Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=O)=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:17]([OH:19])[C:14]2[CH:13]=[CH:12][C:11]([N:7]3[C:8]4[C:4](=[N:3][CH:2]=[N:1][CH:9]=4)[N:5]=[CH:6]3)=[CH:16][CH:15]=2)=[O:29])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ncc2[nH]cnc2n1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N(O)c1ccc(-n2cnc3ncncc32)cc1

Procedure:
The title compound can be synthesized from purine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 45.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccc(C(F)(F)F)cc1
Yield: 71.4 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol), 4-(trifluoromethyl)benzoic acid (63 mg, 0.33 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 1-hydroxybenzotriazole (46 mg, 0.34 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (110 mg, 68%) was obtained as a white powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[O:34])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=2)=O)=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[O:34])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:16]/[C:17](=[N:36]\[OH:37])/[C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)NCCNC(=O)c1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 151, step 3, N-(2-acetylamino-ethyl)-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=475.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:38](=[O:41])[CH2:39][CH3:40])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N(C)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by propanoyl chloride (32 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 108 mg, 63%. 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.52 (2 H, d, J=6.06 Hz) 7.57-7.76 (2 H, m), 7.30 (2 H, dd, J=8.46, 5.68 Hz, 7.15 (2 H, t, J=8.84 Hz), 6.52 (1 H, s), 5.05-5.43 (2 H, m), 4.46-4.62 (0.5 H, m), 4.38 (1 H, d, J=12.63 Hz), 3.85-4.00 (3.5 H, m), 3.05-3.23 (1 H, m), 2.77 (2 H, s), 2.65 (1 H, s), 2.55-2.63 (1 H, m), 2.39 (1 H, q, J=7.33 Hz), 2.29 (1 H, q, J=7.33 Hz), 1.41-1.80 (4 H, m), 0.98 (3 H, q, J=7.49 Hz); m/z (APCI+) for C26H30N5O2F 464.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1Cl)CC1C2C(=CC=C(O)C=2)CCC1NC(=O)OC(C)(C)C.[OH-].[K+].Cl[C:59]([F:69])([F:68])C(C1C=CC=CC=1)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:59]([F:69])[F:68])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCc2ccc(OC(F)F)cc2C1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Tert-butyl [1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (180 mg, 0.464 mmol, prepared analogously to tert-butyl [1-(3,4-dichlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate, cf. Example 34.2 and potassium hydroxide (1.4 g, 25 mmol) were suspended in acetonitrile (4 mL). After stirring the two phase system for 45 min at room temperature the reaction mixture was cooled to −15° C. and a solution of 2-chloro-2,2-difluoro-1-phenylethanone (442 mg, 2.32 mmol) in acetonitrile (1 mL) was added dropwise over 30 min. The reaction mixture was warmed to room temperature and then heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane, silica gel). Yield: 30 mg (0.069 mmol, 15%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:27]([CH3:29])[CH3:28])[C:24](Cl)=[O:25])=[CH:19][CH:18]=1.[C-:30]#[N:31].[Na+]>O.CCCCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:27]([CH3:29])[CH3:28])[C:24]([O:12][CH:11]([C:30]#[N:31])[C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
A 500 ml round-bottomed flask equipped with a paddle stirrer was charged with 100 mmol of 3-phenoxybenzaldehyde, 100 mmol of 2-(4-chlorophenyl)-3-methylbutanoyl chloride, 120 mmol of sodium cyanide, 10 ml of water, and 200 ml of n-heptane. The molar ratio of water to sodium cyanide was 4.64, all NaCN being dissolved. The mixture thus formed was stirred and analysed. Table VI presents the yields and purities of the desired ester after the reaction time indicated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:14])=O.CN(C)C=O>CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccccc1C(=O)Cl

Procedure:
To a stirred solution of 2-Methoxy-benzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Methoxy-benzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: C([NH:3][C@@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:8](/[CH:11]=[CH:12]/[C:13]#[C:14][CH2:15][CH3:16])[CH2:9][S:10][C@H:5]12)=O.P(Cl)(Cl)([Cl:37])=O>CO.CCOCC>[ClH:37].[NH2:3][C@@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:8](/[CH:11]=[CH:12]/[C:13]#[C:14][CH2:15][CH3:16])[CH2:9][S:10][C@H:5]12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC#C/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: CO
Solvent: CCOCC
Product: CCC#C/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Product: Cl
Reaction time: 0.67 h

