Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:49][C:48]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)[O:19][C:45](=[O:46])[C:44]=1[S:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)c1ccc(OCCCc2ccccc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCCc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(3-phenylpropoxy)acetophenone (1.28 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 139-142° C.; 1H NMR (400 MHz, DMSO-d6) δ2.04 (m, 2 H), 2.84 (m, 4 H), 2.98 (t, 2 H), 4.40 (t, 2 H), 6.68 (s, 1 H), 7.18 (m, 12 H), 7.75 (d, 2 H), 11.86 (bs, 1 H).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[OH-].[Na+].O.C(OCC)C>CO>[NH2:12][C:5]1[C:6]([CH3:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(Cl)nc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: Cc1nc(Cl)cc(C(=O)O)c1N
Temperature: 25 °C
Yield: 95.7 %

Procedure:
3-Amino-6-chloro-2-methylisonicotinic acid methyl ester (100 mg) was dissolved in methanol (2 mL) and 2N aqueous sodium hydroxide solution (2 mL) was added. The reaction mixture was stirred under reflux for 2.5 hours. After cooling to room temperature, water and diethyl ether were added, the layers were separated and the aqueous layer was washed with diethyl ether. The aqueous layer was acidified by addition of 2N hydrochloric acid and the formed precipitate was 3× extracted with MTB-ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 89 mg of the title compound of the formula
Reaction SMILES: [CH3:1][C:2]1([CH:7]=[CH:8][O:9][C:10](=[O:12])[CH3:11])[NH:5][C:4](=[O:6])[CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])[NH:5][C:4](=[O:6])[CH2:3]1
Reactant: CC(=O)OC=CC1(C)CC(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1(C)CC(=O)N1

Procedure:
A solution of 4-methyl-4-(2-acetoxyvinyl)-2-azetidinone (10.0 g, 0.065 mole) in 200 ml ethyl acetate containing 100 mg of 10% Pd/C is hydrogenated on a Parr shaker at 25° C. under 40 psi hydrogen for 15 minutes. The mixture is filtered through a bed of Supercel and washed with additional ethyl acetate. The combined filtrate is evaporated in vacuo to give 4-methyl-4-(2-acetoxyethyl)-2-azetidinone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]1)[CH:6]=[CH:5]2.[F:21][C:22]([F:31])([F:30])[CH:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[F:21][C:22]([F:31])([F:30])[CH:23]1[CH2:28][CH2:27][CH:26]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([CH2:12][N:13]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]2)[CH:6]=[CH:5]3)[CH2:25][CH2:24]1
Reactant: COC(=O)C1CN(Cc2ccc3cc(O)ccc3c2)C1
Reactant: OC1CCC(C(F)(F)F)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(Cc2ccc3cc(OC4CCC(C(F)(F)F)CC4)ccc3c2)C1
Yield: 27 %

