Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:13]([CH2:25][CH3:26])[N:12]=1.[OH-].[NH4+]>>[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[C:22]([N+:1]([O-:4])=[O:2])[CH:23]=2)=[C:13]([CH2:25][CH3:26])[N:12]=1
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCc1nc(N)nc(N)c1-c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A stirred solution of 75 mL of 70% nitric acid and 75 mL of concentrated sulfuric acid warmed to about 50° C. from the heat of solution. To this was added 25 grams (0.10 mole) of 2,4-diamino-5-(4-chloro-phenyl)-6-ethylpyrimidine (commercially available) during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at 50° C. for about 1 hour. After this time, the reaction mixture was allowed to cool to ambient temperature where it was stirred for about 18 hours. The reaction mixture was then poured into 1000 mL of ice containing 110 mL of concentrated ammonium hydroxide. The resultant solid was collected by filtration and recrystallized from aqueous ethanol, yielding 29.2 grams of 2,4-diamino-5-(4-chloro-3-nitrophenyl)-6-ethylpyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].O>CN1C(=O)CCC1>[CH3:22][O:21][C:19](=[O:20])[CH2:18][N:4]([C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[CH3:5]
Reactant: COC(=O)CBr
Reactant: CNc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CN(C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of the 2,4-Difluoro-N-methylaniline (Avacado Research Chemical, Heysham UK) (1.43 g, 10 mmole) in NMP, and K2CO3, was added methyl bromoacetate (0.945 ml, 10 mmole) and stirred at room temperature for 24 hours. The reaction mixture was added to water and extracted with ethyl acetate (3×50 ml), the organic extracts were washed 6× with water, dried (MgSO4) amd evaporated to give the product as a oil.
Reaction SMILES: [C:1]([C:9]1[CH:35]=[CH:34][C:12]([O:13][CH2:14][CH:15]([OH:33])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:20]([OH:32])[CH:19]=2)=[CH:11][C:10]=1[OH:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](O)(=[O:41])/[CH:38]=[CH:39]/[CH3:40]>>[C:37]([O:33][CH:15]([CH2:14][O:13][C:12]1[CH:34]=[CH:35][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([OH:36])[CH:11]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:20]([OH:32])[CH:19]=1)(=[O:41])/[CH:38]=[CH:39]/[CH3:40]
Reactant: O=C(c1ccccc1)c1ccc(OCC(O)COc2ccc(C(=O)c3ccccc3)c(O)c2)cc1O
Reactant: C/C=C/C(=O)O
Product: C/C=C/C(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Yield: 75.1 %

Procedure:
97 g (0.2 mole) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-2-propanol were esterified analogously to Example 1 with 103 g (1.2 moles) of crotonic acid. After crystallization from an acetone/ethanol mixture (ratio by volume 1:2), 83 g (75 percent of theory) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl crotonate were obtained in the form of fine white crystals having a melting point of 99° to 103° C. and a purity of 99 percent (HPLC). The structure of the compound obtained was confirmed by UV, IR and NMR spectra.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)[O:6][N:5]=1)[CH3:2].C1C(=O)N([Br:41])C(=O)C1>ClC(Cl)(Cl)Cl>[Br:41][CH2:9][C:8]1[C:4]([O:3][CH2:1][CH3:2])=[N:5][O:6][C:7]=1[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1
Reactant: CCOc1noc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1noc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1CBr
Yield: 98.8 %

Procedure:
A mixture of 3-(3-ethoxy-4-methylisoxazol-5-yl)-1-trityl-1H-1,2,4-triazole (2.4 g, 5.5 mmol) and NBS (1.1 g, 6.2 mmol) in tetrachloromethane (150 mL) was boiled under reflux for 3 h. The reaction mixture was cooled, filtered and concentrated in vacuo to give crude title compound (2.8 g). The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: BrCc1ccccc1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1ccccc1

