Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)(=O)C>C(O)C.[Fe]>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]2[OH:1]
Reactant: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2c(O)c1C(=O)OCC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(N)cc2c(O)c1C(=O)OCC
Yield: 75.1 %

Procedure:
A stirred mixture of diethyl 4-hydroxy-6-nitroquinoline-2,3-dicarboxylate (4.4 g, 13 mM), powdered iron (6.6 g, 118 mM) and glacial acetic acid (18.5 g, 307 mM) in ethanol (80 mL) was refluxed for 20 hr under a nitrogen atmosphere. The reaction mixture was cooled and filtered and the filtrate was concentrated. The dark residue was chromatographed (eluant: methylene chloride/methanol; 98/2) over silical gel to provide (3.01 g, 75.3%) the title compound as light orange crystals, mp 219°-221° C. MS(CI): 305 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[O:17][C:16](=[O:18])[NH:15][N:14]=3)=[CH:11][C:10]([C:19]([F:22])([F:21])[F:20])=[N:9]2)=[N:6][CH:7]=1.[CH3:23]CN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[O:17][C:16](=[O:18])[N:15]([CH3:23])[N:14]=3)=[CH:11][C:10]([C:19]([F:20])([F:21])[F:22])=[N:9]2)=[N:6][CH:7]=1
Reactant: O=c1[nH]nc(-c2cc(C(F)(F)F)nn2-c2ccc(Br)cn2)o1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1nc(-c2cc(C(F)(F)F)nn2-c2ccc(Br)cn2)oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Step-5: 5-(1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2(3H)-one: To a stirred and (0° C.) cooled solution of step-4 intermediate (4.0 g, 11.43 mmol) and DIPEA (3.99 mL, 22.85 mmol) in DCM (50 mL) was added a solution of triphosgene (1.35 g, 4.57 mmol) in DCM (20 mL) over a period of 10 min. Reaction mixture was warmed to room temperature and stirred overnight. The reaction was cooled to 0° C. and quenched with ice water (5 mL). Water (25 mL) was added to the above mixture followed by DCM (100 mL). The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 3.0 g (70%) of the title compound as pink semisolid. 1HNMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H, D2O exchangeable), 8.71 (d, J=2.5 Hz, 1H), 8.39 (dd, J=2.5 & 8.5 Hz, 1H), 7.90 (d, T=8.5 Hz, 1H), 7.70 (s, 1H); ESI-MS (m/z) 376, 378 [(MH)+, Br79,81].
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([NH:9][CH:10]=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[N:21]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])=[N+:22]=[N-:23]>C1COCC1>[C:1]([O:5][C:6](=[O:12])[C@@H:7]([N:9]([C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[N:21]=[N+:22]=[N-:23])[CH:10]=[O:11])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC=O)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)N(C=O)C(=O)c1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A stirred solution of (2S)-2-formylamino-propionic acid tert-butyl ester (3.524 g, 20.3 mmol) in anhydrous THF (50 mL) was treated at −78° C. with LDA (20.3 mmol) and the reaction was stirred for 15 min. A solution of 2-azidobenzoyl chloride (T. Okawa, T. Sugimori, S. Eguchi and A. Kakehi, Heterocycles, 1998, 47, 1, 375-382) (20.6 mmol) in anhydrous THF (20 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 1 h before being quenched with saturated aq.NH4Cl. The reaction was allowed to warm to room temperature and the organic layer was washed with saturated aq.NH4Cl, dried (MgSO4), filtered and evaporated and residue was purified by flash chromatography (20% ethyl acetate in hexane) to afford the sub-title compound as a pale yellow oil (3.437 g, 53%): 1H NMR (400 MHz CDCl3) δ 1.49 (9H, s), 1.60 (3H, d), 5.18 (1H, m), 7.27 (2H, m), 7.40 (1H, d), 7.59 (1H, t), 8.60 (1H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:7]OS(C1C=CC(C)=CC=1)(=O)=O)[C:3]([O:5][CH3:6])=[O:4].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:19])([CH2:7][O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Oc1ccccc1
Reactant: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)COc1ccccc1
Yield: 414 %

