Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][C:34]([C:30]3[NH:31][CH:32]=[CH:33][N:29]=3)=[CH:42][CH:41]=1)=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: O=C(O)c1ccc(-c2ncc[nH]2)cc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc(-c3ncc[nH]3)cc2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
3-{[4-(1H-Imidazol-2-yl)-benzoylamino]-methyl}-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 4-(1H-imidazol-2-yl)-benzoic acid. 1H NMR (DMSO-d6) δ ppm 8.90 (d, J=8.1 Hz, 1H) 8.77 (t, J=4.6 Hz, 1H) 7.91-8.00 (m, 3H) 7.83-7.89 (m, 2H) 7.52-7.59 (m, 3H) 7.47 (s, 2H) 7.43 (dd, J=6.7, 2.7 Hz, 2H) 4.46 (d, J=4.8 Hz, 2H) 3.40 (s, 3H). MS calcd. for C28H20F3N5O4 [(M+H)+] 548.1, obsd. 548.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:14][O:15][CH3:16]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:14][O:15][CH3:16])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COCCl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCOc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
A solution of 3-nitrophenol (5.00 g, 36 mmol) in 100 mL of anhydrous DMF at 0° C. was treated with NaH (2.16 g 54 mmol) in several portions over 5 min. After 10 min, Bu4NI (1.33 g, 3.6 mmol) was added and followed by dropwise addition of ClCH2OCH3 (4.1 mL, 54 mmol). The reaction mixture was stirred at 25° C. for 21 h before being quenched with the slow addition of 100 mL of H2O. The aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, washed with 10% aqueous NaHCO3 (100 mL), H2O (4×50 mL), dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography (SiO2, 4×15 cm, 10% EtOAc/hexane) provided 11 (5.83 g, 89%) as a pale yellow solid: 1H NMR (CDCl3, 250 MHz) δ 7.86 (m, 2H), 7.34 (m, 2H), 5.22 (s, 2H), 3.46 (s, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 157.5, 148.9, 129.9, 122.6, 116.5, 110.9, 94.4, 56.1; IR (film) νmax 3099, 2959, 2829, 1619, 1584, 1537, 1349, 1237, 1153, 1081 cm−1; FABHRMS (NBA/NaI) m/z: 206.0430 (C8H9NO4+Na+ requires 206.0429). Anal. Calcd for C8H9NO4: C, 52.46; H, 4.95; N, 7.65. Found: C, 52.37; H, 4.89; N, 7.61.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:23]=1)=[O:21].BrCC(C1C=CC(OC(F)F)=C(OCC2CC2)C=1)=O>>[CH2:1]([O:8][CH2:9][C:10](=[O:17])[CH:11]([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:23]=1)=[O:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Reactant: COc1ccc(C(=O)CBr)cc1OC1CCCC1
Agent: O=C(CBr)c1ccc(OC(F)F)c(OCC2CC2)c1
Product: CCOC(=O)C(CC(=O)c1ccc(OC)c(OC2CCCC2)c1)C(=O)COCc1ccccc1
Yield: 75 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 45-(b) except for using 7.65 g (32.4 mmol) of ethyl 4-benzyloxy-3-oxobutyrate in place of ethyl 4-(4-methoxybenzyloxy)-3-oxobutyrate, and using 8.45 g (27 mmol) of 2-bromo-1-(3-cyclopentoxy-4-methoxyphenyl)ethanone obtained in Reference example 47-(a) in place of 2-bromo-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethanone, respectively, whereby 9.49 g of the title compound was obtained as a yellowish oil. (Yield: 75%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].CC(C)([O-])C.[K+].Cl[C:18]1[C:23]([CH3:24])=[C:22]([Cl:25])[CH:21]=[C:20]([CH3:26])[N:19]=1.[Cl-].[NH4+]>[Cu]I.N1C=CC=CC=1>[Cl:25][C:22]1[CH:21]=[C:20]([CH3:26])[N:19]=[C:18]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:23]=1[CH3:24]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Cc1cc(Cl)c(C)c(Cl)n1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Product: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36726.6 %

Procedure:
