Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C@H:30]([CH3:33])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C@H:30]([NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH3:33]
Reactant: C[C@@H](N)CO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](C)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (R)-2-aminopropan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=433.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]4[CH2:31][CH3:32])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:33]=O>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH3:33])[CH2:27][CH:26]4[CH2:31][CH3:32])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC[C@H]1CNCCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1
Reactant: C=O
Product: CCC1CN(C)CCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Compound 193 was coupled with formaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 452. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.68 (s, 1H), 8.36 (d, 2H), 7.92 (d, 1H), 7.67 (m, 2H), 6.99 (d, 2H), 6.72 (s, 1H), 5.07 (d, 1H), 4.36 (s, 1H), 3.43 (m, 7H), 3.04 (m, 4H), 2.36 (s, 1H), 2.05 (m, 1H), 2.00 (s, 3H), 1.15 (t, 3H).
Reaction SMILES: C([O:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:14](=[N:15][N:16]([CH3:21])[N:17]=2)[N:13]([CH3:22])[C:11]1=[O:12])(=O)C.Cl.C(OCC)C>CO>[CH3:22][N:13]1[C:14]2[C:18](=[N:17][N:16]([CH3:21])[N:15]=2)[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:23])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2nn(C)nc2n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2nn(C)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-3,8-dimethyl-8-azaxanthine (66 mg, 0.204 mmol) in methanol (15 ml) was added an anhydrous solution of hydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). The mixture was stirred at room temperature for 24 hours and then the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-3,8-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (37 mg, 65% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=[N:10][OH:11])[CH:3]=1.[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH2:12][CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1nc(Br)cc(C=NO)n1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cc1nc(Br)cc(C2=NOC(c3ccccc3)C2)n1
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a cold solution of 6-bromo-2-methylpyrimidine-4-carbaldehyde oxime (0.4 g, 1.852 mmol Preparation #17) and styrene (0.257 mL, 2.222 mmol) in DCM (10 mL) was added sodium hypochlorite solution (0.229 mL, 3.70 mmol). The reaction mixture was stirred for about 2 h and diluted with DCM (50 mL), successively washed with water (2×30 mL) and brine (1×30 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure. The resulting mixture was purified by silica gelchromatography eluting with 40% EtOAc in hexane. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 3-(6-bromo-2-methylpyrimidin-4-yl)-5-phenyl-4,5-dihydroisoxazol 0.25 g (42.4%), 1H NMR (400 MHz, DMSO): δ 8.00 (s, 1H), 7.40 (m, 5H), 5.90 (m, 1H), 3.93 (m, 1H), 3.41 (m, 1H), 2.64 (s, 3H), MS m/z: 320 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH2:30][CH2:31][CH3:32])[CH:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:12]1[CH:28]=[CH:29][C:9]([OH:8])=[CH:10][C:11]=1[CH2:30][CH2:31][CH3:32]
Reactant: [H][H]
Reactant: CCCc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cc(O)ccc1OCCc1nc(-c2ccccc2)oc1C
Yield: 78 %

Procedure:
A solution of 4-[2-(4-benzyloxy-2-propylphenoxy)ethyl]-5-methyl-2-phenyloxazole. (1.2 g, 2.8 mmol) in THF (50 mL) was treated with 5% Pd/C (0.15 g) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated. The crude product was purified by radial chromatography using 15% ethyl acetate in hexanes to give a tan solid (0.74 g, 78%): 1H. NMR (400 MHz, CDCl3) δ 7.99 (dd, J=7.8 Hz, 2.4 Hz, 2H), 7.44-7.39 (m, 3H), 6.65-6.47 (m, 3H), 4.11 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.43 (t, J=7.8 Hz, 2H), 2.39 (s, 3H), 1.46 (q, J=7.2 Hz, 2H), 0.85 (t, J=7 Hz, 3H).
Reaction SMILES: FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24]([O:28][C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([CH2:38][CH:39]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:40][PH:41](=[O:43])[OH:42])=[CH:34][CH:33]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[CH2:16]([P:41]([CH2:40][CH:39]([CH2:38][C:35]1[CH:36]=[N:37][C:32]([NH:31][C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])=[CH:33][CH:34]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45])(=[O:42])[OH:43])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C[PH](=O)O
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)CP(=O)(O)Cc1ccccc1
Yield: 216.2 %

