Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([NH2:32])[CH3:31]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][NH:32][CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH3:31])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C=O
Reactant: CC(N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNC(C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 and 1-pyridin-2-yl-ethylamine with NaBH(OAc)3 gave (3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amine as a pale yellow oil. 1H NMR (CDCl3) 1.48 (d, 3H, J=6.9 Hz), 2.19 (s, 3H), 3.70-3.83 (m, 2H), 4.02 (q, 1H, J=6.9 Hz), 7.06 (dd, 1H, J=5.4, 7.5 Hz), 7.13-7.18 (m, 1H), 7.36-7.40 (m, 1H), 7.47 (d, 1H, J=7.8 Hz), 7.66 (dt, 1H, J=1.8, 7.8 Hz), 8.40 (d, 1H, J=3.9 Hz), 8.55-8.57 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9](=[O:21])[C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=2)([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[Cl:20][C:16]1[N:15]=[C:14]([O:13][C:10]([CH3:12])([CH3:11])[C:9]([NH:8][C:3]2[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(Oc1cccc(Cl)n1)C(=O)Nc1ncccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(Oc1cccc(Cl)n1)C(=O)Nc1ncccc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 4.2 %

Procedure:
To a solution of N-(3-Amino-pyridin-2-yl)-2-(6-chloro-pyridin-2-yloxy)-2-methyl-propionamide (0.15 g, 4.9 mmol) and pyridine (0.042 g, 5.3 mmol) in DCM (5 ml) at 0° C. was added Methane sulfonyl chloride (0.06 g, 0.04 ml, 5.3 mmol) drop wise over a period of 5 min. The reaction mixture was stirred for 1 h. The reaction mixture was quenched with water (2 ml) extracted in DCM (20 ml), washed with brine (5 ml), dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude material thus obtained was purified by flash column affording 2-(6-Chloro-pyridin-2-yloxy)-N-(3-methanesulfonylamino-pyridin-2-yl)-2-methyl-propionamide (0.08 g, 5%). 1H NMR (400 MHz, CDCl3): δ 1.790 (s, 6H), 2.87 (s, 3H), 6.67 (t, 1H, J=8 Hz), 6.78 (d, 11-1, J=8 Hz), 6.91 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=8 Hz), 7.57 (t, 1H, J=8 Hz), 8.69 (d, 1H, J=8 Hz), 9.11 (brs, 1H). MS (EI) m/z: 385 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14](=O)[CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:26].[OH-].[NH4+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[NH:12][CH:13]=[C:14]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[N:26]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)CCc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(C)(C)Cc1c[nH]c(CCc2ccc(Br)cc2)n1
Temperature: 160 °C

Procedure:
A mixture of 3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propionamide (71.5 g, 202 mmol), ammonium acetate (770 g, 10 mol) and acetic acid (700 mL) was heated at 160° C. for 20 h. Upon cooling, the reaction mixture was poured onto ice (600 mL), and the pH was adjusted to ˜10 with concentrated ammonium hydroxide. The product was extracted with ethyl acetate, and the extracts were dried over sodium sulfate and concentrated to provide 2-[2-(4-bromophenyl)ethyl]-4-(2,2-dimethylbutyl)-1H-imidazole, which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](/[N:8]=[CH:9]/[N:10](C)C)=O)=[CH:4][CH:3]=1.O.[NH2:16]N>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[N:8]=[CH:9][NH:10][N:16]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(-c2nc[nH]n2)cc1
Temperature: 120 °C