To a 2 liter flask equipped with a mechanical stirrer, a reflux condenser and a nitrogen inlet was charged 250 ml of pyridine. The flask was cooled in an ice bath and charged with 42.5 g (0.312 mmol) of 2,4,6-trimethylphenol and 35.1 g (0.313 mol) of potassium t-butoxide. The flask was warmed to room temperature and charged with 50.0 g (0.284 mol) of 2,4-dichloro-3,6-dimethylpyridine and 13.5 g (0.071 mol) of copper (I) iodide. The reaction mixture was heated to reflux for two hours and then cooled to 0° C. The reaction was diluted with 500 ml of hexanes, then mixed with 1000 ml of saturated ammonium chloride (NH4Cl). After warming to room temperature, the mixture was stirred overnight. The layers were separated and the organic layer was washed with 3×125 ml of 1M ammonium hydroxide (NH4OH), 2×250 ml of 3N sodium hydroxide (NaOH), 1×250 ml of 1N hydrochloric acid (HCl) and 1×250 ml of water. After drying over sodium sulfate (Na2SO4), the solids were removed by filtration and washed with hexane. The filtrate was concentrated under vacuum to a brown oil. The residue was mixed with 250 ml methanol and stirred overnight. The resulting slurry was filtered under vacuum. The off-white solids were washed with methanol then dried to obtain 31.6 g (40.4%) of the title compound.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[O:13]=[C:14]1[N:20]2[CH2:21][CH2:22][C@H:19]2[C:18]2=[C:23]([C:26]([OH:28])=O)[N:24]=[CH:25][N:17]2[C:16]2[CH:29]=[CH:30][S:31][C:15]1=2.N>CN(C)C=O>[O:13]=[C:14]1[N:20]2[CH2:21][CH2:22][C@H:19]2[C:18]2=[C:23]([C:26]([NH2:3])=[O:28])[N:24]=[CH:25][N:17]2[C:16]2[CH:29]=[CH:30][S:31][C:15]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
7.65 g (47 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 12.43 g (45 mmol) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid in 70 ml of dimethylformamide. The resulting pale brown solution was heated to 50° for 45 minutes. Subsequently, the solution was cooled to room temperature and 10.9 ml of aqueous ammonia solution were added dropwise. After stirring for a further 30 minutes the reaction mixture was poured into 100 ml of ice-water and the resulting precipitate was filtered off and rinsed with water, ethanol and subsequently with ether. After drying at 70°/10 Torr there were obtained 11.0 g (89%) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxamide as colourless crystals of m.p. >250°.
Reaction SMILES: [CH3:1][C:2]1[C:3](I)=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[N+:13]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18])([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.[Cu]>[N+:13]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:3]1[C:2]([CH3:1])=[C:10]([CH3:11])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])([O-:15])=[O:14]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(C(=O)O)c(I)c1C
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)O)c(Nc2ccccc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
10 g of 3,4-dimethyl-2-iodobenzoic acid, 6 g of 2-nitroaniline, 250 mg of powdery copper and 25 g of potassium carbonate were added to N,N-dimethylformamide and heated under reflux while stirring for 2 hr. Then the reaction mixture was cooled to room temperature and diluted with water. After adjusting the pH value thereof to pH 4 with conc. hydrochloric acid, it was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 2.5 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][O:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CNC1(NC)CCCCC1>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:8]2[CH:9]=[CH:10][C:6]([O:5][CH2:4][C:3]3[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=3[Br:1])=[N:7]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(I)cc1
Reactant: Brc1ccccc1COc1cc[nH]n1
Agent: CNC1(NC)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1ccc(-n2ccc(OCc3ccccc3Br)n2)cc1
Temperature: 100 °C
Yield: 19.2 %

Procedure:
A suspension consisting of 3-(2-bromobenzyloxy)-1H-pyrazole (0.20 g, 0.91 mmol), 4-chloroiodobenzene (0.17 g, 0.73 mmol), Cul (9 mg, 0.05 mmol), K2CO3 (0.05 mg, 0.38 mmol) and N,N′-dimethylcyclohexanediamine (72 μL, 0.46 mmol) in 2 mL of toluene was heated to 100° C. for 20 h. The mixture was then cooled to room temperature and directly subjected to column chromatography (SiO2, hexane/ethyl acetate=100:0 to 80:20). The product was obtained as a colorless solid (140 mg, 0.14 mmol, 53% yield).