Procedure:
A stirred suspension of the product of Stage (b) (633 mg) in methanol (5 ml) and ether (5 ml) was treated dropwise with phosphorous oxychloride (250 μl) with ice-bath cooling. After 90 mins the ice-bath was removed and stirring continued for 40 mins at room temperature. The solution was concentrated and added to vigorously stirred ether (75 ml). The precipitated solid was collected by filtration, washed thoroughly with ether and dried in vacuo to give the title compound as a solid (442 mg); νmax (Nujol) 2600 (NH3+), 2200 (C≡C), 1783 cm-1 (β-lactam); τ(DMSO-d6) values include 2.93 (CH=CH--C≡C), 3.74 (--CH=CH--C≡C), 4.66, 4.78 (6H,7H), 7.60 (--C≡C--CH2 --).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7](=[O:18])[CH:6]([CH3:19])[N:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[CH:30]2.FC(F)(F)C(O)=O>C(O)C(F)(F)F.C(OCC)(=O)C>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:2]3[N:11]=[CH:10][C:9]4[N:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:7](=[O:18])[CH:6]([CH3:19])[N:5]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:4]=4[N:3]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1c1ccccc1
Solvent: OCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)N(c2ccccc2)c2cnc(Nc3ccc4[nH]ncc4c3)nc2N1c1ccccc1
Temperature: 125 °C
Yield: 40 %

Procedure:
To a mixture of 2-chloro-7-methyl-5,8-diphenyl-7,8-dihydropteridin-6(5H)-one (175 mg, 0.5 mmol), 5-aminoindazole (99 mg, 0.75 mmol), in trifluoroethanol (2 mL) in a microwave reactor vial was added trifluoroacetic acid (171 mg). The vial was then sealed and heated in a microwave reactor at 125° C. for 30 minutes. The reaction mixture was then diluted with ethyl acetate (25 mL) and washed with aqueous saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4) and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (40%).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=O.[F:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:37])[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:25]=[C:26]([CH2:27][C:28]([OH:30])=O)[C:17]=3[C:16]=2[CH:15]=1.CNC.O>O1CCCC1>[F:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:37])[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:25]=[C:26]([CH2:27][C:28]([N:3]([CH3:4])[CH3:1])=[O:30])[C:17]=3[C:16]=2[CH:15]=1
Reactant: O=C(O)Cc1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Cc1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A suspension of 1.7 g (10.5 mmol) of 1,1′-carbonylbis-1H-imidazole and of 3 g (8.9 mmol) of 8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid in 300 ml of tetrahydrofuran is stirred at 40° C. for 3 h. The mixture is cooled to room temperature, 10 ml of liquefied dimethylamine are added and the mixture is stirred for 2 h. After standing overnight, 300 ml of water are added and the precipitate is collected by filtration and recrystallized from dimethylformamide. 0.8 g (2.2 mmol) of solid is obtained.
Reaction SMILES: C[O:2][P:3]([CH2:7][N:8]([S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)(=[O:12])=[O:11])[CH3:9])(=[O:6])[O:4]C.Br[Si](C)(C)C>ClCCl>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=[C:13]1[S:10]([N:8]([CH2:7][P:3](=[O:2])([OH:6])[OH:4])[CH3:9])(=[O:11])=[O:12]
Reactant: COP(=O)(CN(C)S(=O)(=O)c1cc2ccccc2s1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN(CP(=O)(O)O)S(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 550 mg (1.58 mmol) of the compound (xiv) in 10 mL of anhydrous dichloromethane at 0° C., 0.49 mL of bromotrimethylsilane was added. The mixture was warmed up to room temperature and left overnight. Dichloromethane was evaporated; the oily residue was dissolved in another 10 mL of dichloromethane, filtered, again evaporated and redissolved in 10 mL of MeOH. The methanolic solution stirred at room temperature 30 min., evaporated and the residue was triturated with a mixture ether/hexane to form a white crystalline product which was separated by filtration (390 mg, 70%): 1H NMR: (300 MHz, DMSO-D6) δH 2.88 (s, CH3), 3.21 (d, J=12.1 Hz, 2H), 7.49-7.61 (m, 2H, Ar—H), 8.01-8.17 (m, 3H, Ar—H).
Reaction SMILES: N[C@H](C(O)=[O:11])CC1C=CC=CC=1.C1(N[C@H](C(O)=O)C)CCCCC1.C1C2C(=CC=CC=2)C=CC=1N[C@H](C(O)=O)C.N[C@H](C(O)=O)CCC1C=CC=CC=1.N[CH:55]([CH2:59][CH2:60][CH2:61][CH2:62]CC)[C:56]([OH:58])=O.[CH3:65][C:66]#[N:67]>>[NH2:67][CH2:66][CH2:65][C:60]1[CH:61]=[CH:62][C:56]([OH:58])=[C:55]([OH:11])[CH:59]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCC(N)C(=O)O
Reactant: CC#N
Agent: C[C@H](NC1CCCCC1)C(=O)O
Agent: C[C@H](Nc1ccc2ccccc2c1)C(=O)O
Agent: N[C@@H](CCc1ccccc1)C(=O)O
Product: NCCc1ccc(O)c(O)c1