Procedure:
To a vial was added methyl 1-((6-hydroxynaphthalen-2-yl)methyl)azetidine-3-carboxylate (271 mg, 1.0 mmol), 4-(trifluoromethyl)cyclohexanol (252 mg, 1.5 mmol, 1.5 equiv), PPh3 (524 mg, 2.0 mmol, 2.0 equiv) and toluene (0.8 mL) under N2 atmosphere. While stirring, DIAD (404 mg, 2.0 mmol, 2.0 equiv) was added to the reaction mixture quickly at r.t and stirred for 10 min. The reaction mixture was then purified by silica gel chromatography (PE:EA=5:1) to give the title compound (114 mg, 28%) as a slight yellow oil. ESI-MS (M+1)+: 408.2. 1H NMR (400 MHz, CD3OD) δ: 7.76 (d, 1H), 7.70 (d, 1H), 7.66 (s, 1H), 7.36 (dd, 1H), 7.24 (d, 1H), 7.17 (dd, 1H), 4.86-4.76 (m, 1H), 3.74 (s, 2H), 3.70 (s, 3H), 3.56-3.51 (m, 2H), 3.32-3.34 (m, 3H), 2.33-2.22 (m, 1H), 2.20 (d, 2H), 1.82-1.67 (m, 6H).
Reaction SMILES: CC([O-:5])(C)C.[K+].[CH3:7][CH:8]1[O:13][C:12]2[CH:14]=[CH:15][C:16]([CH:18]=O)=[CH:17][C:11]=2[NH:10][C:9]1=[O:20].[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:7][CH:8]1[O:13][C:12]2[CH:14]=[CH:15][C:16](/[CH:18]=[CH:22]/[C:23]([O:24][CH2:25][CH3:21])=[O:5])=[CH:17][C:11]=2[NH:10][C:9]1=[O:20]
Reactant: C1CCOC1
Reactant: CC1Oc2ccc(C=O)cc2NC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)/C=C/c1ccc2c(c1)NC(=O)C(C)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
In a 100 mL round bottom flask equipped with a magnetic stir bar was added t-BuOK (352 mg, 3.14 mmol) and THF (5 mL). The solution was cooled to 0° C. Triethylphosphonoacetate (0.576 mL, 2.88 mmol) was added slowly by syringe pump over 30 min. Using 13 (500 mg, 2.62 mmol) in THF (5 mL), the aldehyde was added via syringe pump over 30 min at 0° C. When the addition was complete, the reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched with sat aqueous NH4Cl (10 mL) and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient of 25-50% EtOAc in hexanes. The appropriate fractions were combined and concentrated in vacuo to give the title compound as a white solid (631 mg, 92% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.20 Hz, 3H) 1.43 (d, J=6.82 Hz, 3H) 4.18 (q, J=7.16 Hz, 2H) 4.70-4.77 (m, 1H) 6.38 (d, J=15.92 Hz, 1H) 7.13 (d, J=2.02 Hz, 1H) 7.33 (dd, J=8.72, 2.15 Hz, 1H) 7.56 (d, J=15.92 Hz, 1H) 10.78 (s, 1H). ESI-MS: m/z 262.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:50]([F:53])([F:52])[F:51])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([NH:16][CH2:17][C@@H:18]4[C@H:22]5[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH2:38][C:39]7[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=7[O:47][CH3:48])[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH2:13]3)[NH:7][C:6]=2[CH:49]=1.[C:54]([BH3-])#N.[Na+].C(O)(=O)C.C=O>CO>[Cl:1][C:2]1[C:3]([C:50]([F:51])([F:52])[F:53])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:13][CH:14]([N:16]([CH2:17][C@@H:18]4[C@H:22]5[O:23][C:24]([CH3:26])([CH3:27])[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH2:38][C:39]7[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=7[O:47][CH3:48])[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH3:54])[CH2:15]3)[NH:7][C:6]=2[CH:49]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CNC3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mg, 0.10 mmol) in methanol (2.5 mL) was treated with sodium cyanoborohydride (84 mg, 1.3 mmol). The pH of the solution was adjusted to ˜6 by the dropwise addition of a 10% (v/v) solution of glacial acetic acid in methanol. The mixture was treated with 37% aqueous formaldehyde (0.12 mL, 1.7 mmol) dropwise and the mixture was stirred at room temperature till complete by LCMS. After 2 h, the reaction was complete and the reaction mixture was concentrated to remove the methanol. The aqueous solution that remained was diluted with 7 mL NaHCO3 and the aqueous phase was extracted with three 10 mL portions of CH2Cl2. The organic phase was dried over Na2SO4, filtered, and concentrated to yield a colorless stiff foam/glass. The crude material was purified by flash chromatography (20 g silica gel; 4% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (62 mg, 80%) as a colorless glass: MS (ESI+) for C39H45ClF3N7O4 m/z 768.0 (M+H)+; MS (ESI−) for C39H45ClF3N7O4 m/z 766.3 (M−H)−; HPLC purity 92.1% (ret. time, 3.29 min).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[F:44][C:45]([F:57])([F:56])[C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH2:55])[CH2:53][CH3:54])=[CH:48][CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[F:56][C:45]([F:44])([F:57])[C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH:55][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:53][CH3:54])=[CH:48][CH:47]=1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (50 mg, 0.180 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (27 mg, 0.197 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.197 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(6-trifluoromethyl-pyridin-3-yl)-propylamine hydrochloride (48 mg, 0.20 mmol) and triethylamine (55 mg, 0.54 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 45 mg (54%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide as white solid. LC/MS (method 5): Rt=4.12 min; m/z=465.35 (M+H+). 1H-NMR (400 MHz): δ (ppm)=8.76 (1H, s), 8.26 (1H, d), 8.01 (1H, d), 7.89 (1H, d), 7.24 (1H, s), 4.93-4.98 (2H, m), 4.84 (1H, d), 4.20-4.29 (2H, m), 3.92-3.99 (2H, m), 3.79-3.84 (1H, m), 3.69 (2H, bs), 2.07 (1H, m), 1.96 (1H, m), 1.77-1.89 (3H, m), 1.56 (1H, m), 1.19 (3H, d), 0.92 (3H, t).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6](=[N:8][OH:9])[CH3:7])[CH3:5].C(O)(C)(C)C.CC([O-])(C)C.[K+].[CH3:21][O:22][N:23]([C:28]1[C:29](Cl)=[N:30][CH:31]=[CH:32][CH:33]=1)[C:24](=[O:27])[O:25][CH3:26]>CS(C)=O>[CH3:21][O:22][N:23]([C:28]1[C:29]([O:9][N:8]=[C:6]([CH3:7])[C:4](=[N:3][O:2][CH3:1])[CH3:5])=[N:30][CH:31]=[CH:32][CH:33]=1)[C:24](=[O:27])[O:25][CH3:26]
Reactant: COC(=O)N(OC)c1cccnc1Cl
Reactant: CON=C(C)C(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CON=C(C)C(C)=NOc1ncccc1N(OC)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 70° C., a mixture of 1.2 g (9.2 mmol) of 2-methoxyimino-3-hydroxyiminobutane and 25 ml of tert-butanol was treated with 1.03 g (9.2 mmol) of potassium tert-butylate, and the mixture was stirred for 1 hour. The reaction mixture was freed from solvent under reduced pressure at approximately 40° C. The residue was introduced into 15 ml of dimethyl sulfoxide, and 2 g (9.2 mmol) of methyl N-methoxy-N-(2-chloropyridin-3-yl)carbamate, dissolved in 3 ml of dimethyl sulfoxide, were added at 50° C. The mixture was stirred for 2 hours at 100° C., and the reaction mixture was transferred to approximately 150 g of ice and extracted with tert-butyl methyl ether. The organic phases were combined, washed with water, dried, and the solvent was removed, under reduced pressure. The resulting residue was purified by column chromatography over silica gel using cyclohexane/ethyl acetate (2:1). This gave 470 mg (17%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)C(C)C)(C)C.[F:33][C:34]([F:45])([F:44])[CH2:35]OS(C(F)(F)F)(=O)=O.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:35][C:34]([F:45])([F:44])[F:33])[CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1nc(C2CCNCC2)sc1COc1ccc(C#N)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C2CCN(CC(F)(F)F)CC2)sc1COc1ccc(C#N)c(Cl)c1
Yield: 114 %