Procedure:
Argon was bubbled through a mixture of BSTFA (0.3 mL; 1.3 mmol), benzyl bromide (0.1 mL; 0.7 mmol), and CH2Cl2 (1.5 mL) for 10 minutes. 2-({6-[(tert-Butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-ethoxy-3-oxopropylphosphinic acid (50 mg; 0.13 mmol) was added, and the reaction mixture was refluxed under argon for 1 h. The solution was concentrated to afford 0.13 g of crude benzyl[2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-ethoxy-3-oxopropyl]phosphinic acid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)C.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>O>[OH:23][NH:22][C:14](=[NH:15])[C:13]1[CH:16]=[CH:17][C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)=[N:11][CH:12]=1
Reactant: NO
Reactant: CC(C)N1CCN(c2ccc(C#N)cn2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(C(=N)NO)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A mixture of 6-(4-isopropylpiperazin-1-yl)nicotinonitrile (2.3 g, 10 mmol), ethanol (25 mL), hydroxylamine hydrochloride (2.1 g, 30 mmol), potassium carbonate (2.2 g, 16 mmol) and water (5 mL) was stirred for 30 min at rt and then at reflux temperature for 3 h. The reaction mixture was left at rt for 2 days and then the solid formed was isolated by filtration. The solid was dried, boiled with ethanol (200 mL) and filtered hot to remove inorganic impurities. The filtrate was evaporated to give 2.0 g (76%) of N-hydroxy-6-(4-isopropylpiperazin-1-yl)nicotinamidine.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([C:36]1[N:40]([CH3:41])[N:39]=[N:38][CH:37]=1)[CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:41][N:40]1[C:36]([C:24]([CH:25]2[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)=[O:23])=[CH:37][N:38]=[N:39]1
Reactant: Cn1nncc1C(O)C1CN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Product: Cn1nncc1C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Dess-Martin periodinane (10.9 g, 25.7 mmol) was added in one portion to a stirring solution of tert-butyl 3-(hydroxy(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidine-1-carboxylate (4.60 g, 17.1 mmol, Intermediate 59: step a) in dry dichloromethane (86 mL). The resulting mixture was stirred at 23° C. After 18 h, a mixture containing equal parts water, saturated aqueous sodium thiosulfate solution, and saturated aqueous sodium bicarbonate solution was added (200 mL). Dichloromethane (100 mL) was added. The resulting biphasic mixture was stirred for 15 min. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was concentrated. The residue was purified by flash-column chromatography on silica gel eluting with dichloromethane initially, grading to 5% methanol-dichloromethane to provide the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11](I)[CH2:12][CH3:13]>COCCOC.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH3:8][O:7][C:1](=[O:6])[CH:2]([C:3](=[O:4])[CH3:5])[CH2:11][CH2:12][CH3:13]
Reactant: CCCI
Reactant: COC(=O)CC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: COCCOC
Product: CCCC(C(C)=O)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl acetoacetate (10.8 mL, 100 mmol) in DME (50 mL) is added dropwise to a suspension of NaH (95% dry, 2.44 g, 100 mmol) in DME (250 mL) cooled to 0° C. The resulting solution is stirred at room temperature for 1 hour. Bu4NI (3.7 g, 10 mmol) is added, followed by PrI. The mixture is then stirred at reflux for 6 hours. The solvent is removed in vacuo and water (200 mL) and EtOAc (200 mL) are added. The layers are separated and the aqueous layer is extracted with EtOAc (200 mL). The combined extracts are washed with brine (200 mL) and dried (Na2SO4). Evaporation of the solvent provides a light yellow oil. Flash column chromatography of the residue by silica gel, eluting with 7:1 hexane, EtOAc provides the title product as a colorless oil. LC-MS, M+1 159.2 2. Preparation of 6-methyl-5-propyl-2-thio-2,3-dihydropyrimidin-4-one
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[CH2:14]([NH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(NCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a stirred solution of ethyl 3-amino-2-methylbenzoate (1.00 g, 5.58 mmol) in DCE (20 ml) was added benzaldehyde (569 μl, 5.58 mmol) followed by acetic acid (0.64 ml, 11.2 mmol). The reaction was stirred at room temperature for 1 h and then sodium triacetoxyborohydride (1.77 g, 8.37 mmol) was added and the reaction stirred for 2 h. Distilled water (20 ml) was added and solid NaHCO3 was added until the aqueous phase was pH7 and the phases were separated. The aqueous phase was washed with DCM (2×5 0 ml), the combined organics were then washed with brine (50 ml), dried using Na2SO4, filtered and evaporated to afford the title compound as a yellow oil (1.52 g, 96%) which was used in the next stage without any further purification. LC-MS 95%, m/z=270.0, 1H NMR (500 MHz, Chloroform-d) δ 7.42-7.32 (m, 4H), 7.32-7.28 (m, 1H), 7.17-7.06 (m, 2H), 6.73 (dd, J=7.8, 1.1 Hz, 1H), 4.40 (s, 2H), 4.36 (q, J=14.3, 5.3 Hz, 2H), 4.08 (br. s, 1H), 2.35, (s, 3H), 1.39 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=O.[NH2:12]OS(O)(=O)=O>O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[C:5]#[N:12]
Reactant: O=Cc1c(Cl)ccc(Br)c1F
Reactant: NOS(=O)(=O)O
Solvent: O
Product: N#Cc1c(Cl)ccc(Br)c1F
Temperature: 50 °C
Yield: 100 %

