Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)C.C([Li])CCC.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[CH:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[OH:19])[CH:13]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1cccc2ccccc12
Temperature: -120 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml 3-neck flask round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet is added 100 ml of anhydrous diethyl ether and 62.5 ml of 1.6 molar butyllithium solution (in hexane). The system is cooled to -120° C. and 15.90 gm of 3-bromopyridine in 50 ml of tetrahydrofuran is added over 2 hours. After addition of the 3-bromopyridine, the system is stirred for an additional 45 minutes. At this time, 15.60 gm of 1-formylnaphthalene in 50 ml of tetrahydrofuran is added to the system while still maintaining a temperature of -120° C. The system is kept at -120° C. for an additional 3 hours after addition of the 1-formylnaphthalene and afterwards is allowed to come to room temperature. After 10 hours at room temperature, the system is quenched with saturated ammonium chloride (in water). The system is adjusted to pH 2 with HCl solution. The solution is extracted with diethyl ether. The aqueous solution is made basic with a 5% NaOH solution. The product is extracted with methylene chloride and dried over sodium sulfate. The methylene chloride is removed by stripping and the residue is triturated with hexane to give the 3-pyridyl-1-naphthylcarbinol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:2]1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:2]1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccsc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccsc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.9 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(thiophen-3-ylmethoxy)-phenyl)-acetohydroximoyl chloride (150 mg, 0.532 mmol) described in Manufacturing Example 77-1-4 and 3-ethynyl-pyridin-2,6-diamine (45.2 mg, 0.339 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (185 μL, 1.33 mmol). This reaction mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (73 mg, 36%).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)CC)C>C(O)C>[C:14]1(=[O:23])[N:13]([CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-bromomethylphthalimide (5.28 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 4.29 g of the desired product (69.4%, pale yellow crystals).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[O:36][CH:35]=[CH:34][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:17][N:18]4COCC[Si](C)(C)C)=[CH:14][CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1.[NH4+].[OH-]>ClCCCl>[CH:1]1([NH:4][C:5]2[C:6]3[O:36][CH:35]=[CH:34][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:17][NH:18]4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1nn(COCC[Si](C)(C)C)c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CN(C)C(=O)c1n[nH]c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Temperature: 70 °C
Yield: 40.4 %

Procedure:
In a vial, 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide (0.94 g, 0.19 mmol, prepared using E.2 from Preparation #AI.1 with dimethylamine) and an aqueous solution of HCl (6 N, 0.401 mL, 2.41 mmol) in DCE (4 mL) were added. The mixture was heated at about 70° C. for about 15 h. The mixture was concentrated under reduced pressure and 1,4-dioxane (4 mL) and NH4OH (0.956 mL, 7.36 mmol) were added. The mixture was heated at about 75° C. for about 3 h, concentrated under reduced pressure and the residue was suspended in MeOH (1 mL) and filtered. The filtrate was purified by column chromatography eluting with 35 to 85% of 10% MeOH in DCM/DCM (12 g silica gel) to give 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-N,N-dimethyl-1H-indazole-3-carboxamide (0.029 g, 42%): LC/MS (Table 2 Method c) Rt=1.52 min.; MS m/z: 378 (M+H)+. Syk IC50=A
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH:7]([CH:10]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[C:11](O)=[O:12])([CH3:9])[CH3:8]>C1C=CC=CC=1>[CH:7]([CH:10]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[C:11]([Cl:4])=[O:12])([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)CCC(C(=O)O)C(C)C
Solvent: c1ccccc1
Product: CC(=O)CCC(C(=O)Cl)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 6.0 g (0.0468 mole) of oxalyl chloride in 4 ml of benzene was chilled to 0° C under a nitrogen atmosphere. A solution of 4.0 g (0.0234 mole) of 2-isopropyl-5-oxohexanoic acid in 4 ml of benzene was added and the solution was warmed to room temperature, and stirred at room temperature for 20 hours. Evaporation of the solvent under reduced pressure yielded a 2-isopropyl-5-oxohexanoyl chloride residue, and the residue was dissolved in 3 ml of benzene. A 3.1 g (0.0222 mole) quantity of 2-methoxy-4-methylphenol in 5 ml of benzene was added, and the solution was stirred for 20 hours. Ether was added and the solution was washed with water, aqueous saturated sodium chloride, and 5% potassium hydroxide. The organic layer was dried over anhydrous calcium chloride, and the solvent was removed under reduoed pressure to yield a liquid whioh was purified by Kugelrohr distillation bp 120°-125° C./0.04 mm Hg.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[I:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C)nc1I
Temperature: 45 °C
Reaction time: 20 h

