Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[CH2:10][N:11]1[N:15]=[C:14]([NH:16][C:31]([C:27]2[N:28]=[CH:29][O:30][C:26]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:32])[CH:13]=[N:12]1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cccc(Cn3ncc(N)n3)c2)OCCO1
Product: CC(=O)c1cccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=1[CH2:27][CH2:28][CH3:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:30][O:31][CH2:32]Cl.O>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:26][CH2:30][O:31][CH3:32])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:13][C:12]=1[CH2:27][CH2:28][CH3:29])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
Sodium hydride (purity: 50%) (38.9 mg, 0.81 mmol) was added to a mixed solution of 2-(4-benzyloxy-3-propylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (264.0 mg, 0.67 mmol) in tetrahydrofuran (5 mL) under ice-cooling. Then, chloromethyl methyl ether (65.0 mg, 0.81 mmol) was added, followed by stirring overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin-layer chromatography (hexane:ethyl acetate=10:1) to obtain 264.9 mg of the title compound (yield: 90%) as a pale yellow oil.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].O>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=2[F:21])=[O:25])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)c1cccc(F)c1F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1cccc(F)c1F
Temperature: -15 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of t-butyllithium (3.0 mL, 1.2 M in pentane) was added to a cooled (−78° C.) solution of benzyloxy-4-bromobenzene (500 mg, 1.9 mmol) in THF (20 mL). The temperature was raised to −15° C. over a period of 1 h and stirred at −15° C. for an additional 2 h. A slurry of MnCl2.2LiCl2 (1.9 mmol) in THF (13 mL) was added and the mixture was stirred for 30 min allowing the temperature to reach 0° C. 2,3-Difluorobenzoyl chloride was added and the reaction was stirred at r.t. for 1 h. Water (20 mL) was added, stirred for 10 min. The aqueous phase was extracted with dichloromethane (2×20 mL) and the organic phases were combined and washed with brine (20 mL), dried (Na2SO4), filtered and concentrated. Purified by flash chromatography (eluent: 100% heptane→10% ethyl acetate in heptane) to give the title compound 3 (320 mg, 52% yield). 1H-NMR (400 MHz, CDCl3): δ 7.88 (d, J=7.5 Hz, 2H), 7.48-7.15 (m, 8H), 7.08 (d, J=7.5 Hz, 2H), 5.18 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31](O)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([O:1][CH2:2][CH2:3][C:4]4[NH:5][C:6]5[C:11]([CH:12]=4)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=5)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][N:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)noc12
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3[nH]2)ccc2c(-c3ccccc3)noc12

Procedure:
Using the procedures in Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 3-phenyl-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless gum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Yield: 100.3 %

