Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][CH2:21][C:22]([N:27]([CH3:26])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:23])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Reactant: CNc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1)c1ccccc1

Procedure:
As described for example 171, [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid, N-methyl-benzenamine, iPr2NEt, and HATU are reacted to afford the product. LC-MS: 452 (M++1). 1H NMR (CDCl3): δ 3.0–3.2 (m, 4H), 3.3 (s, 3H), 3.6–3.76 (m, 4H), 3.76–3.9 (d, 2H), 4.8–5.0 (s, 2H), 5.6–5.8 m, 1H), 6.1–6.2 (s, 1H), 7.13–7.18 (m, 1H), 7.2–7.25 (m, 2H), 7.36–7.48 (m, 3H), 7.6 (d, 1H), 7.68–7.72 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][N+:17]([CH3:20])=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[BH4-].[Na+]>O.CCO.C(Cl)Cl.[Fe]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[n+]1ccc(-c2cc([N+](=O)[O-])ccc2C(C)(C)C)cc1
Agent: [Fe]
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CN1CC=C(c2cc(N)ccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(2-tert-Butyl-5-nitrophenyl)-1-methylpyridinium (2.1 g, 7.8 mmol, Step C) was added to a 100 mL round-bottom flask and dissolved in a 10% H2O/EtOH mixture. To the flask iron dust (1.31 g, 23.4 mmol, 3 eq) and NH4Cl (460 mg, 8.6 mmol, 1.1 eq) were added. The flask was placed in a 100° C. sand bath and heated to reflux. After 2 h, the solution was cooled to RT and filtered through a pad of Celite®. The resulting solution was stripped down to a yellow solid and redissolved in MeOH (20 mL, anhydrous). The solution was cooled to 0° C. by placing it in an ice bath and slowly adding NaBH4 (450 mg, 11.7 mmol, 1.5 eq). After addition of the NaBH4, the solution was cooled to RT and stirred for 30 min. The solvent was stripped-off under vacuum and the solid was redissolved in CH2Cl2 and filtered. The solution was stripped-off under vacuum to afford of an amorphous clear yellow solid. MS (ES+): 245.2 (M+H)+. Calc'd for C16H24N2: 244.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH2:7][CH:6]2[CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH3:19])=[O:17]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH:6]2[CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH3:19])=[O:17]
Reactant: CNC(=O)CCCC1CN=Cc2ccc(OC)cc21
Agent: [Pd]
Solvent: CO
Product: CNC(=O)CCCC1CNCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound obtained in Example 1 (54 mmol), in the form of a base, is dissolved in 50 ml of methanol and then palladium-on-carbon (150 mg) is added to the solution. The reaction mixture is stirred at ambient temperature and under hydrogen for 4 hours. After removal of the palladium-on-carbon by filtration, the organic phase is evaporated under reduced pressure. The oil obtained is purified by chromatography on silica gel to yield the title product in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7])[CH3:2].[CH:9]1([N:12]=[C:13]=[O:14])[CH2:11][CH2:10]1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:7][CH2:6][C:5]([O:8][C:13](=[O:14])[NH:12][CH:9]1[CH2:11][CH2:10]1)=[N:4][O:3][CH2:1][CH3:2]
Reactant: O=C=NC1CC1
Reactant: CCONC(=O)CCl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CCON=C(CCl)OC(=O)NC1CC1
Temperature: 25 °C

Procedure:
N-Ethoxychloroacetamide (13.7 grams; 0.1 mole), benzene (60 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. Cyclopropylisocyanate (10 grams; 0.12 mole) dissolved in benzene (20 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-cyclopropylcarbamoyloxy)-2-ethoxyiminoethane.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([O:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:15]([I:17])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]3[C:21](=[O:23])[CH2:20][CH2:19][O:18][C:14]=3[C:15]([I:17])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2cc(I)c(OCCC(=O)O)cc2CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(=O)CCO3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