Procedure:
A mixture of methyl 2,2-dimethyl-3-(4-toluenesulfonyloxy)propionate (Intermediate A35, 80 g, 0.28 mol), phenol (28 g, 0.029 mol), potassium carbonate (58 g, 0.42 mol), and 250 mL N,N-dimethylacetamide was stirred and heated at reflux for 4 hr. The reaction mixture was cooled, diluted with ethyl acetate, and poured into water. The organic phase was washed with water and concentrated under reduced pressure. The residue was dissolved in hexanes and washed with water, 1 M sodium hydroxide, and a second portion of water. The concentrated solution was distilled at 15 torr (34-37° C.) to yield 25 g (42%) of the methyl 2,2-dimethyl-3-phenoxypropionate.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=1>C1COCC1>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:3][C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=1
Reactant: Nc1ccccn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2ccccn2)s1

Procedure:
A flame dried round-bottom flask under Ar was charged with NaH (60% dispersionm 0.037 g, 0.91 mmol). Anhydrous THF, 2 mL, was added followed by the addition of 2-aminopyridine (0.032 g, 0.033 mmol). 2-Chloro-thiazole-5-carbonitrile (9-2, 0.044 g, 0.30 mmol) was added and the reaction was heated to reflux. After 2 h the reaction was cooled and quenched by the addition of water. The THF was removed in vacuo and the precipitate which formed was filtered and washed with water. The solid was recrystallized from DMSO to provide a pure sample of the desired product. 1H NMR (DMSO-d6) d 12.23 (s, 1H), 8.40 (m, 1 h), 8.27 (s, 1H), 7.82 (m, 1H), 7.15 (d, 1H, J=8.3 Hz), 7.08 (m, 1H). MS [M+H]+=203.0.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:17][N:16]=1>COCCOC>[BrH:1].[C:7]1([NH:6][C:4]([C:3]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([B:21]4[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]4)=[CH:17][N:16]3[CH:2]=2)=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)C(=O)Nc1ccccc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: COCCOC
Product: Br
Product: CC1(C)OB(c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)OC1(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 32.7 %

Procedure:
To a solution of 1 g of 3-bromo-2-oxo-N-phenylpropionamide in 50 mL of 1,2-dimethoxyethane are added 1.09 g of 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The reaction mixture is stirred for 40 hours at room temperature and then concentrated to dryness under reduced pressure. The residue is taken up in 30 mL of ethanol and refluxed for 90 minutes. After concentrating to dryness under reduced pressure, the solid is triturated in a small amount of ethanol, filtered off and washed with ethanol and then with ethyl ether to give 0.6 g of N-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide hydrobromide (1:1) in the form of a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C=O)C>[Cl:24][CH2:23][CH2:22][CH2:21][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCCCCl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To DMF (80 mL) was added potassium carbonate (5.7 g, 41.1 mmol) and methyl 3-hydroxy-4-methoxybenzoate (5.0 g, 27.4 mmol). The mixture was cooled to 0° C. and 1-bromo-3-chloropropane (8.64 g, 57.9 mmol) in DMF (10 mL) was added dropwise over 30 minutes. The mixture was allowed to warm to r.t overnight. After removing most of the DMF in vacuo, the remaining oil was diluted with H2O and filtered to give methyl 3-(3-chloropropoxy)-4-methoxybenzoate (6.65 g, 25.8 mmol, 94%). 1H NMR (300 MHz, DMSO-d6) δ 7.61 (d, 1H), 7.47 (s, 1H), 7.09 (d, 1H), 4.12 (t, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.78 (t, 2H), 2.23-2.15 (m, 2H); LC-MS (ESI) m/z 259 (M+H)+.
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[NH:5][CH3:6].[CH3:23][N:24]=[C:25]=[S:26]>>[CH2:15]([O:14][C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:4]1[N:5]([CH3:6])[C:25](=[S:26])[N:24]([CH3:23])[C:3]1=[O:22])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC
Reactant: CN=C=S
Product: CN1C(=O)C(CCCCNC(=O)OCc2ccccc2)N(C)C1=S

