Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C@@H:5]1[C:17]2[N:16]([C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH3:19])[C:15]3[C:10](=[CH:11][C:12]([F:34])=[CH:13][C:14]=3[S:30]([CH3:33])(=[O:32])=[O:31])[C:9]=2[CH2:8][CH2:7][CH2:6]1.C1COCC1.CO.[Li+].[OH-]>CC(O)=O>[F:34][C:12]1[CH:11]=[C:10]2[C:15](=[C:14]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:13]=1)[N:16]([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=1)[CH3:19])[C:17]1[C@@H:5]([CH2:4][C:3]([OH:35])=[O:2])[CH2:6][CH2:7][CH2:8][C:9]2=1
Reactant: COC(=O)C[C@H]1CCCc2c1n([C@@H](C)c1ccc(C(F)(F)F)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)n1c2c(c3cc(F)cc(S(C)(=O)=O)c31)CCC[C@@H]2CC(=O)O

Procedure:
To a solution of the above ester (1 eq) in a 3.5/1 mixture of THF/MeOH (0.25M) at 0° C. was slowly added aqueous LiOH 1N (1 eq) and the mixture was stirred at 0° C. for 16 h or until almost complete hydrolysis of the ester; under these conditions, the other minor diastereomer has a much slower rate of hydrolysis. AcOH was added and the solvent was removed in vacuo. The residue was taken up in EtOAc/H2O and the organic layer was washed with brine, dried over Na2SO4 filtered and concentrated. To remove the unreacted methyl ester, the residue was filtered through a pad of silica gel eluting first with 10% EtOAc/toluene and then with 60% EtOAc/toluene containing 1% of AcOH. The residue was swished in 30% EtOAc/hexane and dried under high vacuum at 50° C. for 16 hr to give the desired title compound as a white solid with de and ee >95% (checked by chiral HPLC). MS (−APCI) m/z 496.0 (M−H)−. [α]D=−181° in MeOH.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH:10]([CH2:21][CH2:22]Br)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:22][CH2:21]2)[CH:6]=1
Reactant: Fc1cn[nH]c1
Reactant: O=C(OCc1ccccc1)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1(n2cc(F)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
To a solution of 4-fluoropyrazole (125 mg, 1.45 mmol) in tetrahydrofuran (4 mL) at 0° C. was added sodium hydride (60% suspension in mineral oil, 116 mg, 2.90 mmol). The mixture was stirred at 0° C. for 40 min before benzyl 2,4-dibromobutyrate (0.30 mL, 1.50 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography to afford benzyl 1-(4-fluoro-1H-pyrazol-1-yl)cyclopropanecarboxylate as a clear oil (115 mg, 30.4%). 1H NMR (400 MHz, CDCl3) δ 1.64-1.70 (m, 2H), 1.81-1.86 (m, 2H), 5.14 (s, 2H), 7.22-7.26 (m, 2H), 7.31-7.36 (m, 3H), 7.40 (td, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24](=[O:33])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[S:22])[CH:16]=[CH:17][C:18]=1[OH:19]>>[F:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24](=[O:33])[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[S:22])[CH:16]=[CH:17][C:18]=1[O:19][C:2]1[CH:3]2[C:10]([CH3:11])=[CH:9][S:8][CH:4]2[N:5]=[CH:6][N:7]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Product: CC1=CSC2N=CN=C(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)C12

