Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]#[C:24][Si](C)(C)C)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[CH:29]([S:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:31])[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CC#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O.C(OCC)(=O)C>[C:23]([C:4]1[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])=[CH:40][CH:39]=2)[N:3]=1)#[CH:24]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1C#C[Si](C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl N-[5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (3 g, 6.377 mmol) and (4-isopropylsulfonylphenyl)boronic acid (1.491 g, 6.536 mmol) were dissolved in MeCN (60.00 mL) then treated with water (12.00 mL) and K3PO4 (2.706 g, 12.75 mmol) then degassed/flushed nitrogen (×5 cycles). Treated with Pd[P(tBu)3]2 (162.9 mg, 0.3188 mmol) and reflushed Vac/Nitrogen ×5. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured quickly into a mixture of ethyl acetate (500 mL), water (90 mL) and 1% aqueous sodium metabisulphite at 4° C., shaken well and the layer separated. The organic fraction was dried over MgSO4, filtered and the filtrate was treated with 3-mercaptopropyl ethyl sulphide on silica (0.8 mmol/g)(1 g), pre-absorbed onto silica gel then purified by column chromatography on silica gel eluting with 30-40% EtOAc/petroleu ether. Product fractions were combined and concentrated in vacuo to leave the product as a yellow/ brown viscous oil. Triturated with petroleum ether and some diethyl ether and a small amount of dichloromethane added. Left to stand at room temperature for 30 min and beige crystals formed, isolated by filtration to leave the product as a beige solid (1.95 g, 61%); 1H NMR (400 MHz, DMSO) d 1.20 (m, 6H), 1.39 (s, 18H), 3.50 (m, 1H), 5.01 (s, 1H), 8.03 (m, 2H), 8.46 (m, 2H) and 9.37 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].FC1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.ClCCl.[CH3:39][NH:40][C:41]([NH2:43])=[O:42].N1C=CC=CC=1>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]2)[C:13]([NH:43][C:41]([NH:40][CH3:39])=[O:42])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CNC(N)=O
Reactant: CS(=O)(=O)c1ccc(C(OC2C=CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CNC(=O)NC(=O)C(OC1C=CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
A cooled (0° C.) mixture of rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid (from Example 8100 mg, 0.29 mmol), fluorobenzene (2.5 mL) and N,N-dimethylformamide (1.8 μL). was treated with a 2.0 M solution of oxalyl chloride in dichloromethane (0.18 mL, 0.36 mmol) which caused a vigorous evolution of gas. The reaction was then stirred at 25° C. for 1 h and became light yellow in color. After methyl urea (64 mg, 0.87 mmol) was added, the reaction was heated at 70° C. for 10 min, then pyridine (0.048 mL, 0.60 mmol) was added and the mixture was maintained at 70° C. for 1 h. The cooled reaction was diluted with ethyl acetate (5 mL), then was filtered through celite to remove insoluble materials and the filtrate was concentrated in vacuo. The concentrate was washed with 3N hydrochloric acid (1×20 mL), saturated sodium bicarbonate (1×15 mL), and brine (1×15 mL), then was dried over sodium sulfate, filtered and evaporated under reduced pressure. The reaction product was purified by chromatography (Biotage Flash 40S column, 50/50 hexanes/ethyl acetate) to give 1-[(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetyl]-3-methyl-urea (63 mg, 54% yield) as a white foam: FAB-HRMS m/e calculated for C17H21N2O5SCl (M+H)+ 401.0938, found 401.0921.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:32])[CH3:35]
