Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:32][CH2:31][CH2:29][OH:30])=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:18])([F:20])[F:19])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Reactant: NCCO
Product: O=C(NCCO)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 18 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using ethanolamine instead of methylamine to the title compound (19 mg, 18%) which was obtained as a white solid. MS: m/e=426.1 [M+H]+.
Reaction SMILES: BrC1C=C(F)C(OC(=O)C(C)(C)C)=C(F)C=1C#N.[CH3:19][O:20][C:21]([C:23]1[C:24]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[S:39][CH:40]=[CH:41][C:42]=3[NH:43][S:44]([CH:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])=[CH:34][CH:33]=2)=[C:25]([N+:29]([O-])=O)[CH:26]=[CH:27][CH:28]=1)=[O:22].CCOC(C)=O>CCO>[CH3:19][O:20][C:21]([C:23]1[C:24]([C:32]2[CH:33]=[CH:34][C:35]([C:38]3[S:39][CH:40]=[CH:41][C:42]=3[NH:43][S:44]([CH:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])=[CH:36][CH:37]=2)=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1)=[O:22]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Agent: CC(C)(C)C(=O)Oc1c(F)cc(Br)c(C#N)c1F
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Yield: 89.5 %

Procedure:
Add SnCl2 2 H2O (470 mg, 2.8 mmol) to a solution of 6-nitro-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (250 mg, 0.54 mmol) in EtOH (5 mL). Heat the reaction at 80° C. for 3 hours. Add 100 mL EtOAc and wash it with a saturated solution of NaHCO3, water and saturated aq. sodium chloride (50 mL). Dry over NaSO4, filter and evaporate to dryness to provide 6-amino-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (208 mg). MS (m/e): 429.1(M−1).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]1(=[O:70])[O:69][C:67](=[O:68])[CH2:66][CH2:65][CH2:64]1>N1C=CC=CC=1>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]([O-:69])(=[O:70])[CH2:64][CH2:65][CH2:66][C:67]([O-:6])=[O:68]
Reactant: O=C1CCCC(=O)O1
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: c1ccncc1
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Paclitaxel (0.43 g, 0.5 mmol) and glutaric anhydride (0.68 g, 6 mmol) were dissolved in 5 ml of pyridine and stirred at room temperature for 3 hours. In the end of reaction, the solution was evaporated to dryness in vacuo. The residues were treated with 20 ml water with stirring for 20 min and filtered. The precipitates were redissolved in acetone and water was added to produce fine crystals of paclitaxel-glutarate (0.42 g, 86% yields). The analytic result gave [M+H]+=968 Da by ESMs. The paclitaxel-glutarate complex has the following structure:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(C(=O)O)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(=O)n1ccc2cc(C(=O)O)ccc21
Temperature: 110 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
1-Acetyl-2,3-dihydro-1H-indole-5-carboxylic acid (100 mg) was suspended in 1,4-dioxane (3 ml), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (445 mg) was added thereto and stirred for 16 hours at 110° C. Solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (developing solvent; dichloromethane:methanol 20:1) to give the title compound (98 mg, Y.:99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][N:15]2[C:27](=[O:44])[CH:28]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C=C)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH:28]([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[C:27](=[O:44])[N:15]1[CH:14]([CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CCOC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)N2
Yield: 96.3 %

