Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH2:20][NH:21]C(=O)OCC3C=CC=CC=3)=[N:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>Br.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH2:20][NH2:21])=[N:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1nnc(-c2ccc(OCc3ccccc3)cc2)o1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NCc1nnc(-c2ccc(OCc3ccccc3)cc2)o1

Procedure:
A solution of methyl 2-(((benzyloxy)carbonyl)amino)acetimidate (600 mg, 2.7 mmol) and 4-(benzyloxy)benzohydrazide (654 mg, 2.7 mmol) in methanol (45 mL) was heated at 80° C. in a sealed tube for 3 h. The solvent was removed under reduced pressure and the resulting residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate. A solution of benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (480 mg, 1.12 mmol) in 33% HBr in acetic acid (5 mL) was stirred for 1 h. Diethyl ether was added, and the supernatant was decanted. The process was repeated, and the resulting solid was collected by filtration to yield (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine. A solution of (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine (155 mg, 0.43 mmol), 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid (110 mg, 0.43 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (99 mg, 0.52 mmol), DIPEA (0.224 mL, 1.3 mmol) and HOBt (70 mg, 0.52 mmol) in DMF (20 mL) was stirred overnight. The resulting mixture was diluted with NaHCO3 (saturated, aqueous) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to yield N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide, which was in the next step used without further purification. To a solution of N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide (190 mg, 0.37 mmol) in methylene chloride (5 mL) was added 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (233 mg, 0.55 mmol) and the resulting mixture was stirred overnight, then quenched with excess sodium thiosulfate in saturated aqueous sodium bicarbonate. The mixture was then extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 6.60-8.10 (overlapping m, 14H), 5.15 (s, 2H), 4.75-4.85 (m, 2H), 3.85-4.00 (m, 2H), 2.90-3.10 (m, 2H), 1.50-1.90 (m, 6H).
Reaction SMILES: [CH:1]1([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][C:18]#[N:19]>>[CH:1]1([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]#[N:19])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCC2N1CCNCC1
Reactant: N#CCBr
Product: N#CCN1CCN(C2CCc3ccccc32)CC1

Procedure:
The title compound is synthesized by coupling of 1-Indan-1-yl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=242.2: CtRet=4.25.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]([CH3:11])([C:9]#[CH:10])[C:6]([OH:8])=[O:7]>CCOCC>[CH3:4][C:5]([CH3:11])([C:9]#[CH:10])[C:6]([O:8][CH3:3])=[O:7]
Reactant: C=[N+]=[N-]
Reactant: C#CC(C)(C)C(=O)O
Solvent: CCOCC
Product: C#CC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.4 %