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A176) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [CH2:1]([CH:4]([CH2:23][CH2:24][CH3:25])[CH2:5][O:6][C:7]1[O:11][C:10]([C:12]([O:14][CH2:15]C(CCC)CCC)=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH3:3].C[O-].[Na+]>CO>[CH2:23]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6][C:7]1[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=1)[CH2:24][CH3:25]
Reactant: CCCC(CCC)COC(=O)c1ccc(OCC(CCC)CCC)o1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(CCC)COc1ccc(C(=O)OC)o1

Procedure:
2-Propylpentyl 5-((2-propylpentyl)oxy)furan-2-carboxylate (0.62 g, 1.76 mmol), NaOMe (30% in MeOH, 2 mL) in anhydrous MeOH (75 mL) were stirred at room temperature overnight then concentrated under reduced pressure. The residue was partitioned between aqueous NH4Cl (25%) and hexanes. Organic layer was washed with brine, dried over anhydrous MgSO4, concentrated under reduced pressure. Flash chromatography purification (5%-20% EtOAc—hexanes gradient) gave methyl 5-((2-propylpentyl)oxy)furan-2-carboxylate as a colorless oil. Yield (0.38 g, 85%); 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=4.0 Hz, 1H), 5.27 (d, J=3.5 Hz, 1H), 3.99 (d, J=5.9 Hz, 2H), 3.03 (s, 3H), 1.74-1.83 (m, 1H), 1.20-1.40 (8H), 0.86-0.94 (m, 6H).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]CC1C=CC=CC=1)=[CH:11][C:10]2=[O:31].N12CCN(CC1)CC2>>[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[N:13]3[S:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:12]3=[CH:11][C:10](=[O:31])[C:9]=2[CH:8]=1
Reactant: O=c1cc(-c2ccccc2SCc2ccccc2)[nH]c2ccc(Cl)cc12
Agent: C1CN2CCN1CC2
Solvent: O=S(=O)(Cl)Cl
Product: O=c1cc2c3ccccc3sn2c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
Sulfuryl chloride (0.305 ml, 3.78 mmole, 1.0 equiv.) was added dropwise over 3 min to a suspension of 6-chloro-2-[2-[(phenylmethyl)thio]phenyl]-4(1H)-quinolinone (1.43 g, 3,78 mmole, 1 equiv.) in dry, EtOH-free CHCl3 (190 ml) at -15° C. The mixture was stirred for 0.5 hr, then was heated to reflux. After 20 min, the reaction was cooled to 25° C, and 1,4-diazabicyclo[2.2.2]octane (636 mg, 5.67 mmole, 1.5 equiv.) was added. The nearly homogeneous solution was stirred at 25° C. for an additional 5 min, then was washed with H2O (3×50 ml). The combined aqueous layers, which contained suspended product, were back - extracted with CHCl3, and the combined organic layers were diluted with CHCl3 (200 ml) and MeOH (50 ml) to dissolve suspended solids. Drying (MgSO4), concentration, and silica gel chromatography (CHCl3, then 10% MeOH in 50% EtOAc/CHCl3, then 10% MeOH/CHCl3) gave 3-chloro-5H-[1,2]benzisothiazolo[2,3-a]quinoline-5-one (0.28 g, 26%) as a yellow solid. Two recrystallizations from CHCl3 /EtOAc gave yellow, very fine needles: mp>350° C.; TLC (5% MeOH in 50% EtOAc/CHCl3) Rf 0.32; 1H NMR (CDCl3) δ8.52 (d, J=2.2 Hz, 1 H), 8.00 (app d, 1 H), 7.62-7.74 (m, 3 H), 7.50-7.60 (m, 1H), 7.44 (d, J=8.8 Hz, 1 H), 7.08 (s, 1 H); IR (KBr) 1613, 1587, 1567, 1554, 1539, 1461, 1450 cm-1 ; MS (NH3), m/e (%) 288 (41, (37Cl M+H)+), 286 (100, (35Cl M+H)+). Anal. Calcd for C15H8ClNOS: C, 63.05; H, 2.82; N, 4.90. Found: C, 62.83; H, 2.51; N, 4.75.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH:14]1[CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[C:1]1([O:11][CH2:13][CH:14]2[CH2:16][O:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc2c(OCC3CO3)cccc2c1

Procedure:
A mixture of 1-naphthyl alcohol, chloromethyloxirane, potassium carbonate and methylethylketone was heated at reflux for 5 hours to give 2-(1-naphthyloxy)methyloxirane. This intermediate was treated with 4-benzylpiperidine to give the title compound.