Procedure:
In a similar manner as described for the preparation of Example 10, the title compound was prepared from commercially available 4-chloro-5-methylthieno[2,3-d]pyrimidine and 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol, Compound A of Example 3). 1H NMR (CDCl3) δ 12.42 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 7.88 (dd, 1H, J=13.8, 2.2 Hz), 7.43 (s, 1H), 7.32 (m, 3H), 7.09 (m, 3H), 3.72 (S, 2H), 2.67 (s, 3H); MS(ESI+) m/z 471 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:36]([CH3:38])[CH3:37])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl.C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:36]([CH3:38])[CH3:37])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccccc3)CCC(=O)CC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)N1CCn2c(CC3(c4ccccc4)CCC(=O)CC3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 71.9 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(4-oxo-1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (272) (200 mg, 0.39 mmol) in dichloromethane (25.0 mL) was added triphenyl phosphine (152 mg, 0.58 mmol) and diisopropyl azodicarboxylate (0.12 mL, 0.58 mmol) at room temperature and stirred for 30 min (silica TLC, 5% methanol in ethyl acetate, Rf=0.5). The reaction mixture was concentrated under reduced pressure and purified by normal silica gel (100-200 mesh) column chromatography using gradient polarity mobile phase (50% ethyl acetate in hexane to 5% methanol in dichloromethane) to get pure 9-benzyloxy-2-isopropyl-6-(4-oxo-1-phenyl-cyclohexylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (273) (140 mg, 72.53%) as a white solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].O[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[CH:17]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>ClCCCl>[C:1]([O:5][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[CH:17]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: O=C(O)c1ccc2cc(OCCCCCCO)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: ClCCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc2cc(C(=O)O)ccc2c1

Procedure:
In 270 g of 1,2-dichloroethane were added 108.11 g (1.5 mmol) of acrylic acid, 21.63 g (75 mmol) of 6-(6-hydroxy-hexa-1-yloxy)-2-naphthoic acid obtained in Step 1, 4.28 g (23 mol) of p-toluenesulfonic acid monohydrate, and 0.83 g (7.5 mmol) of hydroquinone, and the solution was refluxed for 4 hours. After evaporation of the solvent, 270 g of water was added to the residue, and the precipitate was collected by filtration and dried in an oven at 40° C. overnight. The dried product was recrystallized from acetone to yield the desired product, 6-(6-acryloyloxy-hexa-1-yloxy)-2-naphthoic acid, as light-yellow powder (16.97 g, Yield: 65%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:29][O:30][C:31](=[O:68])[NH:32][CH:33]([C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:58]=[CH:57][C:56]3[C:51](=[CH:52][CH:53]=[C:54](B4OC(C)(C)C(C)(C)O4)[CH:55]=3)[CH:50]=2)=[CH:47][N:48]=1)=[O:38])[CH:34]([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+].N#N>C1(C)C=CC=CC=1.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.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH3:29][O:30][C:31](=[O:68])[NH:32][CH:33]([C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:58]=[CH:57][C:56]3[C:51](=[CH:52][CH:53]=[C:54]([C:24]4[CH:25]=[CH:26][C:21]([C:18]5[NH:17][C:16]([CH:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:28])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)=[CH:22][CH:23]=4)[CH:55]=3)[CH:50]=2)=[CH:47][N:48]=1)=[O:38])[CH:34]([CH3:36])[CH3:35]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 38.8 %

Procedure:
A solution of (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (244 mg, 0.54 mmol), [2-methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (270 mg, 0.49 mmol) and aqueous K2CO3 (490 μl of a 2M solution, 0.98 mmol) in toluene (3 mL) and DMF (1 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (31 mg, 0.027 mmol) and PdCl2(dppf) (20 mg, 0.027 mmol) then the reaction was heated to 80° C. overnight. After cooling to room temperature, the reaction was quenched with acetic acid, filtered, and then concentrated. The crude product was purified by reverse phase preparative HPLC (10-85% MeCN—H2O; 0.1% formic acid modifier) to afford [1-(2-{5-[6-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (149 mg, 0.19 mmol, 35% yield). 1H-NMR: 400 MHz, (DMSO-d6) δ: 11.82 (s, 1H), 11.79 (s, 1H), 8.21-8.16 (m, 2H), 7.92-7.79 (m, 8H), 7.62 (s, 1H), 7.54 (s, 1H), 7.31-7.29 (m, 2H), 5.10 (m, 2H), 4.09-4.07 (m, 2H), 3.82 (m, 4H), 3.54 (s, 6H), 2.20-1.85 (m, 10H), 0.95-0.86 (m, 12H). LCMS-ESI+: calc'd for C44H53N8O6: 789.4 (M+H+). Found: 789.2 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][O:13][CH3:14].O>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][O:13][CH3:14])=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 918.2 %