Procedure:
To a solution of diazomethane (10 g) in ether (400 mL) was added dropwise 2,2-dimethyl-but-3-ynoic acid (10.5 g, 93.7 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. The mixture was distilled under atmospheric pressure to give crude methyl 2,2-dimethylbut-3-ynoate (14 g), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 2.28 (s, 1H), 1.50 (s, 6H).
Reaction SMILES: Cl.Cl.Cl[C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]1[NH:12][C:13]2[C:21]([N:22]=1)=[CH:20][C:19]1[C:18](=[O:23])[N:17]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][C:15]=1[CH:14]=2.Cl.[CH3:33][C@H:34]([NH2:41])[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1.CCN(CC)CC>CCO>[CH3:33][C@H:34]([NH:41][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]1[NH:12][C:13]2[C:21]([N:22]=1)=[CH:20][C:19]1[C:18](=[O:23])[N:17]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][C:15]=1[CH:14]=2)[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1
Reactant: C[C@H](N)Cc1cccs1
Reactant: O=C1c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2CN1CCCN1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H](Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(CCCN1CCCC1)C3=O
Temperature: 100 °C
Yield: 47.4 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one dihydrochloride (17) (2.2 g, 4.9 mmol), (1S)-1-methyl-2-thien-2-ylethylamine hydrochloride (13b) (870 mg, 4.9 mmol) and Et3N (3.44 mL, 24.5 mmol) in EtOH (20 mL) was heated at 100° C. for 12 h. The mixture was concentrated, diluted with water (20 mL) and extracted with CHCl3 (5×20 mL) the combined organic layer was dried, concentrated to a residue that was purified on silica gel column using 10% NH4OH/methanol in CH2Cl2 to get pure 2-[4-((S)-1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one (18a) (1.2 g, 51%). 1H NMR (DMSO-d6) δ 1.33 (d, 3H, J=3.0 Hz), 1.55-1.85 (m, 6H), 2.3-2.45 9 m, 6H), 3.15-3.25 (m, 2H), 3.56 (t, 2H, J=6.0 Hz), 3.95-4.15 (m, 1H), 4.51 (s, 2H), 6.15 (d, 1H, J=9.0 Hz), 6.91-6.96 (m, 1H), 7.05 (t, 1H, J=3.0 Hz), 7.31-7.36 (m, 2H), 7.66 (s, 0.5H), 7.79 (d, 1H, J=3.0 Hz), 7.93 (s, 0.5H), 11.14 (d, 1H, J=9.0 Hz), 11.24 (bs, 1H). ESI-MS m/z 517.67 (M++1).
Reaction SMILES: [F:1][C:2]1[C:3]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[C:6](Br)[CH:7]=1.[Cu](C#N)[C:32]#[N:33].CN1CCCC1=O>O>[F:1][C:2]1[C:3]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[C:6]([C:32]#[N:33])[CH:7]=1
Reactant: N#C[Cu]C#N
Reactant: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Br)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2C#N)c1
Temperature: 175 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A mixture of 75 mg of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]bromobenzene, 27 mg of copper cyanide and 0.5 ml of N-methyl-2-pyrrolidone was stirred at 170 to 180° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 57 mg of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]cyanobenzene.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([C:20](=O)[CH3:21])[C:15]=3[CH2:23][CH2:24][CH3:25])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1.C(O)=O.[CH:29]([NH2:31])=[O:30].[OH-].[Na+]>O>[F:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([CH:20]([NH:31][CH:29]=[O:30])[CH3:21])[C:15]=3[CH2:23][CH2:24][CH3:25])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1C(C)=O
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1C(C)NC=O
Temperature: 25 °C

Procedure:
214 (0.1 g) and formic acid (0.1 mL) are added to 2 mL of formamide at 160–180° C. The mixture is heated at 160–180° C. for an additional 3 hours. During this period, additional formic acid (0.2 mL) is added. The mixture is cooled to room temperature and poured into water (10 mL). The solution is made alkaline to at least pH 11 with concentrated sodium hydroxide. The solution is extracted with ethyl acetate. The combined organic layers are dried over MgSO4, and the solvent is removed to give the crude product. PTLC separation with 10% MeOH in methylene chloride gives the title product (215). 1H NMR δ (CDCL3) 1.06 (t, 3H, J=7.5 Hz), 1.43 (d, 3H, J=5.1 Hz), 1.55 –1.72 (m, 2H), 2.72–2.80 (m, 1H), 2.86–2.95 (m, 1H), 5.52 (p, 1H, J=5.4 Hz), 5.81 (d, 1H, J=12.3 Hz), 6.08 (d, 1H, J=12.3 Hz), 6.73 (dd, 1 H, J=6, 2.1 Hz)), 6.99 (d, 1H, J=5.7 Hz), 7.12 (d, 1H, J=2.7 Hz), 7.23 (d, 1H, J=2.7 Hz), 7.78 (q, 1H, J=6.0 Hz), 8.12 (dd, 1H, J=6.0, 2.1 Hz), 8.18 (s, 1H), 8.79 (s, 1H). LC-MS: (M+1) 369.13.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>[N+](C)([O-])=O>[CH:14]([C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=1)=[O:17])([CH3:16])[CH3:15]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCc1ccc(C(=O)C(C)C)cc1
Yield: 77 %

