Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.[CH:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:20]([C:22]1[C:31]([CH3:32])=[C:30]([O:33][C:34](=[O:36])[CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21]>O1CCCC1.O>[OH:21][CH:20]([C:22]1[C:31]([CH3:32])=[C:30]([O:33][C:34](=[O:36])[CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)[C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCCCCCC
Reactant: CC(=O)Oc1c(C)c(C=O)nc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC#CC(O)c1nc2ccccc2c(OC(C)=O)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
4.9 ml of a hexane solution of 8.00 mmols of n-butyl lithium was added to a solution of 968 mg (8.80 mmols) of 1-octyne in 10 ml of tetrahydrofuran in an atmosphere of nitrogen at 0° C. and stirred at the same temperature for 15 minutes. The reaction solution was cooled to -78° C., to which a solution of 10 ml of tetrahydrofuran of 1.83 g (8.00 mmols) of 2-formyl-3-methyl-4-acetoxyquinoline was added, following by heating gradually to room temperature and stirring at room temperature for 1 hour. The reaction solution was poured into 100 ml of water, extracted with ethyl acetate and dried with sodium sulfate. The solvent was distilled off under the reduced pressure and resultant residue was purified by silica gel column chromatography (Wako Gel C-200) (solvent: n-hexane ethyl acetate=2:1) to obtain 1.50 g (yield 55%) of 2-(1 hydroxy-2-nonynyl)-3-methyl-4-acetoxyquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]=O)[CH:10]=1.C(O)(=O)C.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:10]=1
Reactant: O=Cc1cc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)ccc1O
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: O=c1cnn(-c2cc(Cl)c(Oc3ccc(O)c(CN4CCCCC4)c3)c(Cl)c2)c(=O)[nH]1
Reaction time: 6 h

Procedure:
To a stirred solution of 2-[3,5-dichloro-4-(3-formyl-4-hydroxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (100 mg) in dichloromethane (3 mL) and dimethylformamide (0.5 mL) was added acetic acid (20 μL), piperidine (35 μL) and sodium triacetoxyborohydride (81 mg). After 6 h, the reaction was diluted into ethyl acetate, washed with saturated sodium bicarbonate, brine, dried (Na2SO4) and concentrated in vacuo to provide a solid mass. Trituration of the solids with ethyl acetate and methanol afforded the title compound of this EXAMPLE as a colorless solid, 73 mg (m.p. 15-217° C.). MS Calc.:463.3; Found:463.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc(C)c(-c2ccnn2C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)sc1-c1ccnn1C
Reaction time: 1 h

Procedure:
A solution of methyl 4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (crude from part a) in THF (4 mL) and 6N NaOH (4 mL) was heated to 70° C. After 1 h, the solution was poured onto H2O and the pH was adjusted to ˜4 with aqueous HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4) and concentrated affording the title compound white was used directly without further purification: LCMS (ES) m/z=223 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:24])[C:22]=3[CH3:23])[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:24])[C:22]=3[CH3:23])[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cnn1C
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1c(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cnn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of N-tert-butyl-2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 98.3 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (224 mg, 152 μL, 1.97 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (1.5 mL), methanol (0.75 mL) and ammonium hydroxide (0.2 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated then purified by chromatography (silica, 10-45% of a 1:4 methanol:dichloromethane solution in dichloromethane) to give N-tert-butyl-2-(1,5-dimethyl-1H-pyrazol-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (18 mg, 55.0 μmol, 56%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.10 (s, 1H), 8.39 (s, 1H), 7.87 (s, 1H), 7.86 (s, 1H), 7.85 (d, J=3.3, 1 H), 3.71 (s, 3H), 2.16 (s, 3H), 1.30 (s, 9H); MS (EI/CI) m/z: 328.2 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.O1CCCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C(C(C)=O)C(C)C.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)CC(C)C
Product: OCC(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 144 h
Yield: 106.7 %