Into a 100 ml flask, the product from step (e) (312 mg, 0.72 mmol) dissolved in DCM (20 ml) was added. The solution was cooled to 0° C., and oxalyl chloride (94 μL, 1.07 mmol) was added, followed by 2 drops of DMF. After 30 minutes, volatiles were evaporated in vacuo and the residue was dissolved in fresh DCM (20 ml) and cooled to 0° C. Aluminum chloride (386 mg, 2.88 mmol) was then added and the reaction mixture stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl, and the organic layer was extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexanes) gave the sub-title compound as a light yellow solid (170 mg). 1H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H); 4.56 (t, J=6.3 Hz, 2H); 4.12 (q, J=7.2 Hz, 2H); 3.68-3.51 (m, 6H); 2.85 (t, J=6.6 Hz, 4H); 1.23 (t, J=7.2 Hz, 3H); MS: ESI (positive): 416 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:8][C:7](=[O:20])[C:6]([O:21][CH3:22])=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].O>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:8][C:7](=[O:20])[C:6]([O:21][CH3:22])=[CH:5]2
Reactant: COc1cc2cc(N)c(OCc3ccccc3)cc2oc1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc2cc(OC)c(=O)oc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-amino-7-benzyloxy-3-methoxychromen-2-one (0.880 g, 2.96 mmol) and K2CO3 (0.820 g, 5.92 mmol) in DMF (50 mL) is added methyl bromoacetate (0.36 mL, 3.85 mmol). The mixture is stirred at 60° C. for 3 h. Additional methyl bromoacetate (0.14 mL) is added, and after 3 h, the mixture is allowed to cool to ambient temperature and poured into water and extracted with EtOAc. The organic layer is washed with water (3×), sat. NaCl, and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using hexanes/EtOAc (7:1) to afford (7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-ylamino)-acetic acid methyl ester as a yellow solid: 1H NMR (CDCl3) δ 7.44-7.33 (m, 5H), 6.79 (s, 1H), 6.75 (s, 1H), 6.36 (s, 1H), 5.13 (s, 2H), 3.95 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H); (M+H)+=370.
Reaction SMILES: [CH2:1]([CH:4]1[C:9]2[C:10](=[O:15])[CH:11]=[CH:12][C:13](=[O:14])[C:8]=2[CH2:7][CH:6]([C:16]([O:18][CH3:19])=[O:17])[O:5]1)[CH2:2][CH3:3].O([CH:24]=[CH:25][CH:26]=[CH2:27])C(C)=O>>[CH2:1]([CH:4]1[C:9]2[C:10](=[O:15])[C:11]3[C:12]([C:13](=[O:14])[C:8]=2[CH2:7][CH:6]([C:16]([O:18][CH3:19])=[O:17])[O:5]1)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:2][CH3:3]
Reactant: C=CC=COC(C)=O
Reactant: CCCC1OC(C(=O)OC)CC2=C1C(=O)C=CC2=O
Product: CCCC1OC(C(=O)OC)CC2=C1C(=O)c1ccccc1C2=O
Yield: 71.9 %

Procedure:
The 1-propyl-3methoxycarbonyl-3,4,5,8-tetrahydro-5,8-dioxo-1H-benzo-[2,3-c]-pyran described in step 3 (76 mg, 0.288 mmol) was stirred with 1-acetoxyl-1,3-butadiene (136 μl, 1.152 mmol) at 45° C. for 20 hours. Solvent was evaporated and the crude product was chromatographed (toluene/ethyl acetate ~100/15, v/v) to give the titled compound (65 mg, 71.9%). m.p. 111.5°-113.6° C. 1H NMR (CDCl3, 250 MHz, Bruker), δ: 0.97 (3H, tr, J=6.7 Hz, CH3), 1.45-1.85 (4H, m, CH2CH2) 2.78 (1H, ddd, J=19.9 Hz, 10.4 Hz, 1.2 Hz, 4-Ha), 2.97 (1H, dd, J=19.9 Hz, 5.4 Hz, 7-He), 3.80 (3H, s, OCH3), 4.51 (1H, dd, J=10.4 Hz, 5.4 Hz, 3-H), 5.04 (1H, br d, J=8.5 Hz, 1-H), 7.72 (2H, m, 7, 8-ArH), 8.07 (2H, m 6, 9-ArH).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg]Br>C(OCC)C>[CH2:1]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:9][C:10]([CH3:23])([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(C)(C)C(C)(O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 2.5 °C