Procedure:
The title compound, MS: m/e=308.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and benzylbromide.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(OCC)(=O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:7][CH2:6]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)cnc3c(F)cc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5c(F)cc(F)cc54)CC3)nc2N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of 1-[2-(4-aminopiperidin-1-yl)ethyl]-5,7-difluoroquinoxalin-2(1H)-one (Intermediate 192, 0.158 g) in methanol (10 mL) were added 3 Å molecular sieve power (0.15 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (92 mg). After 2 hours at reflux, the reaction was cooled to 0° C. and NaBH(OAc)3 (0.19 g) was added. The reaction was allowed to warm to room temperature and was stirred overnight. It was diluted with ethyl acetate, filtered, washed with saturated solutions of Na2CO3 and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel with 0-20% methanol in dichloromethane. Fractions containing product were collected, concentrated, dissolved in a minimum of CH2Cl2, precipitated with diethyl ether, and filtered to yield 104 mg of product.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]3[O:30][C:13]4=[C:14]([NH2:29])[N:15]=[CH:16][C:17]([C:18]5[CH:19]=[N:20][N:21]([CH:23]6[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]6)[CH:22]=5)=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:40]([N:44]=[C:45]=[O:46])[CH:41]([CH3:43])[CH3:42]>CN(C=O)C>[CH2:40]([NH:44][C:45]([N:26]1[CH2:25][CH2:24][CH:23]([N:21]2[CH:22]=[C:18]([C:17]3[CH:16]=[N:15][C:14]([NH2:29])=[C:13]4[O:30][C:10]([C:6]5[C:5]6[S:1][N:2]=[CH:3][C:4]=6[CH:9]=[CH:8][CH:7]=5)=[CH:11][C:12]=34)[CH:19]=[N:20]2)[CH2:28][CH2:27]1)=[O:46])[CH:41]([CH3:43])[CH3:42]
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3cccc4cnsc34)oc12
Reactant: CC(C)CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnsc56)cc34)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-benzo[d]isothiazol-7-yl-4-(1-piperidin-4-yl-1H-pyrazol-4-yl)-furo[2,3-c]pyridin-7-ylamine (20.8 mg, 0.05 mmol) in DMF (0.5 mL) was added diisopropylethylamine (0.05 mL, 6.5 mmol) and isobutyl isocyanate (0.06 mmol). The resulting solution stirred at room temperature overnight. The mixture was concentrated and then purified by MDP to afford the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.51 (s, 1H), 9.12 (d, J=1.5 Hz, 1H), 8.84 (d, J=7.3 Hz, 1H), 8.72 (d, J=7.3 Hz, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 4.53 (m, 1H), 3.03 (m, 4H), 2.18 (m, 2H), 2.06 (m, 4H), 1.83 (m, 1H), 1.76 (d, J=5.8 Hz, 6H); MS (ESI): MS (ESI): 516.64 [M+H]+; HPLC tR=0.86 min (HPLC: Analytical—2 min).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(O)C>[ClH:1].[CH:9](=[C:4]1[C:5](=[O:8])[C:6](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][NH:2][CH2:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCNCC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CNCC1=Cc1ccccc1
Reaction time: 16 h
Yield: 94.3 %

Procedure:
A stirred solution of 10 g of 4-piperidone, hydrochloride, hydrate and 14 g of benzaldehyde in 50 ml of ethanol is cooled to 10° C and treated dropwise with 25 ml of concentrated hydrochloric acid (temperature maintained at less than 25° C during the addition) and refluxed for 4 hours; the product begins to separate soon after refluxing begins. After standing at room temperature for about 16 hours, the resulting solid is filtered, washed with cold ethanol and with ether, and air-dried yielding 19.4 g of material, melting point 272°-274° C, dec.