Procedure:
To a stirred solution of (E)-4-chloro-N-((dimethylamino)methylene)benzamide (9.4 g, 44.6 mmol) in acetic Acid (13.5 ml) was added hydrazine hydrate (1.524 ml, 49.1 mmol). The reaction mixture immediately solidified and was heated to 120° C. for 2 hours. Whereupon was cooled to room temperature and azeotroped with toluene. The crystalline residue was stirred with water for a while. The precipitate was filtered off, washed with water and dried under vacuum. (Yield: 7.27 g, 91%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:29]O.O>C(Cl)(Cl)Cl.C[Re](=O)(=O)=O.[O-2].[O-2].[Mn+4]>[Si:22]([O:21][CH2:20][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N+:17]([O-:29])=[CH:16][CH:15]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCC(CCCc1ccncc1)CO[Si](C)(C)C(C)(C)C
Reactant: OO
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCC(CCCc1cc[n+]([O-])cc1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[5-(tert-butyldimethylsilanyloxy)-4-(tert-butyldimethylsilanyloxymethyl)-pentyl]pyridine (0.43 g) prepared in (4) in chloroform (5.0 mL) were added methyltrioxorhenium (VII) (0.0030 g) and aqueous 30% hydrogen peroxide (0.21 mL). The reaction mixture was stirred at RT for 4 hr. An appropriate amount of manganese dioxide (IV) was added to the reaction mixture. The mixture was stirred for 1 hr. Water was added to the mixture and the mixture was extracted with chloroform. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to obtain the crude title compound.
Reaction SMILES: NC[CH2:3][N:4]([S:28]([CH3:31])(=[O:30])=[O:29])[C:5]1[C:6]([CH:25]2[CH2:27][CH2:26]2)=[CH:7][C:8]2[C:12]([CH:13]=1)=[N:11][N:10]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[C:9]=2[C:21]([NH:23][CH3:24])=[O:22].[C@@H:32]1([C:40]([OH:42])=[O:41])[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=O.[N:43]1C=CC=[CH:45][CH:44]=1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([N:10]2[C:9]([C:21](=[O:22])[NH:23][CH3:24])=[C:8]3[C:12]([CH:13]=[C:5]([N:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:3][CH2:45][CH2:44][NH:43][C:37]([C@H:33]4[CH2:34][CH2:35][CH2:36][C@H:32]4[C:40]([OH:42])=[O:41])=[O:39])[C:6]([CH:25]4[CH2:27][CH2:26]4)=[CH:7]3)=[N:11]2)=[CH:15][CH:16]=1
Reactant: c1ccncc1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCN)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Reactant: O=C(O)[C@H]1CCC[C@H]1C(=O)O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCNC(=O)[C@H]3CCC[C@H]3C(=O)O)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Yield: 8 %

Procedure:
A mixture of Compound (7) (6.4 mg, 0.012 mmol) and cis-1,2-cyclopentanedicarboxylic acid (1.9 mg, 0.014 mmol) in pyridine (0.2 mL) was stirred at RT over the weekend. The solvent was removed under pressure. The crude material was purified by preparative LCMS (5-100% ACN in 0.1% aqueous formic acid) to afford Compound (63) as a white solid (0.7 mg, 8%). ESI-MS m/z calculated for [M+H]+: 660.2/662.2; found: 660.0/662.0; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 0.5H), 7.87 (s, 0.5H), 7.71 (d, J=8.7 Hz, 2H), 7.51 (dd, J=8.8, 2.2 Hz, 2H), 7.40 (d, J=3.7 Hz, 1H), 6.02-5.92 (m, 1H), 5.87 (d, J=4.1 Hz, 1H), 4.05-3.68 (m, 2H), 3.68-3.40 (m, 1H), 3.35-2.95 (m, 3H), 3.21 (s, 3H), 3.05 (d, J=4.9 Hz, 3H), 2.55-2.37 (m, 1H), 2.28-2.11 (m, 1H), 2.10-1.89 (m, 7H), 1.20-0.90 (m, 3H), 0.72-0.47 (m, 1H).
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([OH:22])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:22][CH2:1][CH3:2])[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(OCc2ccccc2)ccc1C(=O)OC

Procedure:
Ethyl iodide (0.14 mL) was added to a mixture of methyl 4-benzyloxy-2-hydroxybenzoate (0.30 g) and potassium carbonate (0.32 g) in N,N-dimethylformamide (2.9 mL) at room temperature with stirring. The mixture was stirred at that temperature for 1.6 hrs and at 50° C. for 1.4 hrs. Water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.29 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1.CO.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[ClH:36].[Br:1][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Brc1cnc(Nc2nc(C3CCNCC3)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate was dissolved in 1:1 CH2Cl2:methanol and 4N HCl in dioxane was added and stirred at room temperature for 1 hour. The solvents were removed to afford the title compound. 1H NMR (d6-DMSO) δ 10.98 (bs, 1H), 8.90 (bs, 1H), 8.70 (bs, 1H), 8.23 (d, 1H), 7.45 (m, 2H), 7.40 (d, 1H), 7.22 (m, 1H), 7.12 (m, 2H), 6.76 (s, 1H), 3.31 (m, 2H), 2.98 (m, 2H), 2.89 (m, 1H), 2.10 (m, 2H), 1.79 (m, 2H). Mass spectrum (apci) m/z=431.2, 433.2 (M+H-2HCl).
Reaction SMILES: [C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([O:18]C(C)C)=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC(=O)C1CCn2c(C(=O)c3cccs3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(c1cccs1)c1ccc2n1CCC2C(=O)O