Reaction time: 72 h
Yield: 71.3 %

Procedure:
(1.6 g, 5.4 mmol) 1-Dibenzylamino-3,3-dimethyl-butan-2-one (Example 19, step 1) was dissolved in diethylether (20 ml) and cooled to 0-5° C. Methylmagnesium bromide (3M in diethylether) (2.2 ml, 6.5 mmol, 1.2 equiv.) was added drop wise at 0-5° C. and the mixture was stirred for 72 hours at room temperature. The reaction mixture was extracted with sat. NH4C1-solution and two times EtOAc. The organic layers were extracted with water, dryed over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (50 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired (RS)-1-dibenzylamino-2,3,3-trimethyl-butan-2-ol (1.2 g, 71% yield) was obtained as a yellow oil, MS: m/e=312.4 (M+H+).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:23]1[C:24]2[N:31]=[CH:30][N:29]([CH:32]([CH3:34])[CH3:33])[C:25]=2[N:26]=[N:27][CH:28]=1.P([O-])([O-])[O-].[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:23]3[C:24]4[N:31]=[CH:30][N:29]([CH:32]([CH3:34])[CH3:33])[C:25]=4[N:26]=[N:27][CH:28]=3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B(O)O)ccc2F)cc1
Reactant: CC(C)n1cnc2c(Cl)cnnc21
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [K+]
Agent: [O-]P([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C(C)C)ccc2F)cc1
Temperature: 100 °C
Yield: 27 %

Procedure:
A stirred solution of 4′-ethylsulfonyl-6-fluorobiphenyl-3-yl-boronic acid (Preparation 65, 30 mg, 0.097 mmol), 4-chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6, 15 mg, 0.077 mmol) and potassium phosphite (33 mg, 0.154 mmol) in dioxane (3 mL) and water (0.7 mL) was degassed with argon for 10 minutes followed by the addition of tricyclohexylphosphine (1.72 mg, 0.006 mmol) and tris(dibenzylideneacetone)palladium(0) (2.82 mg, 0.003 mmol). The resulting mixture was heated at 100° C. for 16 hours. The reaction mixture was filtered to remove inorganics and the filtrate was concentrated in vacuo to remove the volatiles. Purification of the crude residue by preparative TLC eluting with 2% MeOH in DCM afforded the title compound as off white solid in 27% yield, 9 mg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>C1COCC1.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]>[Cl:9][C:3]1[C:2]([NH2:1])=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][N:4]=1
Reactant: C1COCCN1
Reactant: Nc1cc(Br)cnc1Cl
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(N2CCOCC2)cnc1Cl
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-amino-5-bromo-2-chloropyridine (2.0 g, 9.7 mmol), morpholine (1.3 mL, 14.9 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (0.37 g, 0.8 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.36 g, 0.39 mmol) in dry THF (15.0 mL) was degassed by nitrogen. To this mixture was added 1.0M lithium bis(trimethylsilyl)amide in THF (25 mL) dropwise, and the resulting reaction was heated to 60° C. After 2.5 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-20% EtOAc in hexanes) to afford an off-white solid as 2-chloro-5-morpholinopyridin-3-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.35 (1H, d, J=2.7 Hz), 6.67 (1H, d, J=2.7 Hz), 5.33 (2H, s), 3.79 (4H, m), 3.11 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14](Cl)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([F:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([F:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Cl)cc1OC
Solvent: Cc1ccccc1
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)F)cc2)cc1OC

Procedure:
