Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[O-]CC.[Na+].[C:14](OCC)(=[O:22])/[CH:15]=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C.O.C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:8]2[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][C:14](=[O:22])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1Cl
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 65 °C

Procedure:
To a mixture of 20 g of 3-chloro-2-hydrazinopyridine, 56 ml of sodium ethoxide (a 21% solution in ethanol) and 75 ml of ethanol was added dropwise 27 ml of diethyl maleate. The resulting mixture was heated to reflux for 10 minutes. The reaction mixture was allowed to cool to 65° C., and 15 ml of acetic acid was poured into the mixture. The reaction mixture was allowed to cool to room temperature. After 190 ml of water was poured into the reaction mixture, the mixture was adjusted to pH 2 by an addition of 6N hydrochloric acid and then extracted with methyl tert-butyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and a solid was collected by filtration to obtain 4.28 g of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate of the formula:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1
Solvent: CCOC(C)=O
Product: O=C(O)CCc1ccc(C#Cc2cccc(O)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-((3-hydroxyphenyl)ethynyl)phenyl)propanoate (54 mg, 0.19 mmol) according to the general procedure II to a white solid. Rf=0.02 (EtOAc:PE); 1H NMR ((CD3)2CO): δ 7.45 (d, J=7.4 Hz, 2H) 7.31 (d, J=7.6 Hz, 2H) 7.25-7.20 (m, 1H) 7.00 (s, 2H) 6.89-6.86 (m, 1H) 2.95 (t, J=7.7 Hz, 2H) 2.64 (t, J=7.3 Hz, 2H); 13C NMR ((CD3)2CO): δ 173.8, 158.3, 142.8, 132.4, 130.6, 129.5, 125.1, 123.7, 121.8, 118.8, 116.8, 89.7, 89.6, 35.5, 31.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C1(OC)C=CC=CC=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].O>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[N:17]1([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1ccc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[4′-(methoxycarbonyl)-1,1′-biphenyl-4-yl]-1-piperazinecarboxylate (4.5 g) and anisole (6.17 ml) in dichloromethane (45 ml) was added dropwise with stirring trifluoroacetic acid (22.5 ml) at 0° C. The mixture was then stirred for 2 hours at room temperature. To the reaction mixture was added water. The resulting precipitate was collected by filtration and washed with isopropanol and diisopropyl ether to give methyl 4′-(1-piperazinyl)-1,1′-biphenyl-4-carboxylate trifluoroacetate (4.13 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:19][C:20]([CH3:22])=[CH2:21])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:23])[CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:20](=[CH2:21])[CH2:19][N:8]([C:6]1[CH:5]=[C:4]([CH3:23])[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)[N:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1
Reactant: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 85 °C
Yield: 59.9 %

Procedure:
To a degassed solution of (6-chloro-4-methyl-pyridin-2-yl)-(2-methyl-allyl)-(4-trifluoromethyl-phenyl)-amine (340 mg, 1.0 mmol), 4-trifluoromethylbenzeneboronic acid (230 mg, 1.2 mmol), 2N Na2CO3 (1.5 mL) in DME (10 mL) was added tetrakis(triphenylphosphine)palladium (120 mg, 0.1 mmol) under argon. The mixture was heated to 85° C. for 4 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (5-20% methylene chloride in methylene chloride) to give the product as a white solid (270 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.91 Hz, 2H), 7.69 (d, J=8.29 Hz, 2H), 7.59 (d, J=8.67 Hz, 2H), 7.39 (d, J=8.67 Hz, 2H), 7.11 (s, 1H), 6.66 (s, 1H), 4.86 (s, 2H), 4.70 (s, 2H), 2.30 (s, 3H), 1.81 (s, 3H). MS m/e 451.2 (M+H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]([CH3:51])([CH3:50])[CH2:8][O:9][C:10]([N:12]1[C:21]2[C:16](=[N:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C@@H:15]([N:26]([CH2:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=2)[C:27]2[N:28]=[N:29][N:30]([CH3:32])[N:31]=2)[CH2:14][C@H:13]1[CH2:48][CH3:49])=[O:11])=[O:6].Cl>C1COCC1>[C:5]([C:7]([CH3:50])([CH3:51])[CH2:8][O:9][C:10]([N:12]1[C:21]2[C:16](=[N:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C@@H:15]([N:26]([CH2:33][C:34]2[CH:35]=[C:36]([C:44]([F:47])([F:45])[F:46])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=2)[C:27]2[N:28]=[N:29][N:30]([CH3:32])[N:31]=2)[CH2:14][C@H:13]1[CH2:48][CH3:49])=[O:11])([OH:6])=[O:4]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.1 %