Procedure:
At 10° C. a solution of 93 g (0.72 mol) AlCl3 in 250 ml nitromethane is added to a mixture of 66 g (0.62 mol) ethyl benzene and 70 g (0.66 mol) isobutyroyl chloride, after which the mixture is stirred during half an hour. The reaction mixture is poured out into ice and extracted with ether. The solution in ether is washed neutral, dried on MgSO4 and evaporated. The residue is distilled under diminished pressure to obtain p-ethylphenyl isopropyl ketone in a yield of 77%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].[Li+].CC([N-]C(C)C)C.[I:20]I>C1COCC1.C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([O:10][CH3:11])=[C:2]([F:1])[C:7]=1[I:20]
Reactant: COc1c(C)cc(F)cc1F
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C)cc(F)c(I)c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1,5-difluoro-2-methoxy-3-methylbenzene (0.65 g, 4.1 mmol) in THF (1 mL) was added to LDA (4.3 mmol) in THF (10 mL) at −55° C. and the solution stirred for 45 minutes. Solid iodine (1.15 g, 4.5 mmol) was added and the solution allowed to warm to ambient temperature. The solution was diluted with ethyl acetate and washed with sodium bicarbonate (saturated solution 15 mL) and sodium thiosulfate (saturated solution, 15 mL), dried (sodium sulfate) and concentrated. The residue was purified by chromatography (hexanes) to give 1,3-difluoro-2-iodo-4-methoxy-5-methylbenzene: 1H NMR (300 MHz, CDCl3): δ 6.72 (dd, 1H), 3.84 (d, 3H,), 2.26 (s, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][N:11]3[C:19]([S:20][CH3:21])=[C:18]4[C:13]([N:14]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:15](=[O:24])[N:16]([CH3:23])[C:17]4=[O:22])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[OH:32]OS([O-])=O.[K+]>C(Cl)Cl.CO>[N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][N:11]3[C:19]([S:20]([CH3:21])=[O:32])=[C:18]4[C:13]([N:14]([CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:15](=[O:24])[N:16]([CH3:23])[C:17]4=[O:22])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(-n2cncn2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Cn1c(=O)c2c(S(C)=O)n(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.8 %

Procedure:
2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (16 mg, 0.036 mmol) is dissolved in CH2Cl2 (500 μL) and MeOH (500 μL), and then an aqueous solution of Oxone (22.4 mg, 0.036 mmol) is added. The reaction mixture is stirred at room temperature for 2 days, and then purified by a semi-preparative HPLC to give 8 mg of product as off-white solids. MS (ESI) m/z 456.2 [M+H]+.
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C>CO>[OH:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH2:2][N:3]([CH2:15][CH2:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5]2
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: C=CC(=O)OC(C)(C)C
Agent: Br
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCN1CCc2cc(O)ccc2C1
Yield: 79.8 %

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide (345 mg, 1.5 mmol), tert-butyl acrylate (0.44 ml, 3.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.6 ml, 15.0 mmol) in MeOH was irradiated in the microwave at 90° C. for 1800 s. Removal of the solvents gave the residue which was purified on ISCO column (2% to 5% MeOH/CH2Cl2) to provide the title compounds (332 mg, 80%). 1H NMR (400 MHz, CD3OD) δ 6.85 (d, 1H), 6.55 (dd, 1H), 6.54 (s, 1H), 3.55 (s, 2H), 2.83 (m, 4H), 2.76 (m, 2H), 2.54 (dd, 2H), 1.45 (s, 9H). MS (ESI) m/z: Calculated: 277.17; Observed: 277.90 (M++1).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][C:25]([OH:27])=O)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[CH3:30][NH2:31]>C(O)C>[O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][C:25]([NH:31][CH3:30])=[O:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(=O)O)c2c1
Solvent: CCO
Product: CNC(=O)CNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 36-1 by using N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine (prepared in analogy to N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alanine in Example 14-2) and a solution of methylamine in ethanol. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90-7.82 (m, 2 H), 7.77 (d, J=7.58 Hz, 1 H), 7.70 (s, 1 H), 7.61 (td, J=7.45, 1.52 Hz, 1 H), 7.51-7.46 (m, 1 H), 7.34 (d, J=8.34 Hz, 1 H), 7.26 (dd, J=8.46, 1.64 Hz, 1 H), 7.15 (t, J=5.94 Hz, 1 H), 5.86 (s, 1 H), 5.00 (brs, 2 H), 3.90 (d, J=5.81 Hz, 2 H), 3.59 (brs, 2 H), 3.32 (s, 2 H), 2.62 (d, J=4.55 Hz, 3 H), 2.37 (s, 3 H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O.C(O)=O>C1C=CC=CC=1>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14][Cl:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1OS(=O)(=O)c1ccc(C)cc1
Solvent: O=CO
Solvent: c1ccccc1
Product: COc1ccc(CCl)cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 17.5 °C
Yield: 90 %