Procedure:
To a 2-liter Morton flask equipped with a mechanical stirrer and a half-moon paddle is charged 30.50 g (0.125 mole) of 2,2-bis(4-hydroxyphenyl)acetic acid and 1 L of tetrahydrofuran (THF) under a nitrogen atmosphere. LiAlH4 (18.9 g, 0.5 mole) is added with stirring to the reaction mixture over a period of six days. The reaction temperature is about 25° C. at the outset and is increased to 65° C. after one day and maintained at that temperature throughout the remaining five days of the addition of the LiAlH4. After a total of 12.5 days, the reaction mixture is cooled to 0° C. and 100 mL of water is added dropwise to the reaction mixture. The pH of reaction mixture is lowered to a pH of 1 by the addition of 10 percent HCl and the resulting phases are separated. The organic phase is evaporated to form a solid and the solid is dissolved in 500 mL of methyl isobutyl ketone. After washing the resulting solution with 100 mL of an aqueous solution of 5 percent NaHCO3, the solution is concentrated in vacuo to yield 30.7 g of 2,2-bis(4-hydroxyphenyl)ethanol as an orange gum. This gum is recrystallized from 430 mL of water to yield 23.0 g of a light brown solid. Upon vacuum drying at 100° C., the solid melted and lost weight to 21.1 g (yield of 73 percent) which weight loss corresponds to one molar equivalent of water.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8](C)(C1C=CC(C(C)(C)O)=CC=1)O.C(OC=C)(=O)C.[OH:27][C:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([CH3:42])([O:39][CH:40]=[CH2:41])[CH3:38])=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH3:38][C:37]([C:34]1[CH:35]=[CH:36][C:31]([C:28]([O:27][CH:7]=[CH2:8])([CH3:30])[CH3:29])=[CH:32][CH:33]=1)([O:39][CH:40]=[CH2:41])[CH3:42]
Reactant: C=COC(C)(C)c1ccc(C(C)(C)O)cc1
Reactant: CC(C)(O)c1ccc(C(C)(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C=COC(C)=O
Solvent: Cc1ccccc1
Product: C=COC(C)(C)c1ccc(C(C)(C)OC=C)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (67 mg, 0.1 mmol) and sodium carbonate (640 mg, 6 mmol) in toluene (5 ml) were added α,α,α′,α′-tetramethyl-1,4-benzenedimethanol (5 mmol) and vinyl acetate (2.15 g, 25 mmol), followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1-(1-hydroxy-1-methylethyl)-4-(1-methyl-1-vinyloxyethyl)benzene and 1,4-bis(1-methyl-1-vinyloxyethyl)benzene were formed in yields of 11% and 62%, respectively, with a conversion from α,α,α′,α′-tetramethyl-1,4-benzenedimethanol of 95%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[N:6]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH:22]=[CH:21]2>>[ClH:17].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:34]3[CH2:33][CH2:32][N:31]([S:28]([C:23]4[CH:22]=[CH:21][C:20]5[C:25](=[CH:26][CH:27]=[C:18]([Cl:17])[CH:19]=5)[CH:24]=4)(=[O:30])=[O:29])[CH2:36][CH2:35]3)=[O:13])=[CH:14][CH:15]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: Nc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)cs1

Procedure:
In a similar manner to Example 4 except for the use of 4-(2-aminothiazol-4-yl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[CH3:18].O1CCCC1.[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)(=[O:33])=[O:32])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 6.8 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.9 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole, 40 ml of tetrahydrofuran, 1 ml of triethylamine and 0.78 g of 3-fluorobenzenesulfonyl chloride. 0.1 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of a cream solid melting at 195° C.
Reaction SMILES: Cl.N(OCCC(C)C)=O.[NH:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][C@H:19]([C:26]([NH:28][C@H:29]([C:40]([N:42]=[N+]=[N-])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:27])[CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)=[O:17].Cl.[CH3:46][O:47][C:48](=[O:65])[C@H:49]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=1)[NH:50][C:51](=[O:56])[C@H:52]([CH2:54][OH:55])N>O1CCCC1.C(N(CC)CC)C.CS(C)=O.CN(C)C=O>[CH3:46][O:47][C:48](=[O:65])[C@H:49]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=1)[NH:50][C:51](=[O:56])[C@H:52]([CH2:54][OH:55])[NH:42][C:40](=[O:41])[C@H:29]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:28][C:26](=[O:27])[C@H:19]([CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)[NH:18][C:16](=[O:17])[C@@H:11]1[CH2:12][CH2:13][C:14](=[O:15])[NH:10]1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 932 mg. of L-pyroglutamyl-L-histidyl-L-tryptophanyl hydrazide (prepared as described in (b) above) in a mixture of 8.4 ml. of dry N,N-dimethylformamide and 7.0 ml. of dimethyl sulfoxide, cooled to -12° C., is added dropwise 5.16 ml. of 2.325 N hydrogen chloride in tetrahydrofuran. The mixture is cooled to -20° C., 0.4 ml. of isoamyl nitrite is added, and the resulting mixture is stirred at -20° C. for 30 minutes. The mixture, which contains L-pyroglutamyl-L-histidyl-L-tryptophanyl azide, is cooled to -25° C., and to it are added first 1.96 ml. of triethylamine and then 636 mg. of L-seryl-L-tyrosine methyl ester hydrochloride (prepared as described in (c) above). The reaction mixture is stirred at -20° C. for 30 minutes and at 0° C. for 30 minutes and is stored in a refrigerator at -5° C. for 48 hours. It is then filtered and the filtrate is evaporated under reduced pressure. The residue is triturated with tetrahydrofuran, the mixture is stored in the refrigerator for 26 hours, and the solvent is decanted to give a residue of L-pyroglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosine methyl ester, which is dissolved in 20 ml. of methanol. To the solution is added 1 ml. of 99% hydrazine hydrate, and the mixture is stirred at room temperature overnight to give solid L-pyroglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl hydrazide, which is isolated by filtration and dried under reduced pressure; m.p. 215°-217° C., following crystallization from water; [α]D25 -17° (1.01% in N,N-dimethylformamide).
Reaction SMILES: CN(C=O)C.[CH2:6]([Cl:8])Cl.P(Cl)(Cl)(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20](=[O:31])[CH2:19]2>C(Cl)(Cl)Cl.N1C=CC=CC=1.CC(=O)OCC>[Cl:8][C:6]1[N:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:22]2[C:18]([C:19]=1[CH:20]=[O:31])=[CH:17][C:16]([O:15][CH3:14])=[CH:24][CH:23]=2
Reactant: ClCCl
Reactant: COc1ccc2c(c1)CC(=O)N2c1ccccc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)c(C=O)c(Cl)n2-c1ccccc1
Temperature: 0 °C