Procedure:
Add LiOH 2.5 M (1.9 mL, 4.8 mmol) to a solution of (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid 2-methoxycarbonyl-2-methyl-propyl ester (74 mg, 0.10 mmol) in THF (1.9 mL). Stir the mixture at room temperature for 72 h. Acidify with 1 M HCl. Extract the aqueous phase with dichloromethane. Dry the organic layers over Na2SO4, filter, and concentrate. Purify the residue using silica gel chromatography (elution with hexane/ethyl acetate) to afford the title compound (14 mg, 20%). MS (ES+): 698 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>CN(C)C=O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A solution of 1-acetyl-4-(4-aminophenyl)piperazine (1.0 g; 4.6 mmol) (from Step B above) in N,N-dimethylformamide (10 mL) was added dropwise to a cooled (−15° C.) solution of thiocarbonyldiimidazole (855 mg, 4.8 mmol) in N,N-dimethylformamide (10 mL). After the addition was complete, the mixture was stirred at −15° C. for 30 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water was added and the mixture was extracted with ether (4×50 mL). The combined ether layers were washed with brine, dried (MgSO4), filtered, and evaporated to give 1-(acetyl)-4-(4-isothiocyanatophenyl)piperazine (1.0 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[Na+].[CH3:13]I>C1C=CC=CC=1>[CH3:13][N:6]1[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Clc1cccc2[nH]ccc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cn1ccc2c(Cl)cccc21
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 60 g of 4-chloro-1H-indole, 400 ml of benzene, 200 ml of 50% sodium hydroxide solution, 68 g of n-tetrabutylammonium hydrogen sulfate and 68 ml of methyl iodide was stirred at 40° C. for 4 hours and was then cooled. The decanted aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with aqueous sodium chloride, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexanebenzene mixture to obtain 63.85 g of 1-methyl-4-chloro-1H-indole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C(OC(=O)C)(=[O:20])C.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+].C(OO)(=O)C.[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:20])[CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cc(S(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
10 G. of 1-amino-5-phenylthio-2-nitrobenzene in 100 ml. of acetic anhydride is treated with 0.25 ml. of concentrated sulfuric acid. The mixture is kept at 20°-25° C for 2 hours, then neutralized with sodium acetate and the solvent removed under vacuum. The residue is washed with water and methanol and dried. The resulting 1-acetamido-5-phenylthio-2-nitrobenzene is dissolved in 100 ml. of chloroform and treated at -30° C with a solution of peracetic acid (1 equivalent) in 10 ml. of methanol. The solution is warmed slowly to 20°-25° C and kept at the temperature for 12 hours, then washed successively with a solution of sodium bisulfite and a solution of sodium carbonate. Removal of the solvent leaves a gum which is treated with a mixture of 30 ml. of 5 N. sodium hydroxide and 60 ml. of methanol at 20°-25° C for 1 hour. Dilution with water followed by filtration of the product gives 1-amino-5-phenylsulfinyl-2-nitrobenzene which is purified by recrystallization from cyclohexane.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[F:8][C:9]([F:40])([F:39])[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([N:16]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)[CH:15]=1>O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:21]1[N:20]=[C:19]([C:18]2[C:17]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:16][N:14]3[CH:15]=[C:10]([C:9]([F:8])([F:39])[F:40])[CH:11]=[CH:12][C:13]=23)[CH:24]=[CH:23][N:22]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(C(F)(F)F)cc3)nn3cc(C(F)(F)F)ccc23)n1
Reactant: CN(C)CCCN
Solvent: O
Product: CN(C)CCCNc1nccc(-c2c(-c3ccc(C(F)(F)F)cc3)nn3cc(C(F)(F)F)ccc23)n1