Procedure:
To a cooled solution of 3-[(p-Toluenesulfonyl)oxy]-4-methoxybenzyl alcohol 22 (8.0 g, 26 mmol) in benzene (25 mL) was added thionyl chloride (1.9 mL, 26 mmol) slowly over a period of 5-10 min maintaining the temperature around 15-20° C. The reaction was maintained at those conditions for 2 h and checked TLC for the completion. The flask is connected to a high vacuum through a trap containing formic acid under mild heating to remove excess thionyl chloride. The slurry formed after complete removal of thionyl chloride and benzene, filtered, washed with hexane and dried to afford 23. Yield: 90%; white solid mp 102-105° C. 1H NMR: δ 2.43 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 4.50 (s, 2H, CH2), 6.80-7.79 (m, 7H, Ar—H). Anal. Calcd for C15H15ClO4S: C, 55.13, H, 4.63. Found: C, 53.20, H, 4.59.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[CH3:1][C:2]1[N:7]=[C:6]([O:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=2)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1cnc(C)nc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)Cc1cnc(C)nc1Oc1cccc(C(F)(F)F)c1

Procedure:
Ethyl α-(2-methyl-4-chloro-5-pyrimidinyl)-acetate (3 g, 14 mmol), 3-trifluoromethyl phenol (3 g, 14 mmol) and potassium carbonate (11 g, 80 mmol) in dimethylformamide (50 ml) are stirred at +80° C. for 3 hours. The mixture is diluted with ether and washed with brine. Drying over MgSO4 and evaporation of the solvent gives pure ethyl α-[2-methyl-4-(3-trifluoromethylphenoxy)-5-pyrimidinyl]acetate as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.C1(C)C=CC=CC=1>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
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: CC#N
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1cn2cc(-c3ccccc3)ccc2n1
Yield: 65.2 %

Procedure:
0.391 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 0.237 g of phenylboronic acid, 45 mg of tetrakis(triphenylphosphine)palladium, 4 ml of 2M aqueous sodium carbonate solution, 6 ml of acetonitrile and 6 ml of toluene are charged to a microwave tube. The mixture is heated for 20 minutes in the microwave device adjusted to 150° C. After cooling, the organic phase is separated, dried and evaporated. The residue is taken up in a mixture of dichloromethane and pentane. The solid is filtered off and then purified by triturating from methanol to give 0.22 g of N,6-diphenylimidazo[1,2-a]pyridine-2-carboxamide in the form of an ecru solid.
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].C(N1[CH2:29][CH2:28][CH2:27]C1=O)C.C1(CBr)CC1.C(N(CC)C(C)C)(C)C.Cl>O>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:27]4[CH2:28][CH2:29]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: CCN1CCCC1=O
Agent: BrCC1CC1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 54.5 °C
Yield: 100.8 %