Procedure:
Using an analogous procedure to Example 1 Nε-benzyloxycarbonyl-Nα-methyl-L-lysine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: [Mg].[Br-:2].C(O[CH2:6][CH3:7])=O.Cl.[CH2:9]1[CH2:13]O[CH2:11][CH2:10]1>>[CH2:11]([Br:2])[CH2:10][CH2:9][CH2:13][CH2:13][CH2:9][CH2:10][CH2:11]/[CH:13]=[CH:9]\[CH2:10]/[CH:11]=[CH:13]\[CH2:9][CH2:10][CH2:11][CH2:6][CH3:7]
Reactant: [Br-]
Reactant: CCOC=O
Reactant: C1CCOC1
Agent: Cl
Agent: [Mg]
Product: CCCCC/C=C\C/C=C\CCCCCCCCBr
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A 1 liter RBF was charged with magnesium turnings (11.1 g, 463 mmol), anhydrous THF (65 mL) and stir-bar and flushed with nitrogen. In a separate flask, a solution of linoleyl bromide (140 g, 425 mL) in anhydrous THF (150 mL) was prepared, and 20 mL of this solution added to the magnesium. When most of the heat had dissipated, the remainder of the bromide was added over a period of 15 minutes. Temperature was then maintained at 45° C. for 4 h. The reaction was then cooled (0° C.). Using a dropping funnel, a solution of ethyl formate (32.4 g, 438 mmol) in anhydrous THF (150 mL) was added over a 40 minute period. The reaction was stirred overnight at room temperature. The reaction was cooled to −15° C. and 5N HCl (185 mL) added slowly. The mixture was transferred to a 2 L separating funnel separated. Water (150 mL) and hexane (150 mL) were added, the mixture washed, and again the aqueous removed. The organic was washed a final time with water (150 mL) and then concentrated to a yellow oil. The yellow oil was stirred with a mixture of EtOH (210 mL), water (30 mL) and KOH (15.8 g) for 1.5 h at room temp. The EtOH was evaporated and the residue treated with hexane (50 mL). 5N HCl (200 mL) was added via dropping funnel. The organic was washed with water (2×50 mL) evaporated, dried and purified by chromatography (0-5% EtOAc in hexane, 91 g, 81%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][OH:34])[O:13][CH:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N:37]([C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][C:41]=1[Cl:48])=[N+:38]=[N-:39]>CN(C=O)C>[N:37]([C:40]1[CH:47]=[CH:46][C:43]([CH2:44][O:34][CH2:33][C@H:14]2[O:13][CH:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:15]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:42][C:41]=1[Cl:48])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=Nc1ccc(CBr)cc1Cl
Reactant: COC1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1O[C@H](COCc2ccc(N=[N+]=[N-])c(Cl)c2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
Methyl 2,3,4-tri-O-benzyl-D-glucopyranoside (1.16 g, 2.5 mmol) was dissolved in DMF (10 ml) and thereto was added sodium hydride (60% in oil, 120 mg, 3.00 mmol) at 0° C., followed by stirring for 15 min. Then 4-azido-3-chlorobenzyl bromide (740 mg, 3.00 mmol) was added portionwise. The resulting mixture was stirred at 0° C. for 30 min and at room temperature for 3 hr. Ice-water was added and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to give the title compound as a yellow oil (1.48 g, yield 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH3:16][C:17]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH:33]1[CH2:35][O:34]1)([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>C1(C)C=CC=CC=1.CO>[CH3:21][O:20][C:18](=[O:19])[C:17]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH:33]([OH:34])[CH2:35][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:12]=[CH:13][C:14]([F:15])=[C:2]([F:1])[CH:3]=2)[CH2:7][CH2:8]1)([CH3:16])[CH3:22]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccccc1OCC1CO1
Reactant: Fc1ccc(OC2CCNCC2)cc1F
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ccccc1OCC(O)CN1CCC(Oc2ccc(F)c(F)c2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A toluene solution of 4-(3,4-difluorophenoxy)piperidine (0.03 ml, 0.5 M) was mixed with a toluene solution of methyl 2-methyl-2-{[2-(2-oxiranylmethoxy)benzoyl]amino}-propanoate (0.03 ml, 0.5 M). The mixture was diluted with 0.20 ml toluene and 0.05 ml methanol. The reaction mixture was stirred overnight at 100° C. in sealed vials. The product were concentrated in vacuo and used without any purification.
Reaction SMILES: N[C@H:2](C(O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-:13].[Na+]>>[CH2:2]([OH:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Product: OCCc1ccccc1