Procedure:
3-(Dimethylamino)propylamine (0.04 mL) and methyl 4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl sulfone (0.02 g) were mixed at room temperature and heated with an airgun until a homogenous melt was obtained (2 min). Upon cooling, water was added. The precipitated solid was filtered and dried to give the title compound as a white solid (0.012 g); 1H NMR (d6-DMSO) δ 9.52(1H, s), 8.50(1H, bs), 8.16(1H, d), 7.87(4H, dd), 7.69(1H, d), 7.26(1H, bs), 6.34(1H, bs), 3.25(2H, bs), 2.24(2H, bs), 2.11(6H, s), 1.63(2H, bs); m/z 509 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=4)[C:13](=O)[NH:12][N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.P(Cl)(Cl)([Cl:25])=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=4)[C:13]([Cl:25])=[N:12][N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc4c(c3)OCO4)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc4c(c3)OCO4)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(1,3-benzodioxol-5-yl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: C(N[C:9](=[O:38])[CH:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)C1C=CC=CC=1.N([O-])=[O:40].[Na+].[Li+].[OH-].OO>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH:32]1([CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:9]([OH:40])=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=N[O-]
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)NCc2ccccc2)C2CCCCC2)c(OC)n1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of N-benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide (3.50 g, 6.72 mmol, 1.0 equiv) in a mixture of acetic acid (25 mL) and acetic acid anhydride (50 mL) was added at 0° C. in several small portions sodium nitrite (10.20 g, 147.91 mmol, 22.0 equiv) within 1 h. The reaction mixture was stirred overnight allowing to warm up to rt. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was taken up in a mixture of THF:water (3:1, 40 mL) and a pre-prepared solution of LiOH (1.61 g, 67.23 mmol, 10.0 equiv) in hydrogen peroxide (15.24 g, 13.73 mL, 134.46 mmol, 20.0 equiv; 30% solution in water) was added and stirred at rt for 30 min. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 4 by addition of 1 M HCl and the aqueous layer extracted with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. Purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol yielded 1.67 g (57%) of the title compound. MS (ES+): 432 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.[Br:8][C:9]1[C:14]([Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:13]([F:19])[C:12]([F:20])=[CH:11][CH:10]=1.CN(C)[CH:23]=[O:24]>O1CCCC1.CCCCCC.O.C(OCC)(=O)C>[Br:8][C:9]1[C:14]([Si:15]([CH3:16])([CH3:17])[CH3:18])=[C:13]([F:19])[C:12]([F:20])=[C:11]([CH:10]=1)[CH:23]=[O:24]
Reactant: C[Si](C)(C)c1c(Br)ccc(F)c1F
Reactant: CN(C)C=O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: C[Si](C)(C)c1c(Br)cc(C=O)c(F)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, to a solution containing 6.34 mL of N,N-diisopropylamine in 100 mL of tetrahydrofuran, 26.4 mL of 1.57 Mn-butyllithium in hexane was added at 0° C., and stirred at this temperature for 10 minutes. After cooling to −78° C., a solution containing 10.0 g of (6-bromo-2,3-difluorophenyl)trimethylsilane in 100 mL of tetrahydrofuran was added dropwise, stirred at this temperature for 1 hour, then added dropwise with 2.92 mL of N,N-dimethylformamide, allowed to gradually warm to room temperature, and stirred fro 3 hours. After diluting with water and ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (n-hexane), to afford 9.70 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)=[O:16].[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[C:29]2[S:25][C:26](=[O:31])[NH:27][C:28]2=[O:30])=[CH:23][CH:24]=1)=[O:16]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1

Procedure:
4-[3-(5-Methyl-2-phenyl-4-oxazolyl)propionyl]benzaldehyde, the title product of Preparation 4, (16 g, 0.05 mol), thiazolidine-2,4-dione (11.7 g, 0.10 mol and piperidine (0.85 g, 0.01 mol) were combined in 300 mL absolute ethanol, and the mixture refluxed for 24 hours, cooled to 0° C., diluted slowly with 600 mL of ether and, after stirring for 1 hour at 0° C., crude product recovered by filtration. The crude product was triturated with 150 mL of warm acetic acid (40°-50° C.). The resulting slurry was cooled to room temperature, diluted with 300 mL of ether, and 14.2 g (71%) of purified title product recovered by filtration; mp 224°-225° C.
Reaction SMILES: [P:1]([O:5][CH2:6][C@:7]([NH:31]C(=O)OC(C)(C)C)([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH:20]3[CH2:25][CH2:24][C:23]4([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21]3)[CH:15]=2)[CH:10]=1)[CH3:8])([OH:4])([OH:3])=[O:2].C(O)(=O)C.Cl>O>[P:1]([OH:3])([OH:4])([O:5][CH2:6][C@:7]([NH2:31])([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH:20]3[CH2:21][CH2:22][C:23]4([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:24][CH2:25]3)[CH:15]=2)[CH:10]=1)[CH3:8])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(O)O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: C[C@](N)(COP(=O)(O)O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Yield: 36 %