Procedure:
2-Chloro-5-nitropyridine (500.0 mg), methyl 4-hydroxybenzenecarboxylate (958.6 mg) and potassium carbonate (1.31 g) were suspended in acetonitrile (5 mL), and heated under reflux for 16 hours. Water (50 mL) was added to the reaction liquid, extracted with ethyl acetate (50 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (50 mL), water (50 mL) and saturated saline water (50 mL) in that order. The organic layer was dried with magnesium sulfate, and evaporated under reduced pressure to obtain the entitled compound (867.7 mg) as a brown solid.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10].C([O:34][N+:35]([O-])=[O:36])(C)C>C(O)(C)(C)C>[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[C:19]([N+:35]([O-:36])=[O:34])[C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
Potassium tert-butoxide (1.70 g, 15 mM) and (20S)-20-hydroxymethylpregn-4-en-3-one (1.65 g, 5 mM) are mixed together in tert-butanol (25 mL), and heated at reflux temperature under argon atmosphere for 75 minutes. Iso-propylnitrate (0.51 mL, 5 mM) is then added to the refluxing reaction mixture, resulting in an exothermic reaction. After one minute, the reaction vessel is removed from heat and allowed to cool to room temperature. The cooled mixture is then made acidic by addition of acetic acid (5 mL), and stirred overnight. The mixture is then diluted with dichloromethane so as to form a separate phase sufficient to solubilize the synthesized product. Subsequently, the solids are removed by filtration and washed with dichloromethane. The materials in both the filtrate and wash(es) are combined together and concentrated. The residue is then redissolved in dichloromethane, then purified by flash chromatagraphy on silica gel to give (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one. The crystallization of this material from aqueous acetone gives white needles (m.p. 166°-168° C.).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[C:38]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:39](=[O:43])[O:40]2)=[CH:35][CH:34]=1>O1CCCC1>[C:1]([NH:8][C@H:9]([C:14]([NH:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[C:38]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:39](=[O:43])[O:40]2)=[CH:35][CH:34]=1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 1.16 g (5 mmol) of Boc-L-leucine and 0.70 ml (5 mmol) of triethylamine in 12 mL of tetrahydrofuran (dried over sodium/lead alloy) at -15° was added 0.66 mL (5 mmol) of i-butyl chloroformate. After 10 min., 1.19 g (5 mmol) of 7-amino-3-phenylcoumarin suspended in 6 mL of tetrahydrofuran was added. The mixture was stirred at -15° for 30 min. and then overnight at room temperature. The reaction mixture was then reduced to dryness on a rotary evaporator at 1.6 kPa and 60°. The residue was taken up in 100 mL of ethyl acetate, washed twice with 25-mL portions of 1 N aqueous sodium bicarbonate and twice with 25-mL portions of saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was dried overnight at room temperature and 3 Pa to yield 1.91 g. (84.8%) of crude product as a yellow foam which was purified by chromatography on a silica gel column eluted first with methylene chloride and then with 5% methanol in methylene chloride. Product recovery was 66.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[H-].[Na+].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:16][C:15]([O:14][CH2:12][CH3:13])=[O:25])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
To a solution of 3-nitrobenzaldehyde (49 g, 295 mmol) and (diethoxy-phosphoryl)-acetic acid ethyl ester (72.74 g, 325 mmol) in DMF (300 ml) at 0° C. was added NaH (14.2 g, 354 mmol) portionwise and stirred for 1.5 hrs at r.t. The reaction mixture was poured into water to give colorless crystals, which were collected by filtration and washed with water and hexane to give the product ethyl 3-(3-nitrophenyl)acrylate (63 g, yield 96.6%). 1H NMR MeOD 400 MHz. δ 8.42-7.62 (m, 4H), 7.74-7.70 (d, 1H), 6.68-6.64 (d, 1H), 4.28-4.22 (m, 2H), 1.34-1.30 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.CCOCC.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Nc1ccnc(Cl)c1
Reactant: C1COCCN1
Solvent: CCOCC
Product: Nc1ccnc(N2CCOCC2)c1
Temperature: 200 °C
Reaction time: 0.17 h

Procedure:
A stirred mixture of 45.8 g (356 mmol) 4-amino-2-chloropyridine in 124 ml morpholine was heated at 200° C. for 30 min in a microwave oven. The resulting yellow solution was then cooled to room temperature whereupon crystals appeared. 400 ml ether was then added and the suspension stirred for 10 minutes before being filtered. The filter cake was washed with ether and dried to afford 92.9 g of crystalline material (87% yield of desired product) which 1H NMR analysis revealed to comprise 60 wt % 2-morpholin-4-yl-pyridin-4-ylamine and 40 wt % morpholine. This material was used in the next step without any further purification. ES-MS m/e (%): 180 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.C(N(C(C)C)C(C)C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:72][CH:73]([SH:75])[CH3:74]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([S:75][CH:73]([CH3:74])[CH3:72])[CH:12]=1)=[O:17]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Reactant: CC(C)S
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(SC(C)C)c1
Yield: 88.8 %

