Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.Cl.O.[Zn]>[Cl:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)cc1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5.0 g, 16.75 mmol) in dioxane (200 ml) was added water (20 ml), Pd(PPh3)4 (924 mg, 0.80 mmol), K3PO4 (7.0 g, 32.98 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (6.3 g, 33.17 mmol) with stirring overnight at 100° C. under nitrogen. The resulting mixture was concentrated under vacuum and dissolved in water (250 ml), extracted with ethyl acetate (3×200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was re-crystallized from 50% ether in hexane to afford 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline as a yellow solid (4.2 g, crude). Next, to a solution of 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline (3.7 g, crude) in ethanol (300 ml) and hydrogen chloride (3.0 ml) was added Zn powder (4.55 g, 70.0 mmol) in several bacthes with stirring for 20 min at room temperature. The resulting solution was stirred for 7 h at 85° C. The solids were filtered out and the filtrate was concentrated under vacuum to give a residue, which was dissolved in water (100 ml). The mixture was adjusted to pH 7 with saturated aqueous sodium carbonate, extracted with ethyl acetate (3×300 ml) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column eluted with 10% to 50% ethyl acetate in petroleum ether to produce 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (2.9 g,). Finally, the solution of 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine (150 mg, 0.52 mmol) in pentafluoropropanoic acid (1 ml) was stirred overnight at 80° C. The result mixture was diluted with water (50 ml) and adjusted to pH 7 with saturated aqueous sodium carbonate. The resulting solution was extracted with ethyl acetate (3×50 ml), combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 0.5% to 6.5% ethyl acetate in petroleum ether to produce 5-chloro-2-(pentafluoroethyl)-6-[4-(trifluoromethyl)phenyl]-1H-1,3-benzodiazole as a white solid (112.6 mg, 52%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][C:22]=4[O:33][CH3:34])[CH:19]=3)[N:14]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:13]=2)[CH:9]=[N:8]1.[CH3:48][C@H:49]1[CH2:51][O:50]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:48][C@@H:49]([OH:50])[CH3:51])[CH2:31][CH2:32]5)=[CH:23][C:22]=4[O:33][CH3:34])[CH:19]=3)[N:14]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:36])=[O:37])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: COc1cc(N2CCNCC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1cc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(2-methoxy-4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (180 mg. 0.267 mmol) was alkylated using (S)-2-methyloxirane (47 mg, 0.802 mmol), DIPEA (207 mg, 1.604 mmol) and ethanol (5 mL) to get 120 mg (crude) of the titled compound. MS: m/z=695.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:14])[CH2:10][C:11](=[O:13])[N:29]1[CH2:28][CH2:27][CH2:26][CH2:24]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: C[C@H](CC(=O)N1CCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-butyric acid (150 mg, 0.74 mmol) and HATU (309 mg, 0.81 mmol) in DMF (2 mL) was added pyrrolidine (0.19 mL, 2.21 mmol). The resultant yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated to afford ((R)-1-methyl-3-oxo-3-pyrrolidin-1-yl-propyl)-carbamic acid tert-butyl ester as a colorless oil which was used without further purification.
Reaction SMILES: [CH2:1](Br)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([C:13]1([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([OH:27])[CH:21]=2)[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)[CH3:12]>>[CH2:1]([O:27][C:22]1[CH:21]=[C:20]([C:13]2([CH2:11][CH3:12])[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[O:14]2)[CH:25]=[C:24]([F:26])[CH:23]=1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCC1(c2cc(O)cc(F)c2)COC(C)(C)O1
Reactant: BrC/C=C/c1ccccc1
Product: CCC1(c2cc(F)cc(OC/C=C/c3ccccc3)c2)COC(C)(C)O1
Yield: 2 %

Procedure:
Using the procedure described in Example 6, (E)-cinnamyl bromide was reacted with 4-ethyl-4-(5-fluoro-3-hydroxyphenyl)-2,2-dimethyl-1,3-dioxolane to give 4-[3-((E)-cinnamyloxy)-5-fluorophenyl]-4-ethyl-2,2-dimethyl-1,3-dioxolane in 2% yield, as an oil.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[OH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]([C:7]1[O:8][C:4]2[CH:3]=[C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:23][OH:22])[CH:29]=3)[CH:21]=[CH:20][C:5]=2[C:6]=1[CH3:19])=[O:10]
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Reactant: OCc1cccc(B(O)O)c1
Product: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(CO)c3)ccc12