Procedure:
tert-Butyl (2R)-1-(phosphonooxy)-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propan-2-ylcarbamate (13.6 mg, 0.0000248 mol) was dissolved in acetic acid (0.78 mL, 0.014 mol) and 10 M of hydrogen chloride in water (0.2 mL) was added and the mixture was stirred for Id. Lypholyzing gave (2R)-2-amino-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propyl dihydrogen phosphate as a white solid (4.0 mg, 36%). LCMS give a single peak Rf=1.64 min (431.41, [M-16]+, 100%, 895.73, [M+M+1], 20%). 1H NMR (400 MHz, MeOD) δ=7.82-7.89 (m, 3 H), 7.56 (d, J=5.5 Hz, 1 H), 7.27 (s, 1 H), 7.21 (d, J=8.6 Hz, 1 H), 4.54-4.47 (m, 1 H), 4.14-4.17 (m, 2H), 1.99-1.90 (m, 2 H), 1.86 (s, 3 H), 1.78-1.66 (m, 4 H), 1.50 (m, 8 H), 1.42-1.30 (m, 4 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]1=[O:17])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:1]([O:5][C:6](=[O:18])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:26](=[O:28])[CH3:27])[C:11]1=[O:17])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(N)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(NC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.6 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(3-Amino-2-oxo-2H-pyridin-1-yl)-butyric acid tert-butyl ester (500 mg, 1.98 mmol) in dichloromethane (5 mL) was added triethylamine (220 mg, 2.18 mmol) followed by acetic anhydride (202 mg, 1.98 mmol). The reaction mixture was stirred at room temperature for 12 hours and then partitioned between EtOAc and aqueous 1M HCl. The organic layer was washed with saturated aqueous NaHCO3, brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (40% ethyl acetate/hexane) to afford the title compound as a colourless oil (569 mg, 97%): 1H NMR (400 MHz, CDCl3) δ 0.87 (3H, t), 1.40 (9H, s), 1.91 (1H, m), 2.13 (3H, s), 2.19 (1H, m), 5.38 (1H, dd), 6.26 (1H, t), 6.99 (1H, d), 8.33 (1H, d), 8.43 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7](O)[CH:8]2[O:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([NH:21][CH2:22][C:23]#[CH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]([CH2:22][C:23]#[CH:24])[CH2:9][CH:8]([OH:10])[CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#CCNCc1ccccc1
Reactant: OC(Oc1ccc(Cl)cc1)C1CO1
Product: C#CCN(Cc1ccccc1)CC(O)COc1ccc(Cl)cc1

Procedure:
Upon refluxing 6.36 g. of 1-p-chlorophenoxy-2,3-epoxypropanol with 5 g. of N-benzylpropargylamine in 50 ml. of ethanol and subsequent removal of the solvent as in Example 1, a yellow oil is obtained. Placing this oil on a silica gel column and eluting said column with ethyl acetate produces the pure yellow liquid 1-(N-benzylpropargylamino)-3-p-chlorophenoxy-2-propanol which shows IR and NMR spectra in accordance with its structure and proper analyses for C19H20NO2Cl.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=O)[N:15]=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.[O:53]1[CH2:58][CH2:57][CH:56]([CH2:59][NH2:60])[CH2:55][CH2:54]1>CN(C=O)C.O>[Br:1][C:2]1[N:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:60][CH2:59][CH:56]2[CH2:57][CH2:58][O:53][CH2:54][CH2:55]2)=[O:19])[N:15]=1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1Br
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Yield: 100 %

Procedure:
A solution of the compound (1.8 g, 5.23 mmol) obtained in step 7, HATU (2.386 g, 6.27 mmol), DIEA (1.093 mL, 6.27 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.723 g, 6.27 mmol) in DMF (1 mL) was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50% ethyl acetate/hexane→5% methanol/ethyl acetate) to give 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (2.31 g, 5.23 mmol, 100%) as a colorless oil