Procedure:
A solution of DMF (2.3 ml) and DCM (2.3 ml) under argon was cooled to 0° C. With stirring, phosphorus oxychloride (2.14 ml, 22.9 mmol) was added within 15 min, and the mixture was stirred for further 30 min at 0° C. Then the compound of step 2 (557 mg, 2.33 mmol), dissolved in chloroform (5.77 ml) and pyridine (1.15 ml), was added to the cooled solution. The reaction mixture was stirred at room temperature overnight. The mixture was slowly poured into 300 ml of ice and after a few minutes EA was added. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. Column chromatography of the residue on silica gel (EA/HEP 1:8) yielded 456 mg of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C1(=O)OC(C)CO1>[Pd].C(OCC)C.ClCCl>[CH:16]1[CH:17]=[CH:18][C:13](/[CH:12]=[CH:11]/[C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC1COC(=O)O1
Product: O=[N+]([O-])c1ccc(/C=C/c2ccccc2)cc1
Temperature: 130 °C
Reaction time: 4.5 h

Procedure:
Under argon, a solution containing 218 mg of p-nitrobromobenzene, 141 mg of styrene, 0.3 ml of triethylamine, and 1 ml of propylene carbonate stabilized colloid solution with a palladium content of 4.023 mg is heated at 130° C. with stirring in a sealed vessel for 4.5 h. At the end of the reaction, 2 ml of diethyl ether/dichloromethane (1:1) is added, and the mixture is filtered. The yield of desired product as determined by GC is 96%.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5]C(=O)OC(C)(C)C)[CH2:2]1.C(N(CC)CC)C.[C:20]([Cl:23])(=[O:22])[CH3:21].Cl.O1CCOCC1>O1CCCC1.CCOCC.CN(C)C=O>[ClH:23].[C:20]([N:1]1[CH2:2][CH:3]([NH2:5])[CH2:4]1)(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)N1CC(N)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of tert-butyl azetidin-3-ylcarbamate (1.00 g, 5.81 mmol) [Ark Pharma, AK26432] in tetrahydrofuran (50 mL) was treated with triethylamine (1.6 mL, 11.6 mmol) followed by N,N-dimethylformamide (15 mL) and cooled to 0° C. The reaction mixture was treated with acetyl chloride (495 μL, 6.97 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with ether and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated give a crude residue that was used immediately without purification. The intermediate azetidine was diluted with methylene chloride (30 mL), treated with 4.0 M hydrogen chloride in dioxane (22.0 mL, 88.0 mmol), and stirred at rt for 30 min. The reaction mixture was diluted with ether and the precipitated solid was collected by filtration in order to give the desired product (550 mg, 63%) as a HCl salt. LCMS calculated for C5H11N2O (M+H)+: m/z=115.1; found: 115.2.
Reaction SMILES: C([Mg]Br)(C)C.[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)[CH3:7].N1(C([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=O)C=CN=C1.N1C=CC=CC=1C(O)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.C([O-])(O)=O.[Na+]>C1COCC1>[O:13]=[C:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:14]
Reactant: CCOC(=O)CC(=O)O
Reactant: O=C(c1ccccn1)n1ccnc1
Agent: CC(C)[Mg]Br
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
A solution of isopropylmagnesium bromide (2M in Et2O; 36.5 mL, 73.0 mmol) was added to 4.36 mL (36.6 mmol) of malonic acid monoethyl ester in 30 mL of THF under N2 at 0° C. The reaction was stirred at 0° C. for 30 min, at room temperature for 30 min, and then at 40° C. for 30 min. The mixture was subsequently cooled to 0° C. and a imidazol-1-yl-pyridin-2-yl-methanone solution (prepared by stirring 3.00 g (24.3 mmol) of pyridine-2-carboxylic acid with 4.7 g (29 mmol) of CDI in 30 mL of THF for 12 h) was slowly added. The reaction was allowed to warm to room temperature and stirred for 12 h. The mixture was then poured into ice cold 1M H3PO4 (150 mL). Solid NaHCO3 was added to the mixture until the pH reached 7. The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with NaHCO3 (100 mL) and brine, dried with MgSO4, filtered, and concentrated to provide 2.5 g ethyl 3-oxo-3-pyridin-2-yl-propionate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:23])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@:9]2([OH:22])[CH3:21])=[CH:4][CH:3]=1.O1CCOCC1>Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:23])[CH2:13][CH2:12][NH:11][CH2:10][C@:9]2([CH3:21])[OH:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)[C@@](C)(O)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@]1(O)CNCC[C@]1(O)c1ccc(Cl)cc1