Procedure:
710 mg 2-Chloro-4-(4-methyl-2-piperidin-4-yl-thiazol-5-ylmethoxy)-benzonitrile were dissolved in 20 ml tetrahydrofuran. 0.55 ml N,N-Diisopropylethylamine and 710 mg 2,2,2-Trifluoroethyl-trifluoromethanesulfonate were added and the reaction mixture heated under reflux for two hours. The cooled reaction mixture was diluted by addition of 100 ml ethyl acetate, washed with 20 ml water and brine then dried over MgSO4. The solvent was removed in vacuo to obtain 1.0 g crude 2-Chloro-4-{4-methyl-2-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-thiazol-5-ylmethoxy}-benzonitrile.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([Br:11])[CH:5]=1.O.[NH2:14][NH2:15]>CO>[Br:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([NH:14][NH2:15])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc(C)c(Br)c1
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NN)cc1Br
Temperature: 80 °C
Yield: 50.1 %

Procedure:
A mixture of methyl-3-bromo-4-methylbenzoate (5.0 g, 21.8 mmol, 1.0 eq) and hydrazine hydrate (5 mL, 99 mmol, 4.5 eq) in methanol (50 mL) was heated to 80° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated under vacuum. The residue was taken in ethyl acetate (100 mL) and washed with water (2×50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under reduced pressure to afford 2.5 g (50%) of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H, D2O exchangeable), 8.02 (d, J=1.0 Hz, 1H), 7.74 (dd, J=1.0, 8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 3.35 (s, 2H, D2O exchangeable), 2.38 (s, 3H); ESI-MS (m/z) 229, 231 [(MH)+, Br79,81].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]3[CH:10]2[C:11](=[O:16])O[C:13]3=[O:15])=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:11](=[O:16])[CH:10]3[CH:14]([CH:9]3[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]2=[O:15])=[CH:21][CH:20]=1
Reactant: COc1ccc(C2C3C(=O)OC(=O)C32)cc1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)C3C(C2=O)C3c2ccc(OC)cc2)cc1
Temperature: 180 °C
Yield: 63 %