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH2:16]([O:18][C:19](=[O:31])[C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:21])[CH3:17].C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:31])[C@H:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:21][C:11](=[O:13])[C:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])([CH3:10])[CH3:14])[CH3:17]
Reactant: CCOC(=O)[C@@H](N)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](COCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of BOC-α-methylalanine (3.05 g, 15 mmol), O-benzyl-L-serine ethyl ester hydrochloride (3.89 g, 15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl, 2.88 g, 15 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT, 2.04, 15 mmol) in methylene chloride (150 mL) is added triethylamine (1.52 g, 15 mmol). The mixture is stirred overnight and then concentrated in vacuo. The residue is re-dissolved in ethyl acetate and washed with water, 1 N HCl, water, and brine. The solution is dried over sodium sulfate and concentrated to yield N-[2-(BOC-amino)-2-methylpropionyl]-O-benzyl-L-serine ethyl ester of the formula
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O)(=O)C.[BH4-].[Na+]>CN(C=O)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: CCCCCCC=O
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCCCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and heptanal (3.4 mL, 24 mmol) and acetic acid (2 mL) in DMF (20 mL) was heated until all solid was dissolved. To the mixture was added sodium borohydride (605 mg, 16 mmol) and kept at room temperature for 18 h. To the mixture was added sodium borohydride (150 mg, 3.9 mmol) and kept at room temperature for 1 d. The mixture was extracted with ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (100 mL). The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silca Gel, 33% EtOAc:CH2Cl2) to give 2-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dione as a yellow solid (610 mg, 41% yield): mp, 107-109° C.; 1H NMR (DMSO-d6) δ 0.82-0.87 (m, 3H, CH3), 1.24-1.29 (m, 8H, 4 CH2), 2.00-2.04 (m, 1H, CHH), 2.43-2.62 (m, 2H, CH2), 2.82-2.96 (m, 1H, CHH), 3.23-3.31 (m, 2H, CH2), 5.06 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.51 (t, J=5.9 Hz, 1H, NH), 7.01 (d, J=7.0 Hz, 1H, Ar), 7.07 (d, J=8.6 Hz, 1H, Ar), 7.57 (dd, J=7.4, 8.4 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.91, 22.03, 22.17, 26.28, 28.42, 28.69, 30.98, 31.22, 34.84, 48.55, 109.03, 110.36, 117.13, 132.18, 136.24, 146.43, 167.29, 168.96, 170.05, 172.77; Anal Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found: C, 64.62; H, 6.76; N, 11.13.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[C:15](=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].Br[CH:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[C:15](=[O:20])[N:14]([CH:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCCC(Br)CCC
Reactant: Cc1ccc(-c2cccc3c2OC(C)C(=O)N3)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)N1C(=O)C(C)Oc2c(-c3ccc(C)cc3C)cccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 8-(2,4-dimethylphenyl)-2-methyl-2H-1,4-benzoxazin-3(4H)-one (300 mg, 1.12 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydride (43 mg, 1.68 mmol). After the mixture was stirred at 80° C. for 30 min, 4-bromoheptane (804 mg, 4.49 mmol) was added. The mixture was stirred at 80° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 5% ethyl acetate/n-hexane to afford 186 mg (30%) of the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[CH:16][CH:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:34]CCl.Cl>C(O)C>[ClH:34].[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:17](/[CH:16]=[N:15]\[O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=CC2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCO/N=C\C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The above ester (5.0 g, 12 mmol) was dissolved in ethanol (100 ml) and a 2 N aqueous sodium hydroxide solution (27 ml) was added. The mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo to give an oily residue. Dichloromethane (160 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (5.5 ml) was added. The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over magnesium sulphate and the solvent was evaporated in vacuo to give 4.1 g of the title compound as a foam. The material isolated consists of an approx. 1:5 mixture of the E/Z isomers.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)=[C:15]2[N:14]=[C:13]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:12]=1[C:38](=[O:40])[CH3:39].[N:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C>[NH2:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)=[C:15]2[N:14]=[C:13]([CH:32]2[CH2:33][CH2:34][N:35]([S:47]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)(=[O:49])=[O:48])[CH2:36][CH2:37]2)[C:12]=1[C:38](=[O:40])[CH3:39]
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1c(C2CCN(S(=O)(=O)N3CCOCC3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
DIEA (121 mg, 0.94 mmoL) was added to at 0° C. a mixture of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (64.3 mg, 0.15 mmoL) and morpholine-4-sulfonyl chloride (28.9 mg, 0.15 mmol) in DMF (3 mL). After stirring at 0° C. for 0.5 h and then room temperature for 2 h, the mixture was purified by prep-LC to afford 1-(7-amino-5-(1-(morpholinosulfonyl)piperidin-4-yl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone, LCMS tR=3.83 Min (5 min run, UV254nm). Mass calculated for, M+ 561.66, observed LC/MS m/z 567.66 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:18][CH:17]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Br)cc2)CC1