Procedure:
(2,4-Dichloro-phenyl)-[6-(3-hydroxymethyl-phenyl)-3-methyl-benzofuran-2-yl]-methanone was prepared via a Suzuki coupling of (6-Bromo-3-methyl-benzofuran-2-yl) (2,4-dichloro-phenyl)-methanone and 3-(Hydroxymethyl)phenylboronic acid as described in method 1 step 5. 1H-NMR (CDCl3) δ 7.62 (d, J=8 Hz 1H), 7.57-7.53 (m, 1H), 7.48 (dd, J=9 Hz, J=2 Hz, 1H), 7.46-7.44 (m, 2H), 7.40 (d, J=2 Hz, 1H), 7.37-7.33 (m, 2H), 7.30-7.26 (m, 2H), 4.68 (s, 2H), 2.51 (s, 3H).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:17])[C@@H:10]([OH:24])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C@H:39]([CH3:43])[C:40](O)=[O:41]>>[C:25]1([C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:40](=[O:41])[C@H:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])[CH3:43])[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:17])[C@@H:10]([OH:24])[CH2:9]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: O[C@H]1CC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]2[C@]1(O)c1ccccc1
Agent: Cl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)C[C@H](O)[C@@]2(O)c1ccccc1
Yield: 80.1 %

Procedure:
By working in accordance with Example 1, starting from 0.5 g of (3aS,4S,5S,7aS)-7,7-diphenyl-4-phenyl-perhydroisoindole-4,5-diol hydrochloride and 0.25 g of (S)-2-(2 -methoxyphenyl)-propionic acid, 0.52 g of (3aS, 4S, 5S, 7aS)-7,7-diphenyl-4-phenyl-2-[-2-(2-methoxyphenyl)-(S)-propionyl]-perhydroisoindole-4,5 diol is obtained in the form of a white solid which melts with decomposition at 158° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:17]([O:19]C)=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CN(C)C(=O)OC(C)(C)C)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CC1(C(=O)O)CCOCC1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 97.7 %

Procedure:
Methyl 4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}tetrahydro-2H-pyran-4-carboxylate (2.81 mmol) was dissolved in methanol (7.3 mL) and water (5.9 mL) and treated with 10 M sodium hydroxide (1.40 mL, 14.0 mmol). The solution was heated at 60° C. overnight. The reaction was cooled to room temperature, and volatiles were removed on a rotovap. The remaining solution was diluted with water and washed with ethyl acetate (2 times). The water layer was cooled with an ice bath and then acidified with a mixture of 1 N aqueous HCl (28.1 mL) and saturated sodium chloride (28.1 mL). The product was extracted with ethyl acetate (3 times), and the organic solution was dried over anhydrous sodium sulfate and filtered. Concentration of the organic solution gave the title compound (750 mg, 97% yield) which was used crude in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:10][N:11]3[C:16]([O:17]CC)=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:10][N:11]3[C:16]([OH:17])=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: CCOc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 60 °C

Procedure:
To a solution of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-ethoxypyrazolo[1,5-a]pyrimidine (11A-1; 250 mg, 0.653 mmol) in THF (6.5 ml) was added water (1.5 ml) and 1M tetrabutylammonium hydroxide in water (3.3 ml, 3.3 mmol). The reaction was heated at 60° C. overnight, cooled, diluted with ethyl acetate and water, and then adjusted to pH 4.5 with 1M aqueous HCl. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated to afford, after trituration from ethyl acetate, I-12A-1a as a tan solid (138 mg, 60%): +APcI MS (M+1) 354.1; 1H NMR (400 MHz, CD3OD) δ 7.79 (d, J=7.1 Hz, 1H), 7.49–7.43 (m, 1H), 7.42–7.35 (m, 3H), 7.30 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 5.93 (d, J=7.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.[C:30]([NH2:34])(=[O:33])[CH:31]=[CH2:32].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:32][CH2:31][C:30]([NH2:34])=[O:33])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: C=CC(N)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCC(N)=O)CC4)cc3C)ncc2Cl)n[nH]1