Procedure:
Product characterization: Reverse phase HPLC: linear gradient from 15 to 65% MeCN in 15 minutes using a Symmetry C18 column (150×4.6 mm×5 μm, 100 Å, Waters), compound 6a tr: 7.83 min, compound 6b tr: 9.36 min, compound 6c tr: 9.61 min, compound 6d tr: 11.75 min, compound 6e tr: 7.85 min, compound 6f tr: 10.58 min. (Confirmed by HPLC-MS). Mass spectrometry (HPLC-MS): compound 6a: 516.5 Da, compound 6b: 522.5 Da, compound 6c: 566.2 Da, compound 6d: 640.4 Da, compound 6e: 530.3 Da, compound 6f: 510.4 Da. Yield (after purification): compound 6a: 10.8%, compound 6b: 7.2%, compound 6c: 10.9%, compound 6d: 9.6%, compound 6e: 9.1%, compound 6f: 8.2%.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:6]1[C:22]2[CH2:21][C@H:20]3[N:23]([CH2:25][CH2:26][C@@:12]45[C@H:19]3[CH:18]=[CH:17][C@H:15]([OH:16])[C@@H:13]4[O:14][C:10]([C:11]=25)=[C:8](O)[CH:7]=1)[CH3:24].O.CN1[C@@H]2CC3=CC=C(O)C4O[C@H]5C(CC[C@@H]2[C@]5(C=43)CC1)=O>CCO.C(#N)C>[CH3:24][N:23]1[C@@H:20]2[CH2:21][C:22]3=[CH:6][CH:7]=[C:8]([O:2][S:1]([OH:5])(=[O:4])=[O:3])[C:10]4[O:14][C@H:13]5[C:15]([CH2:17][CH2:18][C@@H:19]2[C@:12]5([C:11]=43)[CH2:26][CH2:25]1)=[O:16]
Reactant: O=S(=O)(O)O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: CN1CC[C@]23c4c5ccc(OS(=O)(=O)O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 81 °C
Yield: 48.3 %

Procedure:
Morphine sulfate (30.0 g), water (30 mL), and EtOH (60 mL) were added to a reaction flask. The reaction mixture was agitated to form a suspension. The reactor was flushed with nitrogen and the reaction mixture was kept under nitrogen throughout the reaction. The reaction flask was charged with the catalyst (RuCl3.xH2O, 0.60 g), and the mixture was heated to reflux (80-82° C.) for 16 h. HPLC analysis indicated that 94.5% (area) hydromorphone was formed. Acetonitrile (30 mL) was added to the reaction mixture and the mixture was heated for 1 h. EtOH (90 mL) was added to the mixture, which was then cooled to 15° C. for 2 h. The mixture was filtered, and the solid was washed with 95% EtOH (2×15 mL). The solid was dried under vacuum at 65° C. for 18 h to give 13.8 g of hydromorphone sulfate as solids (purity>99% area).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([Br:19])=[CH:17][CH:18]=2)[CH2:9]1)=O)(C)(C)C.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[N:15][CH:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)nc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc(OC2CNC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-(6-Bromo-pyridin-3-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (1.08 g, 3.28 mmol) in DCM (30 mL), add TFA (10 mL). Let the mixture be stirred at room temperature for 2 hrs. LC-MS and TLC show reaction was complete. So evaporate all the solvent and excessive TFA. The residue brown solid 5-(Azetidin-3-yloxy)-2-bromo-pyridine trifluoro-acetic acid salt (1.06 g, 95% yield) was used directly for next step.
Reaction SMILES: [CH3:1][P:2]([O:6][CH3:7])(=[O:5])[O:3][CH3:4].[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].CC[O:15][CH2:16][CH3:17]>O1CCCC1>[O:15]=[C:16]([CH2:17][CH2:8][C:9]#[C:10][CH3:11])[CH2:1][P:2]([O:6][CH3:7])(=[O:5])[O:3][CH3:4]
Reactant: CCOCC
Reactant: [Li]CCCC
Reactant: COP(C)(=O)OC
Solvent: C1CCOC1
Product: CC#CCCC(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.2 g of dimethyl methanephosphonate in 52 ml of tetrahydrofuran was added at -78° C. 155 ml of n-butyl lithium (1.59N) and the mixture was stirred for 25 mins at -78° C. To the mixture was added at -78° C. a solution of 1.6 g of the above-mentioned ester in 3.2 ml of tetrahydrofuran. The mixture was stirred for 15 mins and for one hour at room temperature. After addition of 100 ml of ether to the reaction mixture, the mixture was washed with 30 ml of aqueous saturated solution of oxalic acid, 50 ml of water and 40 ml of aqueous saturated solution of sodium chloride. The washed mixture was dried and concentrated to give an oily material. The oily material was distilled under reduced pressure to yield 2.2 g of dimethyl 2-oxo-hept-5-yne-phosphonate (143° to 146° C./0.7 mmHg).
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:5][CH:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[CH3:17][CH2:18]N(CC)CC.O=S(Cl)Cl>C(O)C>[CH2:17]([O:15][C:14]([C:2]1([NH2:1])[CH2:5][CH:4]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:3]1)=[O:16])[CH3:18]
Reactant: CCN(CC)CC
Reactant: NC1(C(=O)O)CC(OCc2ccccc2)C1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C1(N)CC(OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a reactor charged with 1-amino-3-benzyloxy-cyclobutanecarboxylic acid (202.7 g, 0.94 mol) was added ethanol (7.0 l); the mixture was stirred at ambient temperature with mechanical stirring under an N2-atmosphere for 18 minutes. To the reaction mixture was added Et3N (350 ml, 2.51 mol), cooled to −1.8° C. and SOCl2 (170 ml, 2.4 mol) was added carefully keeping the reaction temperature <10° C. The reaction mixture was refluxed for 20 hours 10 minutes (reaction progress followed by TLC monitoring). Upon complete reaction the reaction mixture was cooled to 20° C. and evaporated in vacuo at 35° C. The weight of crude product including salts was 631.2 g.
Reaction SMILES: [OH:1][B:2]([OH:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl.[CH2:14](O)[CH3:15]>O1CCOCC1>[CH2:14]([O:8][C:7]([C:6]1[CH:10]=[CH:11][C:3]([B:2]([OH:12])[OH:1])=[CH:4][CH:5]=1)=[O:9])[CH3:15]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(B(O)O)cc1
Reaction time: 1.5 h

