Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:6]1[S:7][C:8]([C:17]2[N:21]=[CH:20][N:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[C:3]([CH3:5])=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1.C(=O)(O)[O-].[Na+].CCOC(C)=O>C1COCC1.CC(O)C>[Br:35][C:32]1[CH:33]=[CH:34][C:29]2[N:30]([C:2]([C:6]3[S:7][C:8]([C:17]4[N:21]=[CH:20][N:19]([CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)[N:18]=4)=[C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:10]=3)=[C:3]([CH3:5])[N:28]=2)[CH:31]=1
Reactant: CC(=O)C(Br)c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
To a solution of 1-bromo-1-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}acetone (2.96 g, 6.6 mmol) obtained in Example 116-B(vi) in THF (33 mL) and 2-propanol (33 mL), was added 2-amino-5-bromopyridine (5.71 g, 33.0 mmol), and the mixture was stirred at 80° C. for 3 h. The reaction mixture was allowed to cool to rt, and then were added saturated aqueous solution of sodium bicarbonate (60 mL) and EtOAc (150 mL). The aqueous layer was extracted with EtOAc (80 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=20/80→100/0; then MeOH/EtOAc=20/80), and then basic silica gel column chromatography (EtOAc/hexane=10/90→80/20) to give the title compound (520 mg, 15%) as a pale yellow solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:53]=[CH:54][CH:55]=1)[CH2:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:34][C:35]1[CH:36]=[C:37]([CH:53]=[CH:54][CH:55]=1)[CH2:38][N:39]1[CH:43]=[C:42]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([C:17]5[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=5)=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[CH:3]=2)[CH:41]=[N:40]1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5=CCN(C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5=CCN(C)CC5)cc4)cnc32)cc1
Yield: 83 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 3-iodo-5-(4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 66D) (200 mg, 0.351 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (117 mg, 0.386 mmol) using Pd(PPh3)2Cl2 (13 mg, 0.017 mol) and sodium carbonate (112 mg, 1.053 mmol) in toluene/ethanol/water (3/3/2 ml) to afford 180 mg (83% yield) of the titled compound after column purification using 10% methanol in DCM as eluent. MS: m/z=617.9 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]>CO.[Pd]>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)/C=C/c1ccco1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCC1CCCO1
Temperature: 60 °C
Yield: 93.9 %

Procedure:
(E)-3-(Furan-2-yl)acrylic acid (10 g, 72.4 mmol) was treated with Pd/C (1 g) in MeOH (100 mL). The mixture was heated at 60° C. at 60 psi under H2 for 12 hrs. After filtering off the catalyst, the filtrate was concentrated to afford 9.8 g (93%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.42-1.56 (m, 1 H) 1.77-1.96 (m, 4 H) 1.93-2.07 (m, 1 H) 2.41-2.56 (m, 2 H) 3.71-3.79 (m, 1 H) 3.82-3.94 (m, 2 H); MS (DCI/NH4+) m/z 145 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=1.Br.C(=O)(O)[O-].[Na+]>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH:16]=1
Reactant: COc1cccc(C2CCCN2Cc2cccnc2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc(C2CCCN2Cc2cccnc2)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
2-(3-Methoxyphenyl)-1-(3-pyridinylmethyl)pyrrolidine and 48% hydrobromic acid (35 ml) were warmed to 100° C. for 7 hrs. The reaction mixture was cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution, and extracted with dichloromethane (2 times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 ethyl acetate/dichloromethane). The appropriate fractions were collected and concentrated to give 2.2 g (63%) of product, mp 129°-131° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:15]O>>[CH3:15][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CO
Reactant: CC(C)(C)c1cc(C(=O)O)ccc1O
Product: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a 500 mL 3-necked flask equipped with a magnetic stirrer, a nitrogen inlet, and a condenser were added 10.0 g of 3-tert-butyl-4-hydroxybenzoic acid (ICN Biomedicals. Inc., Aurora, Ohio 44202), and 200 mL of MeOH. The solution was acidified by bubbling HCl gas through for 5 min. and was then heated at reflux for 5 h. The solution was cooled to RT and concentrated in vacuo to dryness. The resulting solid was dissolved in EtOAc. The solution was washed three times with 5% aqueous NaHCO3, dried over anhydrous MgSO4 and concentrated to dryness to afford 9.65 g (90%) of methyl-3-tert-butyl-4-hydroxybenzoate as a white crystalline solid, m.p. 144-145° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:19][NH:20][CH:21]=O)=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:20][CH:19]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)c(CNC=O)nc1-c1cccc(F)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 90 °C
Yield: 23.2 %