Procedure:
Referring to FIG. 1, L-phenylalanine is provided as a solution 10, wherein the solution comprises fermentation media 12 containing L-phenylalanine. Alternatively, the fermentation media is combined with a solution of L-phenylalanine. The combined fermentation solution is added 20 to a fermentation bath, which fermentation bath is then inoculated with at least one species of yeast 22. The pH of the fermentation solution is adjusted 40 to a pH of about 7.0 with a base (e.g., NaOH) after which the fermentation solution is allowed to ferment under fermentation conditions 30, providing phenethyl alcohol.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=[O:19])[N:3]=1.CON(C)[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([Li])(C)(C)C>C1COCC1>[C:24]([C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=[O:19])[N:3]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(C(=O)c3ccccc3)nc(C(=O)O)c2C1
Temperature: -78 °C
Yield: 45.1 %

Procedure:
Under a nitrogen atmosphere Compound 1I (0.15 g, 0.43 mmol) was dissolved in THF (2 mL) and N-methoxy-N-methylbenzamide (0.14 g, 0.86 mmol) was added. The resulting solution was cooled to −78° C. and tert-Butyl lithium (1.7M in THF, 1.02 mL, 1.73 mmol) was added dropwise. The resulting mixture was stirred and cooled for 1 h and quenched with NH4Cl saturated solution. The solid was removed by filtration and the filtrate was concentrated, acidified to pH 6 with 5% TFA and extracted with 20% i-PrOH/DCM. The organic layer was concentrated, diluted with DCM, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give product 25A (0.072 g, 45%). LCMS (+ESI) m/z 372.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].CCN(CC)CC>CN(C=O)C.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][Si:10]([C:13]#[C:14][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: Nc1ccc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(N)nc1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 75.7 %

Procedure:
A mixture of commercially available 2-amino-5-bromopyridine (50.0 g, 289 mmol), trimethylsilylacetylene (112 mL, 809 mmol), Et3N (120 mL, 867 mmol), PdCl2(PPh3)2 (4.06 g, 2 mol %) and PPh3 (1.52 g, 2 mol %) in DMF (290 mL) was purged for 10 min with argon. Then CuI (340 mg, 1 mol %) was added and the reaction mixture was heated up to 90° C., stirring was continued at 90° C. for 4.5 h. Cooled to 23° C., the reaction mixture was concentrated in vacuum to remove all volatiles, poured the residue onto water (300 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water (300 mL) and brine (2×250 mL), dried over MgSO4. Removal of the solvent in vacuum left a dark brown residue which was purified by flash chromatography with n-heptane and acetone to give the title compound as a brown solid (41.65 g, 76%). MS (ISP) 191 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:33].[CH:34]([N:37]([CH2:41]C)C(C)C)([CH3:36])[CH3:35].ClC(Cl)([O:46]C(=O)OC(Cl)(Cl)Cl)Cl.C(N)(C)C>ClCCl>[F:33][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:41]([NH:37][CH:34]([CH3:36])[CH3:35])=[O:46]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 0.5 h
Yield: 46 %