Procedure:
To 2-iodo-6-methyl-pyridin-3-ol (1.0 g, 4.25 mmol) and K2CO3 (1.18 g, 8.51 mmol) in acetone (20 mL) was added MeI (0.91 g, 6.38 mmol). The reaction was stirred at 45° C. under N2 for 20 h. The reaction was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography using dichloromethane to afford 1.04 g (98%) of I-95 as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1csc(-c2ccc(Cl)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1csc(-c2ccc(Cl)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 22 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)thiazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mg, yield 22%). 1H NMR (400 MHz, CDCl3) δ 8.53 (t, J=1.5 Hz, 1H), 8.27-8.25 (dt, J=7.8 Hz, 1.3 Hz, 1H), 8.09-8.07 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.89-7.87 (m, 2H), 7.68 (m, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.36-7.34 (m, 2H), 7.09 (s, 1H), 3.92-3.87 (m, 2H), 3.16 (t, J=6.0 Hz, 2H). MS (ESI) m/z: Calculated for C21H14ClF3N4O2S: 478.05. found: 479.0 (M+H)+.
Reaction SMILES: O1CCOCC1.[CH2:7]([O:9][CH:10]1[CH2:15][CH2:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][CH2:11]1)[CH3:8].[CH3:24][N:25]1[CH2:33][C:32]2[C:27](=[C:28]([N+:43]([O-:45])=[O:44])[CH:29]=[CH:30][C:31]=2B2OC(C)(C)C(C)(C)O2)[C:26]1=[O:46].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:7]([O:9][CH:10]1[CH2:15][CH2:14][C:13]([C:31]2[CH:30]=[CH:29][C:28]([N+:43]([O-:45])=[O:44])=[C:27]3[C:32]=2[CH2:33][N:25]([CH3:24])[C:26]3=[O:46])=[CH:12][CH2:11]1)[CH3:8]
Reactant: CCOC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CN1Cc2c(B3OC(C)(C)C(C)(C)O3)ccc([N+](=O)[O-])c2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC1CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 60 °C

Procedure:
Dioxane (20 mL) and water (5 mL) were taken in a three necked RB flask equipped with a nitrogen inlet and a thermometer. The solvents were deoxygenated for 15 min using nitrogen gas. Trifluoro-methanesulfonic acid 4-ethoxy-cyclohex-1-enyl ester (Compound 166D, 300 mg, 1.1 mmol), 2-methyl-7-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one (Compound 205E, 630 mg, 1.64 mmol), tetrakis triphenyl phosphine palladium catalyst (114 mg, 0.01 mmol) and cesium carbonate (889 mg, 2.7 mmol) were added. The reaction mixture was heated to 60° C. for 3 hrs. The solvents were evaporated and the residue was purified over silica gel column using (methanol:methylene chloride: 1:99). Yield: 300 mg (86%). 1H NMR (CDCl3, 400 MHz): δ1.2 (t, 3H, J=7 Hz), 1.8-2.4 (m, 6H), 3.15 (s, 3H), 3.50-3.64 (m, 3H), 4.36 (s, 2H), 5.79 (m, 1H), 7.4 (d, 1H, J=8.1 Hz), 7.63 (d, 1H, J=8.1 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.O=[CH:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CO.[Pd]>[C:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1)=[O:36])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6, 15 mg) in MeOH (2 mL) was added tert-butyl 2-oxoethylcarbamate (20 mg). Pd/C (10% by weight, 10 mg) was added and the reaction mixture was stirred under H2 balloon overnight. The reaction mixture was filtrated and the solvent was then removed under reduced pressure and the residue was carried on to the next step without further purification. ESI-MS m/z 490.1 (MH)+.
Reaction SMILES: [CH2:1]([N:3]([Zr:6](N(CC)CC)([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH2:4][CH3:5])[CH3:2].[Cl-:22].[Cl-].[Cl-].[Cl-].[Zr+4]>O1CCCC1>[Cl:22][Zr:6]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: [Cl-]
Reactant: CCN(CC)[Zr](N(CC)CC)(N(CC)CC)N(CC)CC
Agent: [Zr+4]
Solvent: C1CCOC1
Product: CCN(CC)[Zr](Cl)(N(CC)CC)N(CC)CC
Reaction time: 1 h