Procedure:
Methyl 5-chloro-2-(3-fluorophenyl)-6-[(formylamino)methyl]nicotinate (2.6 g, 8.5 mmol) was stirred in phosphoryl chloride (80 mL) and heated at 90° C. for 1 hour. Evaporation and purification by flash column chromatography with ethyl acetate in hexanes (0-100%) gave the desired compound (0.60 g, 40%). LCMS calculated for C15H11ClFN2O2 (M+H)+: m/z=305.1. found: 304.9. 1H NMR (300 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.91 (s, 1H), 7.60 (m, 1H), 7.43 (m, 3H), 7.38 (m, 1H), 3.60 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:29]1([C:33]2[O:37][N:36]=[C:35]([CH2:38]O)[C:34]=2[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:32][CH2:31][CH2:30]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH:29]1([C:33]2[O:37][N:36]=[C:35]([CH2:38][O:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:34]=2[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:30][CH2:31][CH2:32]1
Reactant: CCOC(=O)c1c(CO)noc1C1CCC1
Reactant: Cc1cccc(C)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(COc2c(C)cccc2C)noc1C1CCC1
Temperature: 90 °C
Yield: 81.8 %

Procedure:
To a solution of 2,6-dimethylphenol (503 mg, 4.12 mmol), triphenylphosphine (1.08 g, 4.12 mmol) and ethyl 5-cyclobutyl-3-(hydroxymethyl)-4-isoxazolecarboxylate (929 mg, 4.12 mmol, from multiple batches) in toluene (10 mL) was added diisopropyl azodicarboxylate (0.741 mL, 4.12 mmol) dropwise. The solution was heated in a microwave reactor to 90° C. for 10 minutes. The solution was then concentrated and the residue was purified by chromatography (silica gel, 2.5% acetone in hexanes) to afford ethyl 5-cyclobutyl-3-{[(2,6-dimethylphenyl)oxy]methyl}-4-isoxazolecarboxylate (1.11 g, 81%). 1H-NMR (400 MHz, DMSO-d6) δ 7.01-6.90 (m, 3H), 5.02 (s, 2H), 4.20 (q, J=7 Hz, 2H), 4.20-4.10 (m, 1H), 2.37-2.30 (m, 4H), 2.14 (s, 6H), 2.11-2.01 (m, 1H), 1.95-1.85 (m, 1H), 1.22 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>>[CH2:17]([NH:16][C:14]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[C:8]([F:12])[C:7]=2[C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[Cl:20])=[O:15])[CH2:18][CH3:19]
Reactant: COc1ccc(Cl)c(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)ccc3Cl)c(F)ccc2c1N

Procedure:
The title compound was prepared from 4-amino-7-fluoro-8-iodo-N-propylcinnoline-3-carboxamide (250 mg, 0.67 mmol) and 2-chloro-5-methoxyphenyl boronic acid (279 mg, 1.50 mmol) according to Method A to afford a solid (181 mg, 72%). 1H NMR (500.333 MHz, CDCl3) δ 8.41 (s, 1H), 7.90 (dd, J=9.1, 5.1 Hz, 1H), 7.49 (t, J=8.7 Hz, 1H), 7.41 (dd, J=6.9, 2.7 Hz, 1H), 6.94-6.92 (m, 2H), 3.79 (s, 3H), 3.44 (q, J=6.7 Hz, 2H), 1.65 (sextet, J=7.2 Hz, 2H), 0.99 (t, J=7.3 Hz, 3H). MS APCI, m/z=389/391 (M+H). HPLC 2.13 min.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH2:9][C:10]3([O:16][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3.Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH2:9][C:10]3([O:16][C:6]=2[CH:5]=[C:4]([O:18][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:3]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3
Reactant: O=C1CC2(CCCCC2)Oc2cc(O)cc(O)c21
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCOc1cc(O)c2c(c1)OC1(CCCCC1)CC2=O
Yield: 65.1 %