Procedure:
To a solution of 1-{[1-(2-tert-butoxycarbonylamino-non-8-enoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester (1.63 g, 2.56 mmoL) in 640 mL of methylene chloride was added 215 mg (0.26 mmoL) of tricyclohexylphosphine[1,3-bis(2,4,6-tri[benzylidene]ruthenium(IV)dichloride. The mixture was heated at reflux for 15 min. The residue was concentrated in vacuo, and then purified by flash chromatography eluting with 30% ethyl acetate/hexane. To further decolorize the sample, the crude product was chromatographed a second time eluting with 50% ether in hexane to give 1.5 g (96%) of 14-tert-butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester as a white solid. 1H NMR (500 MHz, CD3Cl) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.86 (s, 9H), 1.18–1.24 (m, 6H), 1.34–1.64 (m, 14H), 1.86–1.96 (m, 3H), 2.02–2.09 (m, 1H), 2.11–2.17 (m, 1H), 2.19–2.28 (m, 1H), 2.57–2.63 (m, 1H), 3.50–3.54 (m, 1H), 3.71 (dd, J=10.22, 6.26 Hz, 1H), 4.06–4.17 (m, 2H), 4.52–4.58 (m, 2H), 4.75 (d, J=8.55 Hz, 1H), 5.21 (t, J=9.92 Hz, 1H), 5.35 (d, J=7.63 Hz, 1H), 5.45–5.50 (m, 1H), 6.94 (s, 1H). LC-MS (Method A, retention time: 3.88 min), MS m/z 608 (M++1).
Reaction SMILES: [P].P(Cl)(Cl)(Cl)(Cl)Cl.C1(CC([NH:17][CH:18]2[C:52](=[O:53])[N:20]3[C:21]([C:36]([O:38][CH:39]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])=[C:22]([O:25][S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH2:23][S:24][C@H:19]23)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.N1C=CC=CC=1>[NH2:17][CH:18]1[C:52](=[O:53])[N:20]2[C:21]([C:36]([O:38][CH:39]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:37])=[C:22]([O:25][S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH2:23][S:24][C@H:19]12
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)cc1
Yield: 88 %

Procedure:
To a suspension of phosphorus pentachloridepyridine complex prepared from phosphorus pentachloride (2.05 g) and pyridine (0.8 ml) in methylene chloride (40 ml) was added benzhydryl 7-phenylacetamido-3-tosyloxy-3-cephem-4-carboxylate (4.3 g) under ice-cooling with stirring. The mixture was stirred at the same temperature for 30 minutes and cooled in a dry ice-acetone bath. To the solution was added methanol (6 ml) at -30° C. and the mixed solution was stirred at -10° to -5° C. for an hour. The resulting solution was adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (100 ml). The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give benzhydryl 7-amino-3-tosyloxy-3-cephem-4-carboxylate (3.1 g)
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].O.C(=O)(O)[O-].[C:15](O)(=[O:26])[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.Cl>COCCOC>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:15]([NH:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:26]
Reactant: NC(=O)[C@@H](N)CC(=O)O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: NC(=O)[C@H](CC(=O)O)NC(=O)c1ccc2ccccc2n1
Yield: 69.1 %

Procedure:
To a solution of 0.50 g (3.78 mmol) of L-isoasparagine in 5.0 mL H2O containing ~45 mg (1.5 eq) of solid bicarbonate. To this was added a suspension of 1.02 g (3.78 mmol) quinaldic acid, N-hydroxysuccinamide ester in ethylene glycol dimethylether, and the suspension was solubilized by the addition of 10 mL of dimethyfformamide. After 3 hours the solution was acidified by the addition of 5% HCl (aqueous) and the product was filtered and washed with water, dried under vacuum to yield 750 mg (70% yield) of N-(2-quinolinylcarbonyl)-L-isoasparagine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:29][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=3)=[CH:18][N:17]=2)=[CH:26][CH:25]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 0 °C

Procedure:
0.06 mL (0.75 mmol) of methanesulfonic acid chloride was added dropwise at 0° C. to a solution of 167 mg (0.50 mmol) of 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}ethanol and 0.08 mL (1.00 mmol) of pyridine in 5 mL of DCM and the mixture was then stirred for I hour at 0° C. It was combined again with pyridine (0.08 mL) and methanesulfonic acid chloride (0.06 mL) and stirred for 1 hour at RT. Then it was combined with 0.14 mL (1.00 mmol) of triethylamine and after 20 minutes at RT diluted with ice water. The organic phase was separated off, dried over magnesium sulfate, filtered, and the solvent was eliminated in vacuo. Yield: 185 mg (90% of theoretical); C22H18ClNO3S (M=411.902); calc.: molpeak (M+H)+:412/414 (Cl); found: molpeak (M+H)+:412/414 (Cl); HPLC-MS: 6.27 minutes (method H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:10](/[O-:18])=[CH:11]/P(OC)(OC)=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li+].O=[C:21]1[CH2:24][CH:23]([C:25]#[N:26])[CH2:22]1>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH:11]=[C:21]2[CH2:24][CH:23]([C:25]#[N:26])[CH2:22]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1/C([O-])=C/P(=O)(OC)OC
Reactant: N#CC1CC(=O)C1
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(Br)cc1C(=O)C=C1CC(C#N)C1
Temperature: 120 °C