10.00 g (25.6 mmol) of 2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl chloride were mixed with 300 ml of toluene, 4.49 g (25.6 mmol) of 4-aminobenzenesulfonyl fluoride were added and the mixture was heated under reflux for 4 h. After cooling the precipitated solid was filtered off with suction and washed with toluene. 11.71 g (87%) of the title compound having a melting point of 216-219° C. were obtained.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:13]=2[C:12]=1[C:26]1[C:27]([CH3:36])=[C:28]2[C:33](=[CH:34][CH:35]=1)[O:32][CH2:31][CH2:30][CH2:29]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:13]=2[C:12]=1[C:26]1[C:27]([CH3:36])=[C:28]2[C:33](=[CH:34][CH:35]=1)[O:32][CH2:31][CH2:30][CH2:29]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2c3c(sc2c(=O)n1C)CCCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3sc4c(c23)CCCC4)ccc2c1CCCO2
Temperature: 65 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of compound methyl 2-(tert-butoxy)-2-(2-methyl-4-(5-methylchroman-6-yl)-1-oxo-1,2,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-3-yl)acetate (20 mg, 0.04 mmol) in Tetrahydrofuran (THF) (3 mL) and Water (3 mL) was added lithium hydroxide hydrate (20 mg, 0.48 mmol). The mixture was stirred at 65° C. for overnight. The reaction was cooled to room temperature, and solvent was removed by concentrated under reduced pressure to afford an oil, which was acidified with 1N aqueous HCl to pH=3, the resulting precipitate was collected by filtration to afford title product (11.5 mg, 59% yield) as white solid. 1H NMR: (Methanol-d4, 400 MHz) δ 0.99, 1.15 (s, total, 9H), 1.35˜1.52 (m, 2H), 1.69˜1.72 (m, 4H), 1.86 (s, 3H), 2.08˜2.11 (m, 2H), 2.65˜2.75 (m, 2H), 2.85˜2.89 (m, 2H), 3.77, 3.80 (s, total, 3H), 6.72˜6.78 (m, 1H), 6.98˜7.27 (m, 1H). LCMS (m/z) ES+=496 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[OH-].[K+]>O.C(#N)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: ClC1=NN(c2cccnc2)CC1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 69.1 %

Procedure:
Crude 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (54.1 g, 232 mmol, 77.8% purity) was introduced into a 3 L three-neck round bottom flask. Water (530 mL) was then added. The mixture was heated to 60° C. and a potassium hydroxide solution (165 g, 2940 mmol) in water (500 mL) was added. The dark brown mixture was heated to 90° C. A potassium ferricyanide solution (253 g, 768 mmol) in water (700 mL) was added slowly over 30 minutes leading to brown-red mixture. The mixture was stirred at 90° C. for another 1.5 hours. The reaction mixture was cooled to below 45° C. and filtered. The filter cake was washed with water (300 mL) affording crude product as a brown solid. The crude product was then dissolved in acetonitrile (400 mL) and filtered. The organic filtrate was dried and concentrated to afford the title product as a brown solid (28.8 g, 69%, 94% purity).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:24][C:23]([O:20][C@@H:14]1[C@@H:13]2[O:12][C:11]3=[C:10]([O:21][CH3:22])[CH:9]=[CH:8][C:7]4=[C:6]3[C@:5]32[CH2:4][CH2:3][N:2]([CH3:1])[C@H:18]([CH2:19]4)[C@@H:17]3[CH:16]=[CH:15]1)=[O:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2c3c1O[C@H]1[C@@H](OC(C)=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 12 h
Yield: 99.4 %

Procedure:
A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g, 180.2 mmol), triethylamine (18.25 g, 180.2 mmol) and 4-dimethylaminopyridine (0.5 g) in dry ethyl acetate (620 ml) was stirred at rt. under nitrogen for 12 hr, added saturated aqueous sodium bicarbonate solution until no acetic anhydride detected. The organic portion was separated, washed with water (3×120 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 6-acetylcodeine as white solids (34.0 g, 99% yield). IR (KBr)(ν, cm-1): 1725 (st, sharp, 3-AcO); NMR (δH)(CDCl3): 6.66 (1, d, J, 8.2, 2-H), 6.53 (1, d, J, 8.2, 1-H), 5.63 (1, ddd, J, 10.0, 2.4 & 1.0, 7-H), 5.42 (1, dt, J, 9.9 & 2.3, 8-H), 5.22-5.51 (1, m, 6-H), 5.06 (dd, J, 6.7 & 1.0, 5-H, 3.85 (3, s, 3-OCH3), 3.39 (1, dd, J, 6.0 & 3.3, 9-H), 3.03 (1, d, Jjam, 18.6, 10-Hβ), 2.78 (1, dd, J, 5.2 & 2.6, 14-H), 2.63 (1, dd, J, 11.9 & 4.6, 16-Ha), 2.45 (3, s, N--CH3), 2.40 (1, td, J, 12.0 & 3.8, 16-He), 2.33 (1, dd, J, 18.5 & 6.0, 10-Hα), 2.15 (3, s, 6-OAc), 2.06 (1, td, J, 12.0 & 5.0, 15-Ha) and 1.85 (1, dm, J, 12.0, 15-He).