Procedure:
According to the same procedure as in Preparation 46, a mixture of 5,7-dihydroxyspiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 19) (0.248 g, 1.0 mmol), ethyl 4-bromobutyrate (0.215 g, 1.1 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), and acetonitrile (3 ml) is reacted and treated. The resulting extract is concentrated and the residue is purified by a silica gel column chromatography (eluent: acetone and dichlomethane, 1:50) to obtain the title compound as an oil (0.236 g, yield 64.9%).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[NH:7][C:6]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:11][C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=1[CH3:41]>CN(C=O)C>[F:22][CH:2]([F:1])[C:3]1[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[C:32]=2[CH3:41])[C:5]2[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[C:6]=2[N:7]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)F)[nH]c12
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 70 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of methyl 2-(difluoromethyl)-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 68 (500 mg, 1.6 mmol), K2CO3 (442 mg, 3.2 mmol) and 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (480 mg, 1.9 mmol) in DMF (15 mL) was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was poured into water (100 mL) and filtered, the filter cake was collected and purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the desired product (710 mg, 98%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.53 (s, 3H), 3.14 (t, 4H, J=4.5 Hz), 3.73 (t, 4H, J=4.5 Hz), 3.93 (s, 3H), 5.75 (s, 2H), 6.27 (d, 1H, J=7.8 Hz), 7.22 (t, 1H, J=7.8 Hz), 7.30 (d, 1H, J=2.1 Hz), 7.36 (t, 1H, J=51.6 Hz), 7.58-7.61 (m, 2H); LC-MS: m/e=484 [M+1]+
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][C:5]([Cl:12])=[N:6][C:7]=2Cl.[CH2:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:12][C:5]1[N:4]=[C:3]2[C:8]([N:9]=[CH:10][N:2]2[CH3:1])=[C:7]([NH:21][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: NCCc1ccccc1
Product: Cn1cnc2c(NCCc3ccccc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 4 from 9-methyl-2,6-dichloro-9H-purine and phenethyl-amine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@H:28]([O:31][Si](C(C)(C)C)(C)C)[C@@H:27]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1.C(OCC)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[C@H:27]1[CH2:39][O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1COCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A solution of 2.01 g (7.68 mmol) of tetrabutylammonium fluoride in 5 ml of tetrahydrofuran was added, whilst ice-cooling, to a solution of 2.16 g (5.12 mmol) of (2S,3S)-1-t-butoxycarbonyl-2-benzyloxymethyl-3-t-butyldimethylsilyloxypyrrolidine in 5 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the organic extract was washed with 0.5N aqueous hydrochloric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.57 g of the title compound as an oil.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.N(OCCCC)=O.CCOCC.[F:24][B-](F)(F)F.[H+]>C(O)C>[F:24][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1ccc(N)cn1
Agent: CCCCON=O
Agent: [H+]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)c1ccc(F)cn1
Temperature: -3 °C

Procedure:
The methyl 5-aminopicolinate (2.2 g) is dissolved in 5.5 ml 48% fluoroboric acid and 20 ml 95% ethanol. This mixture is cooled, with stirring, to -3° C. and then 1.81 g n-butyl nitrite added dropwise. After a further one-half hour at -3° C., 0.5 ml n-butyl nitrite is added slowly and stirring continued for one-half hour at 0° C. After adding 20 ml ether carefully, the mixture is rapidly filtered, and the solid washed twice with cold hexane. The solid is suspended in 100 ml heptane, and the suspension slowly heated with stirring. At about 60° C., a vigorous exothermic reaction occurs. Heating is then continued to 80° C. A red oil separates on the sides of the flask. The heptane solution is filtered, and the filtrate concentrated to give the desired product. The red oil is dissolved in water, excess sodium bicarbonate solution added, and the solution extracted with ethyl acetate. The ethyl acetate extract is washed with saturated brine, dried and concentrated. The residue is chromatographed on silica gel and the product, methyl 5-fluoropicolinate, eluted with 1:1-ether:hexane. This material is used directly for the preparation of the picolinic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:48])=[C:16]([N:33]([CH3:47])[CH:34]2[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:22][CH:21]=2)[CH:19]=1)=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:22][CH:21]=2)[CH:17]=[C:16]([N:33]([CH3:47])[CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:15]=1[CH3:48])=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
A stirred solution of tert-butyl 4-((5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)(methyl)amino)piperidine-1-carboxylate (1 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (2 mL) was added to it. The reaction was stirred at room temperature for 1 h. On completion, the solution was concentrated to dryness. The residue was purified by solvent washings to afford the title compound (0.07 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1
Reactant: Cc1ccc(OCc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Temperature: 0 °C
Yield: 56.2 %