Procedure:
A mixture of lithium (Z)-1-(5-bromo-2-methoxypyridin-3-yl)-2-(dimethoxyphosphoryl)ethenolate (2.0 g, 5.8 mmol) and 3-oxocyclobutanecarbonitrile (1.1 g, 12 mmol) in p-dioxane (6 ml) was heated at 120° C. by Microwave in 1 h. The mixture was cooled, taken up in H2O, extracted with EtOAc (3×), dried over MgSO4, concentrated to provide the title compound. MS (m+1): 307.0.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([O:13][C@@H:47]2[CH:48]3[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]3)[CH2:46]2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(=O)N1CCN(C(C(=O)O)c2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
2-(4-Acetylpiperazin-1-yl)-2-phenylacetic acid (238 mg, 0.91 mmol) was suspended in dry THF (9 ml) and, with stirring at room temperature under nitrogen atmosphere, DCC (374 mg, 1.81 mmol), HOBT (245 mg, 1.81 mmol) and (R)-quinuclidin-3-ol (231 mg, 1.81 mmol) were sequentially added. The reaction was reacted at the same temperature for three days. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH/NH4OH=97/3/0.3). The product was suspended in THF/Acetonitrile (2/1; 10 ml) and the white solid was filtered off. The colourless solution was evaporated obtaining (R)-quinuclidin-3-yl 2-(4-acetylpiperazin-1-yl)-2-phenylacetate (218 mg, 64.7% yield) as a off-white spongy solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:23]1[CH:24]=[N:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1>O1CCOCC1.O.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>[CH3:1][N:2]1[C:6]([C:23]2[CH:24]=[N:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O)c1ncc(Br)cn1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cnc(C(=O)O)nc1
Temperature: 80 °C
Yield: 74.7 %

Procedure:
To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.35 g, 6.5 mmol) in dioxane/H2O (5:1, 59 mL) was added K2CO3 (2.8 g, 20.3 mmol), tetrakistriphenylphosphine Pd(0) (340 mg, 0.3 mmol), and 5-bromo-2-pyrimidinecarboxylic acid (1.2 g, 5.9 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h. The reaction solution was poured onto H2O (100 mL) and extracted with DCM. The organics were dried (Na2SO4), concentrated under vacuum to give the title compound (0.9 g, 36%) as a tan solid: LC-MS (ES) m/z=437 (M+H)+.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=1>[H][H].[C].[Pd]>[C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: [H][H]
Reactant: Cc1cc(C)c(-c2ncccc2[N+](=O)[O-])c(C)c1
Agent: [Pd]
Product: Cc1cc(C)c(-c2ncccc2N)c(C)c1
Yield: 106.5 %

Procedure:
Palladium-carbon (10%, 0.6 g) was added to a solution of 2-mesityl-3-nitropyridine (5.99 g, 23 mmol) methanol (120 mL), followed by stirring for one day in hydrogen atmospher. The mixture was filtered through Celite and evaporated, to give the title compound (5.2 g) as white crystals.
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH2:5].[C:42]([N:46]=[C:47]=[O:48])([CH3:45])([CH3:44])[CH3:43]>C1COCC1>[OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[NH:5][C:47]([NH:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:48]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)CC1CCCCC1
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1