Procedure:
A mixture of 6-(4-Methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione (crude product from the previous step) and (4-methoxyphenyl)methanamine was heated at 180° C. for 1.5 h. After cooling to room temperature, the reaction mixture was dissolved in CH2Cl2 and purified by flash column chromatography with EtOAc in hexane (20%, 30%, then 40%) to give the title compound as a yellow solid (0.71 g, 63% yield over three steps). MS [M+H]+: 338.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[S:24]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(N2CCC(CO)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reaction time: 4 h

Procedure:
The 4-hydroxymethyl-N-(4-nitrophenyl)piperidine (47.3 g, 200 mmol) obtained in Example 4(1) was dissolved in pyridine (300 ml), and p-toluenesulfonyl chloride (45.8 g, 240 mmol) was added thereto under ice-cooling, followed by stirring for 4 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure, thereby obtaining 4-tosyloxymethyl-N-(4-nitrophenyl)piperidine (72.7 g, 93%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][P:14]([CH2:19][CH:20]1[CH2:22][O:21]1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12].[Cl-].[NH4+]>C1COCC1>[CH2:16]([O:15][P:14]([CH2:19][CH:20]([OH:21])[CH2:22][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:10])[CH:4]=1)(=[O:18])[O:13][CH2:11][CH3:12])[CH3:17]
Reactant: CCOP(=O)(CC1CO1)OCC
Reactant: Cc1cc([Mg]Br)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(O)Cc1ccc(F)c(C)c1)OCC
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
To a solution of 4-fluoro-3-methylphenylmagnesium bromide (0.5M in Et2O, 15.5 mL, 7.75 mmol) in THF (10 mL) at −30° C. was added Cul (196 mg, 1.03 mmol) and the reaction mixture was stirred for 10 minutes. The reaction mixture was warmed to −15° C. and oxiranylmethyl-phosphonic acid diethyl ester (1 g, 5.2 mmol) in THF (10 mL) was added. The reaction mixture was stirred at 0° C. for 2 h. Saturated aqueous ammonium chloride was added. and the product was extracted into EtOAc. The organic solution was dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (20% EtOAc in hexanes to 70% EtOAc in hexanes) provided [3-(4-fluoro-3-methyl-phenyl)-2-hydroxy-propyl]-phosphonic acid diethyl ester (1.37 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][O:61][C:62]1[CH:63]=[C:64]([CH2:68][NH2:69])[CH:65]=[CH:66][CH:67]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:69][CH2:68][C:64]3[CH:65]=[CH:66][CH:67]=[C:62]([O:61][CH3:60])[CH:63]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: COc1cccc(CN)c1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. 1-[3-(Methyloxy)phenyl]methanamine (65.6 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (186 mg) as a light yellow solid. LC-MS (ES) m/z=475 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:17](=O)[CH3:18].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:17]([N:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:11](=[O:16])[CH2:12]1)[CH3:18]
Reactant: CC=O
Reactant: O=C1CNCCN1c1cccc([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CCN(c2cccc([N+](=O)[O-])c2)C(=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
205 b) To a solution of 1-(3-nitro-phenyl)-piperazin-2-one (0.629 g, 2.84 mmol), acetaldehyde (0.20 mL, 3.6 mmol) and acetic acid (0.50 mL, 8.8 mmol) in methanol (10 mL) at room temperature was added solid Sodium cyanoborohydride (0.27 g, 4.3 mmol) in small portions. The mixture was stirred for 18 hours at room temperature. The mixture was evaporated and cold water was slowly added to the residue. The mixture was stirred for 15 minutes and then extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→5% methanol:dichloromethane). 4-Ethyl-1-(3-nitro-phenyl)-piperazin-2-one was isolated as a yellow-orange viscous oil (0.497 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.21 (s, 1H), 8.13 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 3.81-3.76 (m, 2H), 3.37-3.33 (m, 2H), 2.89-2.84 (m, 2H), 2.60-2.53 (m, 2H), 1.20-1.14 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[OH:37][CH:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:39]#[N:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:37][CH:38]([C:39]#[N:40])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: N#CC(O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C#N)c4ccccc4)cc3C)c2cc1OC
Yield: 40.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-hydroxy-2-phenylacetonitrile (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (30 mg, yield 39%).