Procedure:
A solution of 336 mg. of isopropyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 10 ml. of methanol is treated with a solution of 690 mg. of potassium carbonate in 5 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 2 hours, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and 50 ml. of water and the resultant mixture extracted with ethyl acetate (2 × 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate affords 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, identical to the product obtained in Example 10 A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[O:15][CH2:16][CH2:17][CH2:18][CH:19]=3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1>[Pd].ClCCl.CO.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=CCCCO3)c2s1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nc2c(OC)ccc(C3CCCCO3)c2s1

Procedure:
From [7-(5,6-dihydro-4H-pyran-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester by hydrogenation with palladium on charcoal in dichloromethane, methanol and triethylamine. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: 100 °C
Yield: 70.5 %

Procedure:
A mixture of 5-hydroxy-indan-1-one (5.3 g, 35.7 mmol), KJ (0.6 g, 3.6 mmol) and K2CO3 (6.17 g, 44.6 mmol) and benzyl bromide (4.66 ml, 39.3 mmol) in DMF (50 ml) were heated at 100° C. for 1 hr. Addition of H2O (150 ml) and extraction with EtOAc (3×50 ml), washing the organic phase with satd. NaCl solution (100 ml) and drying with MgSO4 and evaporation afforded a brown solid. This material was recrystallised twice from EtOH to afford 5-benzyloxy-indan-1-one (6 g, 25.17 mmol, 70%) as yellow crystals, Mp. 105-106° C., MS m/e=238.1 (M+).
Reaction SMILES: [OH:1][CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].FC1C=C2C(=CC=1)NC(=O)/C/2=C\[C:37]1[NH:46][C:45]2[CH2:44][CH2:43][CH2:42][N:41](C[C@H](O)CN3CCOCC3)[C:40](=[O:57])[C:39]=2[C:38]=1[CH3:58].[O:59]([C:61]1[CH:69]=[C:68]2[C:64]([CH2:65][C:66](=[O:70])[NH:67]2)=[CH:63][CH:62]=1)[CH3:60].N1CCCCC1>C(O)C>[OH:1][C@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12](/[CH:15]=[C:65]3\[C:66](=[O:70])[NH:67][C:68]4[C:64]\3=[CH:63][CH:62]=[C:61]([O:59][CH3:60])[CH:69]=4)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].[CH3:58][C:38]1[C:39]2[C:40](=[O:57])[NH:41][CH2:42][CH2:43][CH2:44][C:45]=2[NH:46][CH:37]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)NC(=O)/C2=C\c1[nH]c2c(c1C)C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Product: Cc1c[nH]c2c1C(=O)NCCC2
Temperature: 45 °C
Reaction time: 16 h
Yield: 167.5 %