Procedure:
A 0.1M stock solution of chlorotris(diethylamino)zirconium in tetrahydrofuran (THF) was prepared in a dry box by the addition of 1.14 g (3 mmol) of tetrakis(diethylamino)zirconium to 233 mg (1 mmol) of zirconium tetrachloride. After standing for 1 h, the mixture was diluted to 40 mL with tetrahydrofuran, and the resulting 0.1M stock solution was stored at -23° in a refrigerated dry box.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[N:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:15](=[O:16])[CH:14]=[N:13][C:12]5[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]4=5)[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Yield: 64.4 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (Intermediate 202, 75 mg) was reacted with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (48 mg) and sodium acetoxyborohydride (0.11) as described for Example 107. Chromatography on silica gel with 0-2% methanol in dichloromethane to give 72 mg of the product.
Reaction SMILES: C([Li])(CC)C.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:17][S:18]SC>O1CCCC1>[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([S:18][CH3:17])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COc1ccccc1C(=O)O
Reactant: CSSC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cccc(SC)c1C(=O)O
Reaction time: 2 h
Yield: 29.6 %

Procedure:
N,N,N′N′-Tetramethylethylendiamine (16 g, 138 mmol) was added drop-wise at −70° C. to a solution of sec-butyllithium (92 mL, 1.3 M in cyclohexane, 120 mmol) in 80 mL tetrahydrofuran. 2-Methoxybenzoic acid (7.0 g, 46 mmol) in 40 mL tetrahydrofuran was added drop-wise at −70° C. over 2 hours. After complete addition stirring was continued at −70° C. for another 2 hours. Dimethyl disulfide (15.2 g, 161 mmol) was added at −70° C. within 10 min. Stirring was continued at −70° C. for another hour and the reaction was allowed to slowly warm up over night. The reaction mixture was quenched with 40 mL water and extracted with 200 mL ethyl acetate. The aqueous phase was adjusted to pH1 by addition of 25% HCl and extracted twice with dichloromethane. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was crystallized with cyclohexane and yielded the title compound as an off-white solid (2.7 g, 30%), MS: m/e=197.4 [(M−H)−].
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Na].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:17])=[N:9][N:8]=1>>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:4][CH2:1][C:2]#[CH:3])=[N:8][N:9]=1
Reactant: C#CCO
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [Na]
Product: C#CCOc1nnc(Cl)c2ccccc12
Temperature: 127 °C
Reaction time: 0.03 h
Yield: 15 %

Procedure:
To 2-propynol (3 mL) is slowly added sodium (70 mg, 3.04 mmol) followed by 1,4-dichlorophthalazine (400 mg, 2.01 mmol). The brown suspension obtained is stirred under argon for 2 min and then heated at 121-133° C. for 2 h. Excess 2-propynol is removed under vacuum, and the residue is diluted with cold water and then extracted with CHCl3 (120 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (25% to 50% ethyl acetate/hexane) to give 66 mg (15%) of 2 as a cream solid, mp 134-136° C. IR 2882, 1404, 1292 cm−1; 1H NMR (CDCl3) δ 2.61 (t, J=2.4 Hz, 1H, C≡CH), 5.33 (d, J=2.4 Hz, 2H, CH2C≡CH), 7.94-8.04 (m, 2H, 6,7-PhthH), 8.24 (m, 5-PhthH), 8.31 ppm (m, 8-PhthH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=O)[N:13]=[N:12]1.[NH2:20][C:21]1[C:22](=[O:34])[N:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH3:27])[C:25]=1[CH3:26].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([NH:20][C:21]2[C:22](=[O:34])[N:23]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[N:24]([CH3:27])[C:25]=2[CH3:26])=[O:19])[N:13]=[N:12]1
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(C2CC2)cc1Cl
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)nnn1-c1ccc(C2CC2)cc1Cl
Temperature: 10 °C
Reaction time: 2.5 h

Procedure:
1-(2-Chloro-4-cyclopropylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (15 g, 54.0 mmol) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A)(11.30 g, 54.0 mmol) were slurried in EtOAc (150 mL). The reaction mixture was cooled to 10° C. and triethylamine (18.82 mL, 135 mmol) was added dropwise, followed by dropwise addition of T3P (50% w/w in EtOAc) (47.7 mL, 81 mmol) over 15 mins, maintaining a temperature <10° C. The reaction mixture was allowed to warm to RT and stirred for 2.5 hrs. The resulting mixture was quenched with sat. sodium bicarbonate (aq) (150 ml). The layers were separated and the organic layer was washed with sat. sodium bicarbonate (aq) (50 ml), water (150 ml) and brine (150 ml). The organic extracts were dried over MgSO4 and charcoal. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The crude material was slurried in ethyl acetate (335 ml) and heated to reflux with stirring. The hot mixture was filtered and the filtrate was seeded and at left to stand at room temperature overnight. The resulting crystalline solid was collected by filtration and dried under reduced pressure at 40° C. over 2 days to yield the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])[CH3:2].[Li+].[CH3:17][CH:18]([N-:20]C(C)C)C>C(#N)C>[CH2:14]([CH:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:17][C:18]#[N:20])[CH:11]=[CH:12][CH:13]=1)[CH3:15]
Reactant: CCC(CC)COc1cccc(C=O)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC#N
Product: CCC(CC)COc1cccc(C(O)CC#N)c1