Procedure:
A mixture of noroxymorphone (62 Kg), N-ethyl-2-pyrrolidinone (186 kg), cyclopropymethyl bromide (37.8 kg) and N,N-diisopropylethylamine (36.2 kg) was heated to 52-57° C. for 24 hours and 45 min. The mixture was then diluted with a solution prepared by mixing hydrochloric acid 37% (30 kg) and water (82 kg). Low boiling compounds were removed by distillation under vacuum keeping the temperature below 70° C. After cooling to 25-30° C. the mixture was further diluted with water (1975 kg). Ammonium hydroxide 4% (206 kg) was then added over three hours till pH=9-10 to precipitate the product. The solid was filtered, washed with water (2×124 kg) and dried under vacuum at 60° C. obtaining 71.3 kg of naltrexone (molar yield 89.6%). HPLC analysis (% by area): naltrexone 99.45%, noroxymorphone 0.16%, 3-cyclopropylmethylnaltrexone 0.28%
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:26]1>CN(C)C=O>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:38][CH2:39]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCN(c2nsc3ccccc23)CC1
Temperature: 20 °C
Yield: 33.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.9 g), triethylamine (4.5 cc) and 4-(1,2-benzisothiazole-3-yl)piperazine (6.6 g) in dimethylformamide (95 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (90 cc), 2-{2-[4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.6 g) is obtained, m.p. 162°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[B:14](OC)([O:17]C)[O:15]C>>[F:1][C:2]1[C:3]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[B:14]([OH:17])[OH:15]
Reactant: COB(OC)OC
Reactant: Fc1ccccc1-c1cccnc1
Product: OB(O)c1cccc(-c2cccnc2)c1F

Procedure:
3-(2-Fluorophenyl)pyridine was lithiated and reacted with trimethyl borate as described in Example 31 to give 2-fluoro-3-(pyridin-3-yl)benzeneboronic acid as a white solid: m/z (ES+) 218 (M++H).
Reaction SMILES: [CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][O:15][P:16]([O:19][P:20]([OH:23])([OH:22])=[O:21])([OH:18])=[O:17])[C@@H:11]([OH:24])[C@H:10]2[OH:25])[CH:2]=1.[OH:26][CH:27]1[O:34][C@H:33]([CH2:35]ON=[N+]=[N-])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:28]1[NH:40][C:41]([CH3:43])=[O:42]>CO.O.[Pd]>[CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][O:15][P:16]([O:19][P:20]([OH:22])([OH:23])=[O:21])([OH:18])=[O:17])[C@@H:11]([OH:24])[C@H:10]2[OH:25])[CH:2]=1.[OH:26][CH:27]1[O:34][C@H:33]([CH2:35][NH2:3])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:28]1[NH:40][C:41]([CH3:43])=[O:42]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CON=[N+]=[N-])[C@@H](O)[C@@H]1O
Agent: [Pd]
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: CO
Solvent: O
Product: CC(=O)N[C@H]1C(O)O[C@H](CN)[C@@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
UDP-GlcNAc6N3 (T5b-12 or F5-9) (100 mg, 0.16 mmol) was dissolved in MeOH—H2O (10 mL, 1:1, v/v) and 20 mg of Pd/C was added. The mixture was shaken under H2 gas (4 Bar) for 1 hr, filtered, and concentrated. The residue was purified by flash column chromatography (EtOAc:MeOH:H2O=3:2:1, by volume) to afford UDP-GlcNAc6NH2 F5-10 in 96% yield (93 mg). 1H NMR (600 MHz, D2O) δ 7.90 (d, J=8.4 Hz, 1H), 5.89-5.93 (m, 2H), 5.48 (dd, J=6.6, 3.0 Hz, 1H), 4.30-4.32 (m, 2H), 4.20-4.23 (m, 2H), 4.08-4.15 (m, 2H), 3.99 (d, J=10.8 Hz, 1H), 3.77 (t, J=9.6 Hz, 1H), 3.45 (d, J=13.2 Hz, 1H), 3.40 (t, J=9.6 Hz, 1H), 3.11 (t, J=12.6 Hz, 1H), 2.02 (s, 3H). 13C NMR (150 MHz, D2O) δ 174.94, 166.39, 151.96, 141.84, 102.79, 94.33, 88.82, 83.29 (J=9.0 Hz), 73.92, 71.82, 69.80, 69.28, 65.30, 53.64 (J=8.9 Hz), 40.70, 22.21. HRMS (ESI) m/z calcd for C17H28N4O16P2 (M+H)− 607.1054, found 607.1068.