Procedure:
A suspension of 4-(dihydroxyboryl)benzoic acid (5.0 g, 30.13 mmol) in ethanol (16.0 mL) was treated with 4N HCl in dioxane (34.0 mL), heated to reflux, stirred for 1.5 hours, and concentrated. The concentrate was partitioned between water (150.0 mL) and diethyl ether (100.0 mL) and the aqueous layer was extracted with diethyl ether (2×100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (APCI) m/e 194 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.07 (m, 2H), 7.81 (m, 2H), 4.41 (q, 2H), 1.41 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:30](=[O:32])[CH3:31])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.CO.[OH-].[Na+]>C1COCC1.C(Cl)Cl.Cl>[C:30]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:6]=1)[CH2:25][C:26]([CH3:28])([CH3:29])[CH3:27])(=[O:32])[CH3:31]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC(C)(C)C)C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(CC(C)(C)C)C(C)=O

Procedure:
(2′-{[Acetyl-(2,2-dimethyl-propyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.152 g, 0.33 mmol) was dissolved in THF (1.5 mL), MeOH (1.2 mL), and aqueous 1N NaOH (0.72 mL), and the mixture was stirred at room temperature for 4 hours. Once no starting material was seen by analytical LCMS, the mixture was diluted with CH2Cl2 and aqueous 1N HCl, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 452.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Cl:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[C:36](Cl)[N:35]=[CH:34][N:33]=1>CC#N>[Cl:31][C:32]1[N:33]=[CH:34][N:35]=[C:36]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=2)[C:37]=1[N+:38]([O-:40])=[O:39]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ncnc(Cl)c2[N+](=O)[O-])c2ccccc12
Yield: 34.2 %

Procedure:
To a stirred solution of tert-butyl (4-hydroxynaphthalen-1-yl)carbamate (20.0 g, 73.0 mmol) in MeCN (200 mL) under N2 was added DBU (13 mL, 87 mmol) and after 1 hr at RT the resulting mixture was treated dropwise with a solution of 4,6-dichloro-5-nitropyrimidine (15.5 g, 80.0 mmol) in MeCN (150 mL). After 2.5 hr at RT the mixture was evaporated in vacuo and the residue was triturated with DCM (150 mL) and isohexane (200 mL). The insoluble residue was separated and set aside and the triturant was evaporated in vacuo. The residue so obtained was partitioned between DCM (200 mL) and sat aq NaHCO3 (200 mL) and the organic layer was separated and evaporated in vacuo. The residue was triturated with EtOAc to give an off white solid (batch 1). The EtOAc triturant was concentrated in vacuo to ˜20 mL and the precipitate which formed was isolated by filtration and washed with EtOAc to afford a second batch of same material, also as an off white solid. The first and second batches of product were combined to afford tert-butyl (4-((6-chloro-5-nitropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (10.4 g, 34%); Rt 2.69 min (Method 2); m/z 439/441 (M+Na)+ (ES+).