300 ml) was cooled to −78° C. At this temperature, a 1.7 M solution of tert-butyllithium in n-pentane (63.1 ml, 107 mmol) was slowly added. The mixture was stirred at −78° C. for 30 minutes before N,N-dimethylformamide (80.0 ml) was slowly added. The cooling bath was removed, and stirring was continued until room temperature was reached. Then, water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.5 g (84% of th.) of the crude title compound which was used in the next step without further purification.