Procedure:
A solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (41 mg, 0.1 mmol), acrylamide (24 mg, 0.33 mmol) and DIEA (87 μL, 0.5 mmol) in NMP (1 mL) was stirred at 80° C. for 10 h. LCMS at this point shows the reaction was not complete, so additional acrylamide (2×36 mg) was added and the reaction continued until LCMS shows the reaction was complete. The crude product was purified by RP-HPLC to give 3-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)propanamide as a white powder; ESMS m/z 483.2 (M+1).
Reaction SMILES: [P:1]([O:44]C(C)(C)C)([O:39]C(C)(C)C)([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@@H:29]3[CH2:34][CH2:33][C@@H:32]([OH:35])[C@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2].Cl.O1CCOCC1>CO>[P:1]([OH:39])([OH:44])([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@@H:29]3[CH2:34][CH2:33][C@@H:32]([OH:35])[C@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OC[C@@H](NC(=O)c1ccc(-c2nc([C@@H]3CC[C@@H](O)[C@H](F)C3)cnc2N)cc1F)c1cc(F)cc(I)c1)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)N[C@H](COP(=O)(O)O)c2cc(F)cc(I)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of (S)-2-(4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (315 mg, 0.392 mmol) was added HCl 4M in dioxane (5 mL, 20.00 mmol) and methanol (Volume: 0.5 mL). The reaction mixture was stirred at room temperature for 1 hour followed by LCMS. The solvent was concentrated off. The crude material was basified and dissolved with 3M NaOH solution with minimal MeOH added. The material was purified by 12 gram Grace Reveleris C18 reverse phase column eluted with 0-15% ACN/water over 18 minutes at a flow rate of 15 ml/minute, without buffers. The desired fractions were collected, acidified with 1 M HCl to pH of 1 and extracted with ethyl acetate (5×). The combined organic layer (800 ml) was washed with minimal water (3×25 ml) to remove salts. The solvent was concentrated off, dissolved in 1:1 ACN/water and lyophilized to give 207 mg of the desired product as HCL salt. (72% yield). LCMS (m/z): 693.2 (MH+), 0.64 min. 1H NMR (<cd3od>) d: 7.87 (s, 1H), 7.81-7.86 (m, 1H), 7.65-7.72 (m, 2H), 7.61 (dd, J=11.7, 1.6 Hz, 1H), 7.46 (ddd, J=8.0, 2.3, 1.4 Hz, 1H), 7.26 (dt, J=9.5, 1.9 Hz, 1H), 5.38 (t, J=5.7 Hz, 1H), 4.29-4.49 (m, 1H), 4.18-4.29 (m, 2H), 3.64 (tdd, J=11.6, 8.6, 4.9 Hz, 1H), 2.76-2.92 (m, 1H), 2.27 (ddd, J=8.8, 5.9, 2.5 Hz, 1H), 2.01-2.13 (m, 1H), 1.76-1.94 (m, 2H), 1.58-1.71 (m, 1H), 1.39-1.55 (m, 1H). 31P NMR (<cd3od>) d: 0.16 (br. s., 1P).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl>[CH2:30]([O:29][C:27]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6]1)=[O:28])[CH3:31]
Reactant: COC(=O)c1cccc(OCC2CCNCC2)n1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(COc2cccc(C(=O)OC)n2)CC1
Temperature: 25 °C