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[NH:27]C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[C:21]1([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]3[NH:8][C:9]([NH2:27])=[N:10][CH:11]=3)=[CH:14][CH:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(C#Cc3ccccc3)cc2)n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2ccc(C#Cc3ccccc3)cc2)[nH]1
Temperature: 0 °C
Yield: 109.7 %

Procedure:
2-tert-butoxycarbonylamino-5-(4-phenylethynylphenyl)imidazole-1-carboxylic acid tert-butyl ester (0.039 g, 0.109 mmol) was dissolved in anhydrous dichloromethane (5 mL) and cooled to 0° C. Trifluoroacetic acid (0.250 mL) was added drop-wise while the reaction continued to stir at 0° C. Upon completion, the reaction was allowed to warm to room temperature over the course of 12 h. Toluene (2 mL) was added and the reaction was evaporated to dryness. The crude TFA salt was then dissolved in dichloromethane (3 mL) and a 2M solution of HCl in diethyl ether (0.10 mL) was added. The solution was again concentrated under reduced pressure and the resulting product triturated with cold diethyl ether (5 mL) to afford 0.031 g (97%) of 5-(4-phenylethynylphenyl)-1H-imidazol-2-ylamine in its corresponding hydrochloride salt form as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 12.27 (s, 1H), 7.74 (d, 2H, J=8.7 Hz), 7.62 (d, 2H, J=8.7 Hz), 7.55 (m, 5H), 7.43 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 147.9, 131.9, 131.2, 128.9, 128.7, 127.9, 125.7, 124.3, 122.1, 121.4, 110.6, 90.3, 89.0; HRMS (ESI) calcd for C17H13N3 (M+) 259.1110. found 259.1113.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([N:7]([CH3:11])[C:8](=[O:10])[CH3:9])[N:6]=1.[Na].[CH3:13][OH:14]>>[CH3:13][O:14][C:2]1[S:3][CH:4]=[C:5]([N:7]([CH3:11])[C:8](=[O:10])[CH3:9])[N:6]=1
Reactant: CC(=O)N(C)c1csc(Br)n1
Reactant: CO
Agent: [Na]
Product: COc1nc(N(C)C(C)=O)cs1

Procedure:
2-Bromo-4-(N-methylacetamido)thiazole is treated with sodium in absolute methanol following the procedure described in Example 1 to give the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1>CS(C)=O.O>[C:1]([CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1)#[N:2]
Reactant: BrCC1COc2ccccc2O1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3 dihydrobenzo[1,4]dioxine) (6.87 g, 30 mmol) in DMSO (90 mL) and stirred at ambient temperature for 20 h. The reaction mixture was then diluted with water (250 mL) and extracted twice with diethyl ether. The diethyl ether was washed with water, then washed twice with brine, dried (Na2SO4) and evaporated in vacuo to yield 2-cyanomethyl-(2,3 dihydrobenzo[1,4]dioxine) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH2:14])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The product from step (iii) was dissolved in dichloromethane (200 ml) and trifluoroacetic acid (100 ml) added. After 18 hrs at room temperature the solvent was evaporated and the resultant gum triturated under ether to give the sub-titled product as a solid (5.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])=O)[N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.N.C[N:43](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:37]([CH2:36][N:33]1[CH:34]=[CH:35][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[N:32]1)(=[O:39])[NH2:43]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC(=O)O)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(N)=O)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-yl)-acetic acid (85 mg, 0.144 mmol), ammonia (0.57 mL, 0.288 mmol, 0.5 M in dioxane), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 109 mg, 0.288 mmol) and iPr2NEt (0.1 mL, 0.43 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (12.3 mg, 14.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C28H28Cl2F2N6O2+H [(M+H)+]: 589.1692. found: 589.1693.