Procedure:
To a suspension of 60% NaH in mineral oil (12.7 g, 31.8 mmol) in anhydrous THF (300 mL) at 0° C. was added 4-bromophenol (50.0 g, 28.9 mmol) dissolved in THF (100 mL) dropwise over 1 h. The reaction mixture was stirred at 0° C. for 30 min, and chloromethylmethyl ether (24.8 mL, 32.6 mmol) dissolved in THF (30 mL) was added dropwise over 20 min. The reaction mixture was stirred overnight at RT. Water (250 mL) was added, and the mixture was extracted with ether (3×250 mL). The combined ethereal extracts were washed with brine, dried (MgSO4), and concentrated. The residue was distilled under vacuum to afford 57.6 g (92%) of 86 as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 3.33 (s, 3H), 5.15 (s, 2H), 6.96 (d, J=9.0 Hz, 2H), 7.43 (d, J=9.0 Hz, 2H).
Reaction SMILES: C(OC(/N=N/C(=O)OC(C)C)=O)(C)C.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([F:29])[C:21]=1[N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49](=[O:52])([SH:51])[CH3:50]>C1COCC1.C(OC(=O)C)C>[C:49](=[O:52])([S:51][CH:25]1[CH2:26][CH2:27][N:22]([C:21]2[C:20]([F:29])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:15])[CH2:23][CH2:24]1)[CH3:50]
Reactant: CC(=O)S
Reactant: OC1CCN(c2c(F)cncc2Cl)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)SC1CCN(c2c(F)cncc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (723.1 mg, 3.576 mmol) was added dropwise to a solution of 1-(3-chloro-5-fluoro-4-pyridyl)piperidin-4-ol (750 mg, 3.251 mmol) and Triphenylphosphine (937.9 mg, 828.5 μL, 3.576 mmol) in THF at −20° C. After stirring for 15 mins, ethanethioic S-acid (272.2 mg, 255.6 μL, 3.576 mmol) was added, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The mixture was then diluted with ethylacetate (30 ml), washed twice with water (20 ml) and with brine. The organic layer was dried with MgSO4 and concentrated in vacuo to a yellow solid that was purified by column chromatography eluting with 5/95 ether/pet ether to elute side products and then 10/90 ether/pet ether. The relevant fractions were combined and concentrated in vacuo to afford S-(1-(3-chloro-5-fluoropyridin-4-yl)piperidin-4-yl) ethanethioate as a green solid. MS (ES+) 289.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]([NH:16]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2>CO>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH2:16])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)C(=Cc1cc(C)c2[nH]ncc2c1)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)C(N)Cc1cc(C)c2[nH]ncc2c1
Yield: 115 %

Procedure:
A solution of 2-benzyloxycarbonylamino-3-(7-methyl-1H-indazol-5-yl)-acrylic acid methyl ester (4.93 g, 13.49 mmol) in methanol (125 mL) was degassed by bubbling nitrogen through it for 30 min and then 10% palladium on charcoal (0.6 g) was carefully added. The mixture was hydrogenated at 40 psi in a Parr shaker apparatus overnight. The catalyst was removed by filtration through a pad of celite and the filtrate was concentrated in vacuo to give the product as a colorless foam (3.62 g, quant.). 1H-NMR (CD3OD, 500 MHz) δ 2.45 (3H, s), 2.99 (1H, Abq), 3.22 (1H, Abq), 3.74 (3H, s), 3.89 (1H, m), 6.91 (1H, s), 7.31 (1H, s), 7.73 (1H, s). Mass spec.: 234.11 (MH)+.
Reaction SMILES: B.O1CCNC2C=C(N)C=CC1=2.[NH2:13][C:14]1[C:15]([Cl:25])=[CH:16][C:17]2[NH:22][C:21](=O)[CH2:20][O:19][C:18]=2[CH:24]=1>>[Cl:25][C:15]1[C:14]([NH2:13])=[CH:24][C:18]2[O:19][CH2:20][CH2:21][NH:22][C:17]=2[CH:16]=1
Reactant: Nc1cc2c(cc1Cl)NC(=O)CO2
Agent: B
Agent: Nc1ccc2c(c1)NCCO2
Product: Nc1cc2c(cc1Cl)NCCO2