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.N1C=CC=CC=1.O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1)(=[O:31])=[O:30]
Reactant: Nc1ccc(SCC(=O)O)c2ccccc12
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)CSc1ccc(NS(=O)(=O)c2cccs2)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
32.5 mg 21 was dissolved in 1 ml THF, to which at 0° C. was added 0.28 ml pyridine solution (0.5 M in THF) followed by 0.5 ml water. Upon stirring, 25.6 mg thiophene-2-sulfonyl chloride in 1 ml THF was added dropwise. Additional 0.28 ml pyridine solution was added. The resulting solution was stirred vigorously at 0° C. and slowly warmed to room temperature. After 4 hours, the organic solvent was removed. The aqueous portion was diluted with 10 ml water and acidified at 0° C. with NaHSO4 solution (0.5 M). The mixture was extracted with ethyl acetate. The organic phase was combined, washed with water and brine and dried over Na2SO4. After removal of Na2SO4, the organic phase was concentrated and the crude product was purified via flash chromatography (5 g silica gel, DCM/CH3OH=20:1) affording 31 mg (58.4%) grey solid. 1H NMR (400 MHz, CD3CN) δ 8.36 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.68 (dd, J=5.0, 1.3 Hz, 1H), 7.62 (ddd, J=8.3, 6.8, 1.2 Hz, 1H), 7.54 (m, 2H), 7.43 (dd, J=3.8, 1.3 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.04 (dd, J=5.0, 3.8 Hz, 1H), 3.78 (s, 2H). LRMS (ES−) 378 (M−H)−; HRMS (ES−) m/z calculated for C16H12NO4S3 (M−H)− 377.9934, found 377.9937.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:13]([NH:18][CH2:19][C@H:20]([C@H:22]2[C@H:29]3[C@H:25]([O:26][C:27]([CH3:31])([CH3:30])[O:28]3)[CH2:24][CH2:23]2)[OH:21])=[N:14][CH:15]=[CH:16][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:13]([NH:18][CH2:19][C:20]([C@H:22]2[C@H:29]3[C@H:25]([O:26][C:27]([CH3:31])([CH3:30])[O:28]3)[CH2:24][CH2:23]2)=[O:21])=[N:14][CH:15]=[CH:16][N:17]=1
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CNc3nccnc3Cl)CC[C@H]2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@@H](CC[C@H]2C(=O)CNc2nccnc2Cl)O1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.75 mL, 31.6 mmol, 3.0 equiv) in DCM (35 mL) was added dropwise to DMSO (3.00 mL, 42.1 mmol, 4.0 equiv) in DCM (35 mL) at −78° C. After 30 minutes, (S)-2-(3-chloropyrazin-2-ylamino)-1-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclo-penta[d][1,3]dioxol-4-yl)ethanol (2-7) (3.30 g, 10.5 mmol, 1 equiv) in DCM (35 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 hour, at which point triethylamine (6.60 mL, 47.3 mmol, 4.5 equiv) was added. The cooling bath was removed, and after 30 minutes the reaction mixture was concentrated. The resulting yellow residue was purified via flash chromatography on a silica gel column (ethyl acetate/hexanes) to yield 2-(3-chloropyrazin-2-ylamino)-1-((3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl)ethanone (2-8) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.92 (d, J=2.7 Hz, 1H); 7.63 (d, J=2.7 Hz, 1H); 5.93 (s, 1H); 4.80 (d, J=5.7 Hz, 1H); 4.73 (t, J=5.4 Hz, 1H); 4.47 (dd, J=19.7, 5.0 Hz, 1H); 4.31 (dd, J=19.7, 4.7 Hz, 1H); 3.17 (d, J=8.1 Hz, 1H); 2.25-2.17 (m, 1H); 1.93-1.84 (m, 2H); 1.78-1.68 (m, 1H); 1.47 (s, 3H); 1.32 (s, 3H). LRMS m/z (M+H) 312.0 found, 312.1 required.