Reaction SMILES: [CH2:1]([C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=1[OH:31])[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].CN1CCCC1=O.[P:39](Cl)(Cl)[Cl:40]>C1(C)C=CC=CC=1>[Cl:40][P:39]1[O:16][C:3]2[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])=[CH:7][C:2]=2[CH2:1][C:17]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=2[O:31]1
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: ClP(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of 25.0 g (0.059 mol) of 2,2'-methylenebis(4,6-di-tert-butylphenol) and 0.57 mL (5.9 mmol) of 1-methyl-2-pyrrolidinone in 275 mL of toluene at ambient temperature is added dropwise 5.16 mL (0.059 mol) of phosphorus trichloride. After the addition is complete, the reaction mixture is refluxed for eight hours. After cooling the mixture to ambient temperature, the toluene is removed in vacuo and the reaction mass is re, crystallized twice from 250 mL of 98% acetonitrile and 2% toluene (% by volume) in acetonitrile. The recrystallization solvent is removed by decantation and the residue is dried under vacuum to give 21.4 g (79% yield) of the title compound as an off-white solid melting at 227°-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:23][C:22]#[CH:21])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20]
Reactant: C#CCBr
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1Cl
Yield: 72.5 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2,4-dichloro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.50 g, 1.61 mmol), propargylbromide (0.16 mL, 1.77 mmol) and potassium carbonate (0.22 g, 1.61 mmol) was stirred for 3 hours under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/2) to obtain a white solid of 2-(2,4-dichloro-5-propargyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.41 g, yield:73.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[O-2:13].[Ca+2]>Cl.O.CC(C)=O>[Cl:1][CH:2]([CH2:8][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1])[CH:3]=[O:13]
Reactant: Nc1ccccc1Cl
Reactant: [O-2]
Agent: Cl
Agent: O=N[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)=O
Product: O=CC(Cl)Cc1ccccc1Cl
Reaction time: 0.17 h
Yield: 164.2 %

Procedure:
To a solution of 2-chloroaniline (12.7 g, 100. mmol) in hydrochloric acid (20% aqueous solution, 40 mL) was added dropwise a solution of sodium nitrite (7.5 g, 110 mmol) in water (20 mL) at 0 to 5° C. After stirring for 10 minutes, a cooled solution of acrolin (15 g, 270 mmol) in acetone (100 mL) containing calcium oxide (2.0 g, 36 mmol) was added gradually, and then followed by a solution of cuprous chloride (1 g, 10 mmol) in acetone (10 mL) containing hydrochloric acid (20% aqueous solution, 2 mL). The mixture was stirred at 0 to 30° C. for 3 hours and then extracted three times with dichloromethane (100 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate followed by a saturated aqueous solution of sodium chloride. The organic layer was separated, dried over sodium sulfate, and evaporated to dryness to give a black viscous oil. The crude product was passed through a short silica gel column to give 12 g of crude product, which was used directly in the next step.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][S:13][C:14]=1Cl)=[O:9])[CH3:6].CN(C=O)C.C1COCC1>O>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][S:13][C:14]=1[S:4][CH2:2][CH3:3])=[O:9])[CH3:6]