Procedure:
A solution of (3S,4S)-tert-butyl 4-(4-chlorophenyl)-3,4-dihydroxy-3-methylpiperidine-1-carboxylate (388 mg, 1.135 mmol) in 4 M HCl in dioxane (10 mL, 40.0 mmol) was stirred at room temperature for 2 hours. The mixture was concentrated in-vacuo, then concentrated 3× from methylene chloride to remove residual HCl and dioxane, to yield the title compound. MS (ESI+)=242.2 (M+H)+, 224.2 (M+H−H2O)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[O:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].Cl.Cl.[NH2:27][C@@H:28]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@H:29]([OH:41])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C)C=O.O>[F:50][C:45]1[CH:44]=[C:43]([CH:48]=[C:47]([F:49])[CH:46]=1)[CH2:42][C@H:28]([NH:27][C:10](=[O:11])[C:9]1[CH:13]=[C:14]([C:16]2[O:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:22][CH2:23][CH3:24])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:29]([OH:41])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nc(C)co2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2nc(C)co2)c1
Reaction time: 8 h
Yield: 26.9 %

Procedure:
A solution of 3-[(dipropylamino)carbonyl]-5-(4-methyl-1,3-oxazol-2-yl)benzoic acid (77.5 mg, 0.23 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (96 mg, 0.23 mmol), HOBt (32 mg, 0.23 mmol), and N-methylmorpholine (83 μL, 0.75 mmol) was stirred in dimethylformamide (2 mL) for 15 min. EDC (73 mg, 0.42 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with water, and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), saturated sodium chloride, dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(4-methyl-1,3-oxazol-2-yl)-N 3,N3-dipropylisophthalamide (40 mg): 1H NMR (300 MHz, CDCl3) δ 8.20 (br s, 1H, —NH), 8.17 (s, 1H), 8.05 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.24–7.08 (m, 5H), 7.02 (d, J=8 Hz, 2H), 6.61 (t, J=8 Hz, 1H), 4.27 (br s, 1H), 3.93 (d, J=4 Hz, 1H), 3.85 (s, 2H), 3.54 (br s, 2H), 3.43 (br s, 2H), 2.84 (d, J=5 Hz, 2H), 2.63 (q, J=8 Hz, 2H), 2.18 (s, 3H), 1.74 (t, J=5 Hz, 2H), 1.41 (d, J=7 Hz, 2H), 1.22 (t, J=8 Hz, 3H), 1.03 (t, J=7 Hz, 3H), 0.64 (t, J=7 Hz, 3H); ESI MS m/z 647 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[OH-].[NH4+].CCN(C(C)C)C(C)C.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O>CO.[Ni].C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][NH:7][C:26](=[O:25])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:9]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cc(C(F)(F)F)c(C#N)cn1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)c(CNC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
6-Methyl-4-(trifluoromethyl)nicotinonitrile (1.0 equiv.) was dissolved in MeOH (0.1 M), wet Raney nickel was added, followed by ammonium hydroxide (32 equiv.). The reaction vessel was evacuated three times, refilled with hydrogen and then equipped with a hydrogen balloon and stirred at room temperature for 48 h. The mixture was filtered through a short pad of celite which was washed with MeOH. Ethanol was added to remove excess water upon concentration. The volatile solvents were removed to afford crude product which was dissolved in DCM. DIEA (1.8 equiv.) was added followed by BOC2O (0.95 equiv.). The reaction was stirred at room temperature for 1 h. The volatile solvent was removed and the residue was purified via Biotage chromatography (10-100% ethyl acetate in hexanes) to afford tert-butyl ((6-methyl-4-(trifluoromethyl)pyridin-3-yl)methyl)carbamate (90% yield); MS(ESI) m/z 290.3[M+1]+