Procedure:
A tube was charged with 66.15D (213 mg, 552 μmol), N-ethyl-N-isopropylpropan-2-amine (143 mg, 1103 μmol) and toluene, evacuated and back-filled with nitrogen three times. Pd2(dba)3, 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (31.9 mg, 55.2 μmol) and propane-2-thiol (63.0 mg, 827 μmol) were added to the mixture and then the mixture was degassed three times. The suspension was refluxed overnight, filtered, and concentrated to give a residue which was purified by silica gel chromatography to give 69.24A as a pale yellow solid (164 mg, 89%). MS ESI m/e: 335.2 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]1([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH:64][CH3:65])[C:48]([N:50]([CH3:63])[C@@H:51]([C:59](=[O:62])[NH:60][CH3:61])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:49])=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:64]([C@@H:47]([C:48](=[O:49])[N:50]([CH3:63])[C@@H:51]([C:59](=[O:62])[NH:60][CH3:61])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:46][C:43]1[CH:42]=[CH:41][C:40]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:45][CH:44]=1)[CH3:65])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.24 g; 0.98 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.2 g; 1.02 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-3-(1,1′-Biphenyl-4-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide (0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (50 mL) was added and the reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (4×20 cm) using ethyl acetate/heptane (2:1) as eluent to afford 0.46 g of ((3E)-4-(((1R)-2-(1,1′-biphenyl-4-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)-carbamoyl)ethyl)methylcarbamoyl)-1,1-dimethylbut-3-enyl)-carbamic acid tert-butylester.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[N:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>C(Cl)Cl>[O-:25][N+:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:14]2[N:13]=[C:12]([N:8]3[CH:9]=[CH:10][N:11]=[C:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=[CH:16][N:15]=2)[CH:20]=1
Reactant: c1ccc(-c2nccn2-c2ccnc(Nc3cccnc3)n2)cc1
Reactant: OO
Solvent: ClCCl
Product: [O-][n+]1cccc(Nc2nccc(-n3ccnc3-c3ccccc3)n2)c1

Procedure:
To a solution of 4-(2-phenyl-1H-imidazol-1-yl)-N-pyridin-3-ylpyrimidin-2-amine (3-3, 0.17 mmol) in CH2Cl2 (1 mL) was added MeReO3 (1 mg) then 30% H2O2 (0.05 mL) with vigorous stirring at room temperature. After 18 hrours additional MeReO3 (1 mg) and 30% H2O2 (0.05 mL) were added. After 18 hours the mixture was concentrated. Purification by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA) gave the title compound as a tan solid after trituration with Et2O. 1H-NMR (500 MHz, d6-DMSO) δ 10.38 (s, 1H), 8.68 (d, J=5.13 Hz, 1H), 8.57 (s, 1H), 7.99 (s, 1H), 7.87 (d, J=5.86 Hz, 1H), 7.55 (m, 6H), 7.27 (bs, 1H), 7.20 (s, 1H), 6.86 (d, J=4.64 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[CH2:15]([O:17][CH:18](OCC)OCC)[CH3:16].C(OC(=O)C)(=O)C>>[CH2:15]([O:17][CH:18]=[C:11]([S:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=1)(=[O:9])=[O:10])[C:12]#[N:13])[CH3:16]
Reactant: Cc1ccc(CS(=O)(=O)CC#N)cc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)S(=O)(=O)Cc1ccc(C)cc1
Yield: 89.7 %

Procedure:
To a solution of 4.4 g (21 mmol) of 2 in 17.5 mL (105 mmol) of triethylorthoformate was added 9.9 mL (105 mmol) of acetic anhydride. The resulting solution was heated to reflux for 18 h before being concentrated to a solid. Recrystallization from AcOEt-hexanes gave 5.0 g (90%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21]O)[CH2:16][CH2:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.C1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][N:46]4[C:42](=[O:52])[C:43]5[C:44](=[CH:48][CH:49]=[CH:50][CH:51]=5)[C:45]4=[O:47])[CH2:18][CH2:19]3)[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCC1CCN(c2cccc(-c3ccc(F)cc3)n2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCC1CCN(c2cccc(-c3ccc(F)cc3)n2)CC1
Yield: 48.9 %

Procedure:
The procedure described in Example 1 (step 1.2.) is followed, Starting from g (6.66 mmol) of 2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethanol, prepared in step 4.1., 2.096 g (7.99 mmol) of triphenylphosphine, 1.077 g (7.32 mmol) of phthalimide and 1.61 g (7.99 mmol) of diisopropyl azodicarboxylate (DIAD), and after chromatography on silica gel, eluting with a 15/85 mixture of ethyl acetate and cyclohexane, gives 1.4 g of pure product in the form of a white powder.
Reaction SMILES: [Si]([O:8][C@H:9]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=1)[CH2:10][NH:11][C:12]([CH3:33])([CH3:32])[CH2:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=1)[C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=[O:18])(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][CH2:20][NH:19][C:17](=[O:18])[C:16]1[CH:29]=[CH:30][CH:31]=[C:14]([CH2:13][C:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=2)([CH3:33])[CH3:32])[CH:15]=1
Reactant: CC(C)(Cc1cccc(C(=O)NCCc2ccccc2Cl)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: F
Solvent: CCN(CC)CC
Product: CC(C)(Cc1cccc(C(=O)NCCc2ccccc2Cl)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77 %