Procedure:
A solution of 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoic acid (460 mg, 1.42 mmol, 1.00 equiv), EDCI (320 mg, 1.68 mmol, 1.18 equiv), HOBT (240 mg, 1.78 mmol, 1.25 equiv), pyridin-3-ylmethanamine (180 mg, 1.67 mmol, 1.17 equiv) and triethylamine (440 mg, 4.36 mmol, 3.06 equiv) in N,N-dimethylformamide (6 mL) was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of ice/water. The solid was collected by filtration and washed with 3×10 mL of hexane. The crude product was purified on a silica gel column eluted with chloroform/methanol (50:1-20:1) to give 0.33 g (56%) of 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a gray solid. LC-MS: (ES, m/z): 414 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 9.16 (s, 2H), 8.56 (s, 1H), 8.46 (s, 1H), 8.00-7.95 (m, 3H), 7.75 (d, 1H), 7.34 (m, 1H), 6.86-6.81 (m, 2H), 6.68 (d, 1H), 4.50 (d, 2H), 3.78 (s, 2H), 2.50 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([SH:12])[CH3:11].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:12][CH2:10][CH3:11])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCS
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCC

Procedure:
Ethyl 2-bromoisobutyrate (28.6, 0.146 mole), ethanethiol (100 g, 0.161 mole), potassium hydroxide (10.3 g, 0.161 mole), ethyl alcohol. Stirred reaction mixture for two hours at room temperature prior to quenching. Crude yield: 117%; after kugelrohr: 77.8%.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C@@H:6]1[CH2:28][C:27]2[C:29](=[O:30])[C:22](=[CH:23][C:24]([C:26]=2OC)=[O:25])[NH:21][C:19](=[O:20])[C:18]([CH3:33])=[CH:17][CH:16]=[CH:15][C@H:14]([O:34][CH3:35])[C@@H:13]([O:36][C:37]([NH2:39])=[O:38])[C:12]([CH3:40])=[CH:11][C@H:10]([CH3:41])[C@@H:9]([OH:42])[C@@H:8]([O:43][CH3:44])[CH2:7]1.[CH2:45]([NH2:48])[CH2:46][CH3:47].Cl>O>[CH3:47][CH2:46][CH2:45][NH:48][C:26]1[C:24](=[O:25])[CH:23]=[C:22]2[C:29](=[O:30])[C:27]=1[CH2:28][CH:6]([CH3:5])[CH2:7][CH:8]([O:43][CH3:44])[C@@H:9]([OH:42])[C@H:10]([CH3:41])[CH:11]=[C:12]([CH3:40])[CH:13]([O:36][C:37]([NH2:39])=[O:38])[CH:14]([O:34][CH3:35])[CH:15]=[CH:16][CH:17]=[C:18]([CH3:33])[C:19]([NH:21]2)=[O:20]
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Reactant: CCCN
Agent: CCCNC1=C2CC(C)CC(OC)[C@@H](O)[C@H](C)/C=C(\C)C(OC(N)=O)C(OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCNC1=C2CC(C)CC(OC)[C@@H](O)[C@H](C)C=C(C)C(OC(N)=O)C(OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 50 ml. of chloroform, 280 mg. of Geldanamycin was dissolved and then, 1 ml. of n-propylamine was added. The mixture was stirred at room temperature for 1 hour and the mixture was charged into 50 ml. of cold water and then, pH was adjusted 3 with 6 N-HCl. The chloroform layer was separated and the water layer was extructed with 50 ml. of chloroform. Both chloroform layers were combined and dehydrated over anhydrous sodium sulfate for 2 hours. Chloroform was distilled off under a reduced pressure to remain a reddish violet solid product. The solid product was recrystallized from acetone-n-hexane to obtain 286 mg. (yield 98%) of 17-n-propylamino-Geldanamycin as reddish violet acicular crystal.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:16][C:17]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]1.Cl>O1CCCC1.C(Cl)Cl>[OH:16][C:17]1([C:20]([O:22][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1(O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)C1(O)CC1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Triethylamine (1.0 ml) and benzyl bromide (650 μl) were added to a solution of 1-hydroxycyclopropanecarboxylic acid (409 mg) in tetrahydrofuran (3.0 ml), and the mixture was stirred at room temperature for 23 hours. Methylene chloride and 1N hydrochloric acid were added to the reaction mixture to separate the mixture into two layers. An organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. A crude product was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (607 mg).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=1[CH3:30])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(F)ccc1N
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccc(F)cc1C
Yield: 11.8 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (2.75 g, 8.2 mmol) and 4-fluoro-2-methylaniline (1.34 g, 10.7 mmol) in acetonitrile (20 ml) was refluxed for 8 h. The solution was cooled and 1.52 g crystallized product was filtered off. The filtrate was evaporated and chromatographed (SiO2 ; CH2Cl2 :MeOH 95:5) yielding 0.4 g of the desired product. Total yield: 1.92 g (57%).