Procedure:
Under a protective gas atmosphere, 100 mg (0.178 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]hydrazine (Example 71E) i)) are dissolved in 0.7 ml of THF and reacted with 19 μl (0.169 mmol) of tert-butyl-isocyanate for 17 h at RT. The reaction mixture is concentrated by evaporation, the residue is dissolved in ethyl acetate and washed with 5% citric acid solution, water and brine, and the inorganic phases are extracted twice with ethyl acetate, dried with Na2SO4 and concentrated by evaporation. Column chromatography (SiO2, ethyl acetate/ethanol 10:1) yields the title compound: TLC Rf (F')=0.16; tRet (V)=15.3 min; FAB-MS (M+H)+ =660.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>[N+](C1C=CC=CC=1)([O-])=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:10]=3[CH2:9][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1CCc1cccc(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=C1c2ccc(Br)cc2CCc2cc(C(F)(F)F)ccc21
Temperature: 100 °C

Procedure:
A mixture of the product from step (iv) (2.31 g) and phosphorous pentoxide (14 g) in nitrobenzene (15 ml) was heated at 100° C. for 8 hours. The solid mixture was added to water, salted out and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated, distilled to remove nitrobenzene and the residue purified by chromatography eluting with 10% ethyl acetate in isohexane. Yield 1.14 g.
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:11]=[CH:10][N:9]=1.[OH-].[Na+]>ClCCl>[OH:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:11]=[CH:10][N:9]=1
Reactant: COCc1ncnc(N2CCCCC2)c1C
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(CO)ncnc1N1CCCCC1

Procedure:
Boron tribromide (8.9 ml) in dichloromethane (25 ml) was added dropwise, under nitrogen, to a stirred solution of 4-methoxymethyl-5-methyl-6-piperidinopyrimidine (5 g) in dichloromethane (100 ml) at 0°-5°. After a further 2 hours the mixture was poured onto ice, the pH raised to 13 (NaOH) and extracted with chloroform. Extracts were dried (K2CO3) and stripped to a residue, which was triturated with diethyl ether to give 4-hydroxymethyl-5-methyl-6-piperidinopyrimidine, 3.80 g, as a crystalline solid, m.p. 79°-81°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:9][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:6][C:7]=1[CH3:8].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.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>[CH3:8][C:7]1[N:6]=[C:5]([CH2:9][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)[CH:4]=[CH:3][C:2]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH3:23]
Reactant: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Br
Reactant: Cc1ccccc1B(O)O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A 40 mL vial was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4[(5-bromo-6-methylpyridin-2-yl)methyl]piperazine-1-carboxylate (1.00 g, 2.70 mmol, 1.00 equiv), (2-methylphenyl)boronic acid (0.730 g, 5.40 mmol, 2.00 equiv), tetrakis(triphenylphosphine)palladium (0.310 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.15 g, 8.32 mmol, 3.08 equiv), dioxane (15 mL), water (3 mL). The resulting solution was stirred overnight at 80° C. and diluted with water (20 mL). The resulting solution was extracted with ethyl acetate (2×20 mL) and the organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (60/40) to provide 1.00 g (92% yield) of tert-butyl 4-[[6-methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 382 [M+H]+.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+]>CC1CCCO1>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:6][CH2:5][CH:3]2[CH2:4][O:1][CH2:2]2)=[CH:14][CH:13]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CBr)cc2)c(C)c1
Reactant: OCC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(COCC3COC3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of oxetan-3-ylmethanol (7 mg, 0.075 mmol) and 4-(bromomethyl)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (31 mg, 0.075 mmol) in 2-methyltetrahydrofuran (2-MeTHF) (1 mL) stirred under nitrogen at room temperature was added sodium hydride (60% dispersed in oil, approximately 2 mg, 0.075 mmol). The reaction mixture was stirred at 20° C. for 3 hours then quenched with water (75 uL). The solvent was removed under a stream of nitrogen to give the crude product. The crude was then purified by mass directed autoprep (ammonium carbonate modifier). The appropriate fractions were concentrated under a stream of nitrogen to give the required product, 2.4 mg. LCMS [LCMS1] Rt 1.34 min, m/z (ES+) 418 (M+H).