Reactant: CCOC(=O)c1ncsc1Cl
Reactant: CCS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ncsc1SCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
0.56 g of ethyl mercaptan sodium salt (80%) was added to a mixture of 0.86 g of 5-chlorothiazole-4-carboxylic acid ethyl ester, 3 ml of DMF and 1 ml of THF, under ice cooling, and then the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.71 g of 5-ethylsulfanylthiazole-4-carboxylic acid ethyl ester.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:22]=[C:16]1[CH:15]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][N:3]([CH3:2])[C:30]([NH:29][C:25]3[CH:24]=[C:23]([CH3:32])[CH:28]=[CH:27][CH:26]=3)=[O:31])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N(C)Cc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and m-tolyl isocyanate (0.29 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH2Cl2 and slurred with acetone to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-m-tolyl-urea as a solid (0.41 g, 52%): mp 208-210° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.57 (99%); 1H NMR (DMSO-d6): δ 1.99-2.08 (m, 1H), 2.24 (s, 3H), 2.28-2.35 (m, 1H), 2.55-2.62 (m, 1H), 2.85-2.92 (m, 1H), 2.96 (s, 2H), 4.36 (d, J=17.3 Hz, 1H), 4.43 (d, J=17.3 Hz, 1H), 4.64 (s, 2H), 5.10-5.17 (dd, J=5.1, 13.2 Hz, 1H), 6.78 (d, J=7.4 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.29-7.25 (m, 2H), 7.45 (d, J=7.2 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 8.38 (s, 1H). 11.02 (s, 1H). 13C NMR (DMSO-d6) δ: 21.17, 22.56, 31.17, 34.71, 46.25, 48.38, 51.56, 117.15, 120.57, 121.71, 122.63, 128.12, 128.43, 129.87, 131.92, 133.87, 137.31, 140.13, 140.27, 155.62, 168.01, 171.01, 172.84. Anal Calcd for C23H24N4O4+0.1 H2O: C, 65.42; H, 5.78; N, 13.27. Found: C, 65.25; H, 5.50; N, 13.14.
Reaction SMILES: CC1(C)[O:13][C@@H:12]2[C@@H:4]([CH2:5][N:6]3[C@@H:11]2[C@H:10]([OH:14])[CH2:9][CH2:8][CH2:7]3)[O:3]1.Cl>C1COCC1>[CH2:8]1[CH2:7][N:6]2[C@@H:11]([C@H:12]([OH:13])[C@H:4]([OH:3])[CH2:5]2)[C@H:10]([OH:14])[CH2:9]1
Reactant: CC1(C)O[C@H]2[C@H]3[C@H](O)CCCN3C[C@H]2O1
Agent: Cl
Solvent: C1CCOC1
Product: O[C@H]1[C@H]2[C@H](O)CCCN2C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of swainsonine acetonide (104 mg, 0.49 mmol) in THF (6.5 ml) was added 6.0 ml of 6M HCl. The colorless solution was stirred overnight at room temperature. The solvent was removed in vacuo, leaving a colorless, viscous oil. The oil was then purified by an ion exchange chromatography (Dowex-1×8). Fractions (visualized with iodine or ninhydrin) were collected and concentrated in vacuo to furnish 68.5 mg(81% yield) of swainsonine as a white solid: mp and mixed mp 140-142 C; [ ]D25 =-75.71 (c 2.33, MEOW); Rf=0.36 in 1-butanol:chloroform:ethanol:concentrated ammonium hydroxide (4:4:4:1); 1H NMR (D2O, ref. DSS, 300 MHz ) 4.34 (m, 1H, B-2), 4.24 (dd, J1,8a =3.7 Hz, J1,2 =6.1 Hz, 1H, H-1), 3.78 (ddd, J=3.9, 9.3 & 10.7 Hz, 1H, H-8), 2.89 (m, 1H), 2.86 (dd, J=2.6 & 11.0 Hz, 1H, H-3), 2.53 (dd, J=7.8 & 11.0 Hz, 1H, H-3'), 2.04 (m, 1H), 1.96 (m, 1H), 1.89 (dd, J8a,8 =9.3 Hz, J8a,1 =3.7 Hz, H-8a), 1.70 (m, 1H), 1.49 (m, 1H), 1.22 (m, 1H); 13C NMR (D2O, ref: CH3CN, 100 MHz) δ23.21, 32.51, 51.72, 60.65, 66.37, 69.08, 69.72, 72.87; HRMS(M+) 173.1052 calcd for C8H15NO3, found 173.1041.