Procedure:
(4-Amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-benzyl)piperazin-1-yl)methanone (0.209 mmol, 0.1 g) and N,N-diisopropylethylamine (0.709 mmol, 0.117 mL, 0.092 g) were stirred in dichloromethane at room temperature. Triphosgene (0.077 mmol, 0.023 g) was added and the reaction mixture stirred for 30 minutes. Isopropylamine (0.417 mmol, 0.036 mL, 0.025 g) was added and the reaction stirred for a further 30 minutes. The reaction was concentrated at reduced pressure and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (20 mg). MS (ESI) m/z 565.5 [M+H]+
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=1.[ClH:12].COC1CCCC1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=O.C1(C)C=CC=CC=1>CCO>[ClH:12].[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:21]([C:20]([O:24][CH2:25][CH3:26])=[O:23])[NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: CCOC(=O)C=O
Reactant: COc1cccc(CCN)n1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: COC1CCCC1
Product: CCOC(=O)C1NCCc2nc(O)ccc21
Yield: 81.2 %

Procedure:
A solution of 2-(6-methoxypyridin-2-yl)ethanamine (14.43 g, 94.81 mmol), 4N hydrogen chloride/CPME (26.1 mL, 104.29 mmol) and 47% ethyl glyoxylate/toluene solution (polymer form) (30.0 mL, 142.22 mmol) in EtOH (175 mL) was heated under reflux for 8 hr. To the reaction mixture were added 4N hydrogen chloride/CPME (26.1 mL, 104.29 mmol) and 47% ethyl glyoxylate/toluene solution (polymer form) (30.0 mL, 142.22 mmol), and the mixture was heated again under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure to half volume, and to the residue was added diethyl ether (ca. 150 mL). The precipitate was collected by filtration, and washed with EtOH/diethyl ether to give crude ethyl 2-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylate hydrochloride (20.01 g, 77 mmol, 82%) as an off-white powder.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]([CH3:36])=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]([CH3:36])=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Cc1cc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2ccccc2nc1Sc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Yield: 16 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (37 mg, 0.14 mmol), potassium carbonate (158 mg, 1.14 mmol, 2-chloro-3-methylquinoline (30 mg, 0.17 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80 ethyl acetate/hexanes eluent ) to give 9 mg (16%) of the title compound as an amorphous foam. mp 185°-193° FDMS: m/e=402.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]([OH:14])=O)[O:9][C:10]=1[CH3:11].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:41][C:42](=[NH:54])[C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]2[O:14][N:54]=[C:42]([C:43]3[CH:44]=[CH:45][C:46]([O:49][C:50]([F:51])([F:52])[F:53])=[CH:47][CH:48]=3)[N:41]=2)[O:9][C:10]=1[CH3:11]
Reactant: N=C(NO)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1oc(C(=O)O)nc1Cc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1Cc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
A solution of 4-(3-bromobenzyl)-5-methyloxazole-2-carboxylic acid (300 mg, 1.0 mmol), EDC.HCl (191 mg, 1.0 mmol) and HOBT (135 mg, 1.0 mmol) in DMF (10 mL) was stirred at RT for 2 h, and then N-hydroxy-4-(trifluoromethoxy)benzimidamide (220 mg, 1.0 mmol) was added. The mixture was stirred at 70° C. overnight, cooled to RT, treated with H2O (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EtOAc:Petroleum ether=1:5) to afford 5-(4-(3-bromobenzyl)-5-methyloxazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a yellow oil (19 mg, 7%). MS (ES+) C20H13BrF3N3O3 requires 479, 481, found: 480, 482 [M+2+H]+(1:1). 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J=8.5 Hz, 2H), 7.41-7.34 (m, 4H), 7.22-7.19 (m, 2H), 3.94 (s, 2H), 2.44 (s, 3H).