Procedure:
Reaction of 3-(2-ethylbutoxy)benzaldehyde with acetonitrile in the presence of LDA gave 3-(3-(2-ethylbutoxy)phenyl)-3-hydroxypropanenitrile. 1H NMR (400 MHz, DMSO-d6) δ 7.22 (t, J=7.2 Hz, 1H), 6.92-6.96 (m, 2H), 6.81-6.83 (m, 1H), 5.89 (brs, 1H), 4.83 (brs, 1H), 3.82 (d, J=6.4 Hz, 2H), 2.73-2.90 (m, 2H), 1.56-1.64 (m, 1H), 1.31-1.44 (m, 4H), 0.87 (t, J=7.6 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([O:14][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([F:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 12.55 mmol) in anhydrous DMF (5 mL) were added chlorotrimethylsilane (1.95 mL, 15.37 mmol) and triethylamine (4.18 mL, 30.0 mmol). The resulting milky mixture was heated at 80° C. for 17 h, then cooled to RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a pale yellow oil (1.86 g, 55%). To a solution of 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.86 g, 6.852 mmol) in acetonitrile (80 mL) was added Selectfluor™ (2.7 g, 7.622 mmol) and the mixture was stirred at RT for 2 h. The resulting solution was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a colourless oil (1.13 g, 76%).
Reaction SMILES: [CH2:1]([N:8]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[C:9](=[O:18])[CH2:10][CH:11]([CH3:17])[CH2:12][C:13]([O:15]C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([N:8]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[C:9](=[O:18])[CH2:10][CH:11]([CH3:17])[CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C)CC(=O)N(Cc1ccccc1)c1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(CC(=O)O)CC(=O)N(Cc1ccccc1)c1ccc(C#N)cc1
Yield: 96.1 %

Procedure:
A solution of the compound obtained in Step 2 (80.0 mg, 0.23 mmol) and 1N aqueous sodium hydroxide solution (1 mL, 1.00 mmol) in methanol (2 mL) and THF (2 mL) was stirred at room temperature for 14 hr. The reaction solution was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give crude 5-(benzyl(4-cyanophenyl)amino)-3-methyl-5-oxopentanoic acid (74.2 mg, 0.221 mmol, 97%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:10][C:9]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:41]CC1.[Li+].[OH-].CO>O>[C:1]([O:5][C:6]([NH:8][C@H:15]1[CH2:16][C@@H:11]([CH2:10][C:9]([OH:41])=[O:37])[CH2:12][CH2:13][C@@H:14]1[N:17]1[CH:25]=[N:24][C:23]2[C:18]1=[N:19][CH:20]=[N:21][C:22]=2[NH:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: COc1ccc(C(=O)Nc2ncnc3c2ncn3[C@H]2CC[C@@H]3CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2ncnc3c2ncn3[C@H]2CC[C@H](CC(=O)O)C[C@@H]2NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A 500 ml two-necked round-bottomed flask was loaded with 5.25 g of PMBzBoc-A lactam 15f (10.36 mmol) and 200 ml of THF. After cooling to 0° C., a solution of 2.17 g of LiOH×H2O (51.8 mmol) in 50 ml of H2O was added dropwise over a period of 20 min. 30 ml of MeOH were then added, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. An ion-exchange resin (Amberlite IR-120, H+ form) was then added until a pH of 7 was reached. The resin was removed by filtration and the solution was concentrated under reduced pressure to a volume of 100 ml. 200 ml of H2O were then added and a pH of 2 was adjusted by addition of 1 M aqueous HCl. The solution was extracted with EtOAc (3×200 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was dissolved in 25 ml of hot MeOH. The product was then precipitated by addition of 10 ml of H2O. The precipitate was filtered, washed with H2O and dried over P4O10 to afford 1.95 g of 16. It was possible to obtain a further 0.57 g from the mother solution and the wash solutions to afford a total yield of 46%.