Procedure:
A mixture of 3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(2-chlorophenyl)ethyl]benzamide (preparation 118), (147 mg, 0.24 mmol) and triethylamine trihydrofluoride (39 μL, 0.24 mmol) was stirred at room temperature for 3 days. The mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 95:5:0.5. The appropriate fractions were evaporated under reduced pressure and the residue was azeotroped with methanolic ammonia to afford the title compound as a colourless solid in 77% yield, 75 mg. 1H NMR (400 MHz, CD3OD) δ: 7.61 (2H, m), 7.37-7.29 (5H, m), 7.23-7.16 (2H, m), 7.12 (1H, dd), 6.74 (1H, d), 4.66 (1H, m), 4.64 (2H, s), 3.63 (2H, m), 3.05 (2H, t), 2.96-2.84 (2H, t), 2.76-2.69 (2H, m), 1.10 (3H, s), 1.04 (3H, s) ppm; LRMS ESI m/z 497 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]=[C:15]=S)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:19]1[CH:35]=[C:34]([NH:36][CH3:37])[C:33]([N+:38]([O-])=O)=[CH:32][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:23]=1.CI>CO>[CH3:31][NH:30][C:28]([C:24]1[CH:23]=[C:22]([O:21][C:20]2[CH:19]=[CH:35][C:34]3[N:36]([CH3:37])[C:15]([NH:14][C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:9]=4)=[N:38][C:33]=3[CH:32]=2)[CH:27]=[CH:26][N:25]=1)=[O:29]
Reactant: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Reactant: S=C=Nc1cccc(Oc2ccccc2)c1
Solvent: CO
Solvent: CI
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2cccc(Oc4ccccc4)c2)n3C)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 dram vial was charged with a solution of 3-phenoxyphenylisothiocyanate (23 mg, 0.1 mmol), diamine 1 (27 mg, 0.1 mmol), and MeOH (0.5 mL) and the reaction was shaken at rt overnight. Methyl iodide (8 uL, 0.13 mmol) was added and the mixture shaken overnight. The reaction was concentrated and the resulting residue purified on reverse phase HPLC. LCMS m/z 466.3 (MH+), tR=2.40 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].[C:8](#N)[CH3:9]>>[CH3:8][CH:9]1[NH:7][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][NH:1]1
Reactant: CC#N
Reactant: CCC(N)CCN
Product: CCC1CCNC(C)N1
Reaction time: 21 h
Yield: 98 %

Procedure:
Sixty grams of 1,3-diaminopentane (96.7% purity, 0.569 mole), 60 g acetonitrile (1.46 moles) and 1 g of wet Raney® nickel (Raney 2800) catalyst were charged to a 300 ml stainless steel autoclave reactor. The mixture was stirred and heated at 90° C. and 500 psig hydrogen pressure for 6 hours. Capillary GC analysis of the cooled product indicated a 36% conversion of 1,3-diaminopentane and 97.4% yield of 2-methyl-4-ethylhexahydropyrimidine. The reactor was recharged with 25 ml (19.5 g) additional acetonitrile and run at 90° C. and 500 psig for 21 hours. Capillary GC analysis of the mixture indicated a 92.1% conversion of 1,3-diaminopentane and 98% yield of 2-methyl-4-ethylhexahydropyrimidine, b.p. 71° C./20 mm Hg. The structure was confirmed by comparison with a mass spectrum of the hexahydropyrimidine obtained by the condensation of 1,3-diaminopentane and acetaldehyde at 50° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH:13]([C:36]([O:38][CH3:39])=[O:37])[CH2:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)=[O:11])=O)(C)(C)C.[ClH:40]>ClCCl>[ClH:40].[NH2:8][CH2:9][C:10]([NH:12][CH:13]([C:36]([O:38][CH3:39])=[O:37])[CH2:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)=[O:11]
Reactant: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)CN
Yield: 78.8 %

Procedure:
A solution of 5-[4-(4-(2-(2-t-butoxycarbonylaminoacetamido)-2-methoxycarbonylethyl)phenoxy)benzyl]thiazolidin-2,4-dione (0.73 g, 1.31 mmol) in dichloromethane (30 ml) was bubbled with HCl gas at −10° C. for 1.25 h. The excess HCl gas was removed by N2 bubbling and the solvent was removed by distillation to provide the title compound (0.51 g, yield 78.8%).