Procedure:
A suspension of 3-bromo-6-chloro-2-fluorobenzaldehyde (9.0 g, 0.04 mol) and hydroxylamine-O-sulfonic acid (7.50 g, 0.07 mole) in water (300 mL) was heated at 50° C. for eighteen hours. The suspension was cooled and the solid was collected to give 3-bromo-6-chloro-2-fluorobenzonitrile (8.8 g, 0.04 mol): 1H NMR (CDCl3): δ 7.75 (m, 1H), 7.25 (m, 1H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Yield: 97.3 %

Procedure:
To a solution of tert-butyl (3R)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 3 (0.23 g, 050 mmol) in methanol (15 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl (3R)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 4 (0.18 g, 93%) as a colorless foam.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].CCN(CC)CC.[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CNOC
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N(C)OC
Reaction time: 2 h

Procedure:
To a CH2Cl2 solution (200 mL) containing N-methoxy-N-methylamine hydrochloride (8.09 g, 82.9 mmol) and Et3N (12.6 g, 124 mmol) was added valeryl chloride (10 g, 82.9 mmol) dropwise at room temperature. The resulting solution bubbled vigorously and stirred for 2 hours after which time it was carefully quenched with H2O. The organic layer was separated and washed with 2.0 N NaOH. The organics were extracted with CH2Cl2, dried (MgSO4) and the solvent removed in vacuo. The resulting colorless oil was taken on without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]#[C:9][CH2:10][OH:11]>C1(C)C=CC=CC=1>[N:1]1([CH2:7][C:8]#[C:9][CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: OCC#CCCl
Solvent: Cc1ccccc1
Product: OCC#CCN1CCCC1
Temperature: 60 °C
Yield: 68.6 %