Procedure:
To a mixture of methyl 6-(piperidin-4-ylmethoxy)picolinate (0.3 g, 1.2 mmol), Et3N (0.2 g, 1.8 mmol) in DCM (10 ml) was added ethyl chloroformate (0.2 g, 1.8 mmol) at 0° C. The reaction was warmed to room temperature, washed with 1N HCl (20 ml), dried over Na2SO4 and concentrated under reduced pressure to give methyl 6-((1-(ethoxycarbonyl)piperidin-4-yl)methoxy)picolinate which used in the next step without further purification. Yield (0.38 g, quant.).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10](=[O:24])[CH:11]([N:13]2[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]2=[O:23])O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:29])=O>O1CCOCC1>[N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10](=[O:24])[CH:11]([N:13]2[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]2=[O:23])[Cl:29])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2 g of poly-Hunig base in 8 ml of dioxan is stirred for 30 minutes at room temperature, 832 mg of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester dissolved in 12 ml of dioxan are added and then slowly a solution of 0.54 ml of thionyl chloride in 10 ml of dioxan is added. The mixture is stirred for 2 hours at room temperature, the poly-Hunig base is filtered off and the filtrate is concentrated by evaporation in vacuo. The residue is purified by chromatography over silica gel with toluene/ethyl acetate (1:1) and yields the 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in crude form.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3](Cl)=[O:4].[OH:16][CH:17]1[O:36][C@H:35]([CH2:37][OH:38])[C@@H:22]([O:23][C@@H:24]2[O:32][C@H:31]([CH2:33][OH:34])[C@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]2[OH:26])[C@H:20]([OH:21])[C@H:18]1[NH2:19].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([C:17]1([O:36][C@H:35]([CH2:37][OH:38])[C@@H:22]([O:23][C@@H:24]2[O:32][C@H:31]([CH2:33][OH:34])[C@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]2[OH:26])[C@H:20]([OH:21])[C@H:18]1[NH2:19])[OH:16])=[O:4]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Reactant: CCCCCCCCCCC(Br)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCC(Br)C(=O)C1(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Alpha-bromolauroyl chloride (0.50 g) was added drop-wise to a 30% aqueous solution of lactosamine (0.7 g) at zero degrees centigrade. The pH of the solution was kept above 9.0 by adding saturated sodium carbonate water solution. The reaction was stirred overnight at room temperature. It was then heated to 36° C. for an additional hour. The final product was obtained by extraction two times with n-butanol. After evaporating butanol, the remaining solid material was washed with cold ethanol. The final product was collected by filtration. The NMR spectra showed that the solid material is the expected product. The yield of the reaction was 75%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:20][C:21](O)=[O:22])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:54]1([CH:60]2[CH2:64][CH2:63][CH2:62][NH:61]2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:20][C:21](=[O:22])[N:61]2[CH2:62][CH2:63][CH2:64][CH:60]2[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: COc1cccc(S(=O)(=O)N(CC(=O)O)c2ccc(Cl)cc2)c1
Reactant: c1ccc(C2CCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)N(CC(=O)N2CCCC2c2ccccc2)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [(4-chlorophenyl)-(3-methoxy-benzenesulfonyl)-amino]-acetic acid (250 mg, 0.7 mmol) in dry dichloromethane (20 mL) were sequentially added EDCI (202 mg, 1.05 mmol), HOBT (142.4 mg, 1.05 mmol), and DIPEA (0.23 mL, 1.40 mmol). The reaction mixture was allowed to stir for 30 minutes under nitrogen at 25° C. 2-Phenyl-pyrrolidine (104 mg, 0.7 mmol) was added and the mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with dichloromethane (20 mL), washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and water. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (30-40% ethyl acetate/hexane) to yield the title compound.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1([CH3:16])[O:15][C:7]2[C:8]([CH3:14])=[N:9][CH:10]=[C:11]([CH:12]=[O:13])[C:6]=2[CH2:5][O:4]1.CO>C(O)(C)C.[O-2].[O-2].[Mn+4]>[CH3:2][C:3]1([CH3:16])[O:15][C:7]2[C:8]([CH3:14])=[N:9][CH:10]=[C:11]([C:12]([NH2:1])=[O:13])[C:6]=2[CH2:5][O:4]1
Reactant: N
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: CC(C)O
Product: Cc1ncc(C(N)=O)c2c1OC(C)(C)OC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
Ammonia gas was bubbled into a solution of 2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carbaldehyde (31.3 g, 151 mmol) in isopropyl alcohol (2.4 L) at 0° C. for about 30 minutes. Manganese (IV) dioxide (210 g, 7.96 mmol) was added, and the solution was stirred for about 15 hours at room temperature. Excess manganese (IV) dioxide was filtered through a celite pad and washed with isopropyl alcohol. The filtrate was evaporated and washed with diethyl ether, water, and then with methyl alcohol to give 2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carboxylic acid amide (78) (23.1 g, 69% yield) as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11](=[N:14][C:15]#[N:16])SC)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C1(C)C(C)=CC=CC=1>[C:15]([N:14]=[C:11]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[NH:10][CH2:9][C:8]1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)#[N:16]
Reactant: NCCc1ccccn1
Reactant: CSC(=NC#N)NCc1ccc(C(C)(C)C)cc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(CNC(=NC#N)NCCc2ccccn2)cc1
Yield: 30.3 %

Procedure:
N-(4-t-butylbenzyl)N′-cyano-S-methylisothiourea (180 mg) was dissolved in xylene (10 ml) and to the solution was added 2-(2-aminoethyl)pyridine (86 mg), followed by refluxing for 7 hours. The resulting mixture was concentrated under reduced pressure and the obtained residue was purified by column-chromatography (acetone/ethyl acetate=1/1) to yield the compound 31-1 (70 mg, 30%) as a liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[NH2:15])([O-])=O.[ClH:16]>CO.[Pd]>[ClH:16].[ClH:16].[N:14]1[NH:13][N:12]=[N:11][C:10]=1[C:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:15])=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2nn[nH]n2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2nn[nH]n2)cc1N
Reaction time: 4 h

Procedure:
To 2-Nitro-4-(2H-tetrazol-5-yl)-phenylamine (6.80 g) in methanol (450 ml) and 40% (v/v) hydrochloric acid (20 ml) was added 10% Pd on carbon. The reaction vessel was evacuated and charged with hydrogen using a balloon. After 4 hours the reaction was analyzed by HPLC. Water was added (100 ml) and the reaction mixture filtered. The catalyst was washed with 50% v/v methanol in water (100 ml). The solvents were evaporated under reduced pressure (175 mBar then 50 mBar) at 40° C. to yield a brownish colored solid 4-(2H-tetrazol-5-yl)-benzene-1,2-diamine dihydrochloride (6.45 g), Rt=4.9 mins. 1H NMR (d6-DMSO, 400 MHz) 7.82 ppm (1H d, 2 Hz), 7.67 ppm (1H, d of d, 8.5 Hz, 2 Hz), 7.03 ppm (1H, d, 8.4 Hz), MS: (Electrospray+) 176.8 m/z (M+), 198.7 m/z (M+Na).