Procedure:
Borane reduction performed using general procedure described above for 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine except 7-Amino-6-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one was used as starting material.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])[CH:21]=[CH:22][CH:23]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:25]3[N:26]=[C:27]([CH3:29])[O:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[O:31])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c(-c2cccc(Cl)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:17]=1[O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].[F:38][C:39]([F:55])([F:54])[C:40]1[CH:41]=[C:42]([S:50](Cl)(=[O:52])=[O:51])[CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1>N1C=CC=CC=1>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:42]([S:50]([NH:15][C:16]2[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:17]=2[O:18][C:19]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])(=[O:51])=[O:52])[CH:41]=[C:40]([C:39]([F:55])([F:54])[F:38])[CH:45]=1.[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(=O)[O-])c(Oc2ccc(C(F)(F)F)cc2N)c1
Agent: OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)O)c(Oc2ccc(C(F)(F)F)cc2NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
Benzhydrol-2-(2-amino-4-trifluoromethylphenoxy)-4-methoxybenzoate (950 mg, 0.0019 mol) and 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (2.4 g, 0.008 mol) were mixed in pyridine, under argon, at room temperature for 16 h. The solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ8.11 (s, 1H), 7.86-7.98 (m, 2H), 7.08-7.32 (s, 10 H), 6.94 (s, 1H), 6.87 (d, 1H), 6.70 (q, 3H), 6.48 (d, 1H), 6.11 (d, 1H), 3.73 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH:23]1(C=O)[CH2:25][CH2:24]1.C([O-])=O.[NH4+]>[Ru](Cl)(Cl)Cl.C(O)(C)C>[CH2:23]1[CH:25]([CH2:1][N:2]2[C@@H:12]3[CH2:13][C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[C:16]5[O:21][CH:6]6[C:7]([CH2:9][CH2:10][C@:11]3([OH:22])[C@:5]6([C:15]=45)[CH2:4][CH2:3]2)=[O:8])[CH2:24]1
Reactant: O=CC1CC1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Agent: Cl[Ru](Cl)Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Reaction time: 0.08 h
Yield: 86 %

Procedure:
Into a round bottom flask was added noroxymorphone (2.19 g, 0.008 mole), cyclopropanecarboxaldehyde (1.07 g, 0.015 mole, 1.00 mL), ammonium formate (2.40 g, 0.038 mole), and isopropanol (20 mL, HPLC grade). After stirring for about 5 minutes, ruthenium (III) chloride (10 mg) was added. The mixture was stirred under nitrogen at room temperature for about 48 hours. HPLC indicated the reaction was complete. To the dark solution, distilled water (1 mL) was added and this mixture stirred for about 18 hours at room temperature. The entire mixture was evaporated under reduced pressure to a thick paste. Distilled water (10 mL) was added and the pH was adjusted to 9.4 from 7.0 using 29% NH3/H2O where a precipitate formed. The precipitate was filtered, washed with distilled water (10 mL), and dried overnight at 90° C. The dried precipitate yielded naltrexone base (2.35 g, 91% yield) as an off white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>CN(C)C(=O)C>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([O:7][C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of potassium carbonate (98.72 g, 0.714 mol) and 550 ml of N,N-dimethylacetamide (DMAC) is added to a 1L, three-necked round-bottom flask equipped with an overhead stirrer, condenser and a nitrogen inlet tube. Nitrogen is bubbled through the solution for 1 hour, following which methyl 3,5-dihydroxybenzoate (60.00 g, 0.357 mol) and 1-fluoro-4-nitrobenzene (100.79 g, 0.714 mol) are added. The slurry solution is stirred and heated to 80°-90° C. under nitrogen for 10 hours, and the mixture is then filtered while hot to remove inorganic salts. The filtrate is kept in a freezer overnight and the yellow crystals are collected by filtration, washed with water and dried. The product is recrystallized from ethyl acetate to yield 68 percent of yellow crystals: mp 180.5°-182.0° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]([CH3:13])[CH2:4]1.I([O-])(=O)(=O)=[O:15].[Na+]>[Ru](Cl)(Cl)Cl>[CH3:12][O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([C:2]([OH:15])=[O:1])[CH2:4][CH:5]1[CH3:13])=[O:10]
Reactant: COC(=O)N1CCC(CO)CC1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Product: COC(=O)N1CCC(C(=O)O)CC1C