Procedure:
Pyrrolidine (7.8 ml, 94 mmol) was added dropwise to a solution of 4-chlorobut-2-yn-1-ol (4.74 g, 45 mmol) in toluene (40 ml) and the mixture stirred and heated at 60° C. for 1 hour. The volatiles were removed by evaporation and the residue was purified by chromatography eluting with methylene chloride/methanol (96/4) to give 4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 69%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[C@@H:13]([CH2:17]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>C(OCC)(=O)C.CO.ClCCl.CN(C)C=O>[N:19]([CH2:17][C@@H:13]1[C@H:14]([OH:16])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@H](O)C1
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
(3R,4S)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (2.33 g), sodium azide (1.81 g), triphenylphosphine (2.67 g), and N,N-dimethylformamide (46 mL) were mixed with one another. While this mixture was cooled on an ice bath, a dichloromethane solution (10 mL) of carbon tetrabromide (3.38 g) was added dropwise. The reaction mixture was stirred for 13 hours at room temperature and additional 3 hours at 60° C., followed by addition of methanol (3 mL) and concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and was washed with a saturated aqueous solution of sodium chloride (2×50 mL), followed by drying over anhydrous sodium sulfate and concentration under reduce pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:hexane=2:1) to give 2.18 g of (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a milky white syrup-like product.
Reaction SMILES: [Si:1]([C:8]1[C:9]([CH:21]=O)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23](#[N:27])[CH2:24][C:25]#[N:26].N1CCCCC1>CCO>[CH3:19][N:18]([CH3:20])[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:21]=[C:24]([C:23]#[N:27])[C:25]#[N:26])[C:8]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:17]2
Reactant: N#CCC#N
Reactant: CN(C)c1ccc2cc(C=O)c([Si](C)(C)C(C)(C)C)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc2cc(C=C(C#N)C#N)c([Si](C)(C)C(C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
415.7 mg (1.2616 mmol) of the compound 14 was dissolved in 9 mL of EtOH, and then added with 83.4 mg (1.2616 mmol) of malononitrile and 1 mL (12.616 mmol) of piperidine, and stirred for 3 hours at room temperature. When the reaction was completed, EtOH was removed by vacuum-distillating, and then the mixture was separated and purified by a column chromatography (eluent: EtOAc/n-hexane(v/v)=¼) without an additional extraction process to obtain 333.4 mg (70%) of an orange solid compound 15. 1H NMR (CDCl3, 300 MHz, 293K): δ 8.70(s, 1H), 8.24(s, 1H), 7.70-7.67(d, 1H), 7.02-6.98(dd, 1H), 6.88(s, 1H), 6.60-6.59(d, 1H), 3.14(s, 6H), 1.05(s, 9H), 0.31(s, 6H). 13C NMR(CDCl3, 75 MHz, 293K): δ 154.13, 152.53, 151.30, 140.20, 131.43, 131.09, 121.46, 119.27, 115.40, 114.88, 114.30, 111.78, 103.41, 40.29, 25.79, 18.38, −4.23. HRMS: m/z calcd. for C22H27N3OSi 377.1923 found 377.1923.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)([CH3:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[Br:22][C:12]1[CH:13]=[CH:14][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Oc1cccc2ncccc12
Solvent: CC#N
Product: CC(C)Oc1ccc(Br)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 5-isopropoxyquinoline (1.87 g, 10.0 mmol) in acetonitrile (100 mL) was added NBS (1.78 g, 10.0 mmol) at 0° C. The mixture was stirred at rt for 2 h before the solvent was removed. The residue was partitioned between EtOAc and H2O. The layers were separated and the organic layer was washed with brine, dried over MgSO4, and concentrated. The crude material was purified by column chromatography (0-10% EtOAc-Hex) to provide 8-bromo-5-isopropoxy-quinoline (92%) as a light brown solid. ESI-MS m/z calc 265.1, found 266.1 (M+1)+. Retention time: 1.44 minutes (3 min run).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][SH:11].[Na]>>[CH3:10][S:11][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CS
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na]
Product: CSCC(=O)OC(C)(C)C
Yield: 96.5 %

Procedure:
Under ice cooling, 33.4 g of tert-butyl bromoacetate was gradually added to 80.0 g of 15% sodium methylmercaptan aqueous solution and the resulting mixture was reacted at room temperature overnight. After completion of the reaction, the reaction mixture was extracted 4 times with ethyl acetate and the extract was washed with saturated sodium chloride aqueous solution. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off to give 26.8 g of crude tert-butyl (methylthio)acetate.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH3-]C#N.[Na+]>CO.COC(OC)OC>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of N-Boc-piperidin-3-yl-formaldehyde 3 ( 5.20 g, 24.4 mmol) in 50 mL of dry methanol and 50 mL of trimethylorthoformate was added aniline (2.50 g, 1.1 eq.), and the mixture was stirred at room temperature for 30 minutes. NaBH3CN (95%, 1.84 g, 1.1 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 30 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography (silica gel, hexane:ethyl acetate (1:1) to afford N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 as white solid (5.60 g, 79%). IR (film, cm−1) 3520, 3263, 3004, 2976, 2932, 2854, 1688, 1589, 1521, 1482, 1422, 1365, 1267, 1243, 1175, 1150, 794, 709; 1H NMR (CDCl3, ppm) 7.20 (t, 2H, J=7.8 Hz), 6.72 (t, 1H, J=6.8 Hz), 6.63 (d, 2H, J=8.3 Hz), 4.00–3.78 (m, 3H), 3.07–2.70 (m, 4H), 2.00–1.20 (m, 5H), 1.48 (s, overlap, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19].B.C1COCC1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:12]([CH2:15][OH:16])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1-c1cc(F)ccc1F
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1-c1cc(F)ccc1F
Temperature: 23 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a stirred solution of 83.27B (0.585 g, 2 mmol) in THF (20 mL) at 0° C. was added borane-THF (4 mL, 4 mmol, 1.0M). The reaction was warmed to 23° C. and stirring was continued for four hours. The reaction mixture was then concentrated in vacuo. The reaction was diluted with 1N HCl and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield 83.27C as a colorless oil (0.485 g, 87% yield).