Procedure:
5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 53f (30 mg, 0.09 mmol) and 6-methoxyl-1,3-dihydro-indol-2-one (13 mg, 0.08 mmol) were dissolved in 1560 of ethanol, and added with 4.4 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (R,Z)-5-(2-hydroxy-3-morpholinopropyl)-2-(6-methoxy-2-oxoindolin-3-ylidene) methyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 77 (22 mg, yield 51%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH:6]([N:8]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)C(C)NC1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A solution of 1.07 g (0.005 mole) of (rac)-3-cyclopentylamino-2-methyl-butanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.4 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-butanoic acid ethyl ester (IV-41).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[C:22](OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-4,4-dimethylpentanoic acid (50 mg, 0.204 mmol) and iodomethane (0.102 mL, 1.631 mmol) were dissolved in tetrahydrofuran (2 mL) at 0° C. and sodium hydride (24.46 mg, 0.611 mmol) was added. The reaction was stirred at 0° C. for a half hour and at room temperature overnight. The reaction was cooled to 0° C. and ethyl acetate (1 mL) was added followed by dropwise quenching with water (2 mL). The solvent was removed in vacuo and the crude material was partitioned between ether and water. The ether layer was separated. The aqueous layer was acidified to pH˜5 using 1 N citric acid and extracted with ethyl acetate. The organic layer was washed with 1 N sodium thiosulfate and brine, dried (Na2SO4) and concentrated in vacuo. The compound was purified using a 4 g silica gel cartridge with a gradient of 0-3% methanol/dichloromethane over 20 minutes to give (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 12.63 (s, 1H), 4.57 (ddd, J=74.4, 9.5, 3.1, 1H), 2.69 (s, 3H), 1.83-1.53 (m, 2H), 1.39 (s, 9H), 0.89 (s, 9H); MS (DSI+) m/z 260 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=O)[N:13]=2)=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[NH2:58][CH2:59][C:60](=[O:62])[CH3:61]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:58][CH2:59][C:60](=[O:62])[CH3:61])=[O:18])[N:13]=2)=[N:6][CH:7]=1
Reactant: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: CC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)CNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.800 g, 1.90 mmol), HOBT-H2O (0.437 g, 2.86 mmol), DIEA (1.36 mL, 7.80 mmol), EDCI (0.547 g, 2.86 mmol), and 1-aminopropan-2-one hydrochloride (0.834 g, 7.61 mmol) in 50 mL THF was stirred at 50° C. for 2 days. The mixture was concentrated and diluted with CH2Cl2 and washed with water, dried over sodium sulfate and concentrated to a residue that was carried on to the next step without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:5]=1[C:20]#[N:21])=[N+:2]=[N-:3].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:23].CC(O)C>O.S([O-])([O-])(=O)=O.[Cu+2]>[C:20]([C:5]1[CH:6]=[C:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][C:4]=1[N:1]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=[N:2]1)#[N:21]
Reactant: COC(=O)c1ccnc(-c2ccc(N=[N+]=[N-])c(C#N)c2)c1
Reactant: C#Cc1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccnc(-c2ccc(-n3cc(-c4ccccc4)nn3)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of methyl 2-(4-azido-3-cyanophenyl)isonicotinate, 54 μl of ethynylbenzene, 72 μl of aqueous 1 M sodium L(+)-ascorbate solution and 2 mg of copper sulfate were added to a mixture of 1.4 ml of water and 1.4 ml of 2-propanol, followed by vigorous stirring overnight at room temperature. The reaction mixture was diluted with 5 ml of water, the precipitate formed was collected by filtration, washed with iced cool water, and dried under reduced pressure to obtain 12 mg of methyl 2-[3-cyano-4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]isonicotinate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([C:16](O)=[O:17])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>O1CCCC1>[CH:19]1([C:11]2([CH2:16][OH:17])[CH2:10][CH:9]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(C(=O)O)(C1CCCCC1)C2
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1C2CCC1CC(CO)(C1CCCCC1)C2
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 8-(tert-butoxycarbonyl)-3-cyclohexyl-8-azabicyclo[3.2.1]octane-3-carboxylic acid (3-2) (1.47 g, 4.35 mmol) in 50 mL of anhydrous tetrahydrofuran was added borane-methyl sulfide complex (8.70 mL, 17.4 mmol, 2.0 M in tetrahydrofuran) dropwise at room temperature. The mixture was stirred at 50° C. for 48 hours and the volatiles were removed under vacuum Purification of the crude residue by flash chromatography over silica gel (50% ethyl acetate/hexanes as eluent) afforded (3-3) as a white solid.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[CH2:9]([O:11][C:12](=[O:38])[CH2:13][C:14]1[CH:15]=[C:16]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)[CH3:10].ICCC.[Cl-].[NH4+]>C1COCC1>[CH2:9]([O:11][C:12](=[O:38])[CH:13]([C:14]1[CH:15]=[C:16]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=1)[CH2:2][CH2:3][CH3:4])[CH3:10]
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCC(C(=O)OCC)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of LDA (4.5 mL of 1.8 M in THF, 8 mmol) was added dropwise to a stirred solution of (5-Benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (3 g, 7.3 mmol) in THF (50 mL) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C. before iodopropane (0.85 mL, 8.7 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. A saturated aqueous solution of ammonium chloride (10 mL) was carefully added and the residue was partitioned between EtOAc and water. The aqueous layers were extracted with EtOAc (×3). The combined organic layers were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 2-(5-Benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (2.2 g) as an oil in 66% yield.