Temperature: 110 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (500 mg), 1-bromo-4-iodobenzene (710 mg) and Cs2CO3 (1.2 g) are dissolved in 1,4-dioxane (15 mL) and purged for 10 minutes with argon. 4,5-Bis-(diphenylphosphino)-9,9-dimethylxanthen (Xantphos, 115 mg) and tris-(dibenzylideneacetone)-dipalladium-(0) (Pd2(dba)3, 45 mg) are added and the mixture is heated for 12 hours at 110° C. Then the mixture is partitioned between saturated aqueous NH4Cl solution and ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 2): tR=1.14 min; Mass spectrum (ESI+): m/z=355 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=O)[CH2:8][CH2:7]1)=[O:5].Cl.[C:14]1([NH:20]N)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:2]([O:3][C:4]([CH:6]1[CH2:12][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:20][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2[nH]c3ccccc3c2C1
Yield: 102 %

Procedure:
4-Cyclohexanonecarboxylic acid ethyl ester (25 g, 147 mmol) and phenylhydrazine hydrochloride (20 g, 139 mmol) were refluxed in 550 mL of anhydrous ethanol overnight. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 34.5 g (96%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]P(OCC)(OCC)=O)[CH:5]=1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[N:34]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[N:35]=[N:36][C:37]=2[CH:38]([CH3:40])[CH3:39])[CH:28]=[CH:27][C:24]=1[CH:25]=O>C(OCC)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[N:34]([C:41]4[C:42]([Cl:48])=[CH:43][CH:44]=[CH:45][C:46]=4[Cl:47])[N:35]=[N:36][C:37]=3[CH:38]([CH3:40])[CH3:39])=[CH:30][C:23]=2[Cl:22])[CH:5]=1
Reactant: CCOP(=O)(Cc1cccc(C(=O)OC)c1)OCC
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(C=O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2Cl)c1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a 0° C. solution of 3-(diethoxy-phosphorylmethyl)-benzoic acid methyl ester (1.2 g, 4 eq) in diethyl ether (15 mL) is added sodium hydride (0.17 g, 4 eq). After 1 h, 2-chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-benzaldehyde (0.44 g, 1 eq) in diethyl ether (5 mL) is added and the reaction is stirred overnight. Upon completion, the reaction is quenched with water. The aqueous solution is acidified with 1N HCl and extracted two times with ethyl acetate. The organic layers are combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via filter chromatography eluting with 10% ethyl acetate:toluene to give 3-(2-{2-Chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-vinyl)-benzoic acid methyl ester (0.459 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)=[O:4].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CCO.C(Cl)(Cl)Cl>[CH2:20]([NH:27][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)[OH:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCOc1ccc(C(=O)CBr)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(C(O)CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a cooled (0° C.) suspension of 2-Bromo-1-(4-octyloxy-phenyl)-ethanone (36.1 g; 110.3 mmol) in EtOH (500 mL) and CHCl3 (100 mL) was added benzylamine (48.2 mL; 441.2 mmol). After 30 minutes the ice-bath was removed and the mixture stirred for another 2 hours at RT. Subsequently the reaction mixture was cooled again to 0° C. and NaBH4 (6.26 g; 165.5 mmol) was added in small portions. The resulting mixture was stirred at 0° C. for 1 hour and thereafter another 4 hours at RT. The reaction mixture was quenched with 1M aqueous HCl (750 mL) at 0° C. and stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 2 N aqueous NaOH. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography (SiO2, EtOAc) to give 2-benzylamino-1-(4-octyloxy-phenyl)ethanol (22.58 g)
Reaction SMILES: [K+].[C:2]([C@@H:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:5]([C:9]([O:11]CC)=[O:10])[C:6]([O-])=[O:7])#[N:3].[H][H]>[Ni]>[CH2:14]([CH:4]1[CH2:2][NH:3][C:6](=[O:7])[C@H:5]1[C:9]([OH:11])=[O:10])[CH:15]([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: CCOC(=O)C(C(=O)[O-])[C@@H](C#N)CC(C)C
Agent: [Ni]
Agent: [K+]
Product: CC(C)CC1CNC(=O)[C@H]1C(=O)O

Procedure:
A vessel was charged with an aqueous solution containing (3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid potassium salt (Formula 23, 411 L from Example 2). Raney Nickel (50% aq solution, Sigma-Aldrich) was added to the mixture, and hydrogen gas was introduced into the vessel over a 20 h period to maintain a pressure of 50 psig in the vessel headspace throughout reaction. The hydrogenation reaction was monitored by H2 uptake and HPLC analysis (C18 column, 4.6 mm×150 mm, detection at 200 nm) of the vessel contents. Following reaction, the aqueous mixture was filtered to remove the Raney Ni catalyst. The pH of the concentrated solution was adjusted to 3.0 using 37% HCl (about 14 L). The resulting solution was extracted three times with EtOAc (50% v/v). The combined organic layers were concentrated under vacuum to afford (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid (Formula 10). MS ink [M+H]+186.1130. 13C NMR (75 ppm, CDCl3) δ 175.67, 172.23, 54.09, 47.62, 43.69, 37.22, 26.31, 23.34, 22.54. Yield 40-42%; 97% ee.