Procedure:
The compound was prepared as described in Reference Compound 4, Step 5 starting from methyl 4-(hydroxymethyl)-2-methylpiperidine-1-carboxylate, sodium periodate (3.53 g, 16.5 mmol) and ruthenium(III) chloride (0.025 g, 0.12 mmol), which resulted in the title compound. MS m/z 200 (M−H)−.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=1.[Br-:17].[Na+].N([O-])=O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].CCOCC>[Br:17][C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=1
Reactant: [Br-]
Reactant: CCOC(=O)c1csc(N)n1
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)c1csc(Br)n1
Temperature: 0 °C

Procedure:
To a sulfuric acid solution (120 mL) of ethyl 2-aminothiazole-4-carboxylate (7.47 g), copper sulfate (10.91 g) and sodium bromide (8.12 g), a solution of sodium nitrite (3.63 g) in ice water was added dropwise over 15 minutes under ice cooling. The resultant mixture was stirred for 30 minutes and for 2 hours at room temperature. Ether was added to the reaction mixture, and the mixture was washed with water. The resultant water layer was neutralized with sodium hydroxide and extracted with ether. The extract was combined with the previously separated ether layer, washed with saturated brine and dried over anhydrous sodium sulfate. After concentrating the combined ether layer under reduced pressure, the resultant residue was purified by column chromatography on silica gel (chloroform), and the resultant crude crystals were recrystallized from hexane to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[O-]CC.[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[CH:16]=1.OC1C=C(C=CC=1)C=O>CN(C=O)C>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[CH:16]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: OCc1cccc(O)c1
Agent: CC[O-]
Agent: O=Cc1cccc(O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2cccc(CO)c2)ccn1
Reaction time: 0.25 h

Procedure:
3-Hydroxybenzyl alcohol (7.93 g, 63.8 mmol) is dissolved in 500 ml of DMF, sodium ethoxide (5.22 g, 76.6 mmol) is added, the mixture is stirred with exclusion of moisture for 15 min and 4-chloropyridine-2-carboxamide (D. Varlet et al. Heterocycles 2000, 53, 797-804) is then added. The mixture is stirred at 138° C. for 70 hours and again a solution of 4 g of 3-hydroxybenzaldehyde and 2.6 g of sodium ethoxide in 100 ml of DMF, which solution is stirred for 15 min, is added. The mixture is stirred at 138° C. for 12 h and then concentrated under reduced pressure. The residue is transferred into saturated KH2PO4 solution and extracted with ethyl acetate. The organic phase is washed with water. The combined aqueous phases are re-extracted with ethyl acetate. The combined dried organic phases are concentrated under reduced pressure and chromatographed on silica gel using a toluene/ethyl acetate gradient. This gives 5.04 g (32.3% of theory) of the target compound having a m.p. of 113° C. and an Rf (SiO2, ethyl acetate) of 0.49.