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:13]([N:15]1[C:19]([S:20][CH2:21][C:22]2[CH2:23][S:24][C@@H:25]3[C@H:45]([NH:46]C(=O)CC4SC=CC=4)[C:44](=[O:55])[N:26]3[C:27]=2[C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[N:18][N:17]=[N:16]1)[CH3:14].CO>C(Cl)Cl>[NH2:46][C@@H:45]1[C:44](=[O:55])[N:26]2[C:27]([C:28]([O:30][CH:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])=[C:22]([CH2:21][S:20][C:19]3[N:15]([CH2:13][CH3:14])[N:16]=[N:17][N:18]=3)[CH2:23][S:24][C@H:25]12
Reactant: CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
A solution of pyridine (2.13ml) in dry methylene dichloride (10ml) was added, over 5 minutes, to a stirred suspension of phosphorus pentachloride (5.47g) in methylene dichloride (20ml). After 10 minutes, the suspension was cooled to 0°, and a solution of diphenylmethyl 3-(1-ethyltetrazol-5-yl-thiomethyl)-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (8.3g) in methylene dichloride (40ml) was added, dropwise, over 10 minutes. The resulting solution was stirred for a further 1 hour, during which time the temperature was allowed to rise to ca. 23°, and then added, over 10 minutes, to a stirred and cooled (0°) mixture of methanol (30 ml) and methylene dichloride (60ml). After 15 minutes, N-hydrochloric acid (50ml) was added, and stirring continued for a further 10 minutes. The organic phase was separated, stirred for 30 minutes with saturated sodium bicarbonate (200ml), and washed with saturated sodium bicarbonate and brine and treated with some charcoal. The suspension was filtered through a kieselguhr pad, the filtrate dried and evaporated to an oily solid (7.47 g). This material was triturated with ethyl acetate (15ml) to give the amine as a pale-yellow solid (3.854g, 58%); [α]D23 - 213° (c 1.14, CHCl3); λmax. (CHCl3) 265nm. (ε 7,900); 268.5 nm. (ε 7,900), and 279.5nm (ε 7,800); τ (DMSO-d6) values include 4.92 (d, J 5 Hz.) and 5.11 (d, J 5 Hz.), (6-H and 7H), and 5.72 (q, J 7 Hz.) and 8.61 (t, J 7 Hz.), (CH3CH2 --).
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[CH:13][CH:14]=2)[N:9]([C:25]2[N:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[CH:26]=2)[CH:8]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=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.O.C(OCC)(=O)C>[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=4)=[CH:13][CH:14]=3)[N:9]([C:25]3[N:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[CH:26]=3)[CH:8]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CNc1cc(-n2cc(Br)c3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1cc(-n2cc(-c3ccc(OC)cc3)c3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
DMF (5 mL) was added to a mixture of 6-(3-bromo-6-(3-nitrophenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (300 mg, 0.710 mmol), K3PO4 (452 mg, 2.13 mmol) and 4-methoxyphenylboronic acid (215 mg, 1.41 mmol) and then the dissolved gas was removed. After adding Pd(PPh3)4 (123 mg, 0.11 mmol), the mixture was stirred at 120° C. for 2 hours. After adding ethyl acetate and water and then filtering using a diatomite pad, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4→1:1). The target compound was obtained as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:21][C:17]1[CH:16]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Clc1cccc(Br)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cccc(Cl)c2)C1=O
Yield: 59.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 200 mg, 1.129 mmol) was reacted with 1-bromo-3-chloro-benzene (0.281 g, 1.471 mmol), 1,4-dioxane (20 mL), copper iodide (0.021 g, 0.110 mmol), trans-1,2-diamino cyclohexane (0.038 g, 0.333 mmol) and potassium phosphate (0.718 g, 3.386 mmol) to afford 192 mg of the product (59.25% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[C:10](=O)[O:9][C:8]([CH3:12])=[N:7]1.[NH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[N:7]=[C:8]([CH3:12])[NH:17][C:10]1=[O:9]
Reactant: COc1ccccc1C=C1N=C(C)OC1=O
Reactant: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccccc1C=C1N=C(C)NC1=O
Temperature: 80 °C

Procedure:
4-(2′-Methoxybenzylidene)-2-methyl-4H-oxazol-5-one (2.4 g) was dissolved in ethanol (50 ml) and aqueous ammonia (20 ml) and potassium carbonate (3 g) were added. The mixture was heated at 80° C. for 10 hr. After cooling, the solvent was evaporated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The precipitated yellow crystals were collected by filtration to give the title compound (2 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][Cl:39]>CN(C=O)C>[Cl:39][CH2:38][CH2:37][CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 50 °C
Yield: 73.4 %

Procedure:
To a stirred solution of 3-hydroxy-N-(benzyloxycarbonyl)morphinan 26 (3.6 mg, 0.009 mmol) in dry DMF (0.16 mL) were added potassium carbonate (4 mg, 0.028 mmol), 1-bromo-3-chloropropane (2.8 μL, 0.028 mmol) sequentially and the mixture was stirred at 50° C. After starting material disappeared on TLC, solvent was removed and column chromatography gave 3 mg (70%) of the title compound: 1H NMR (300 MHz, CDCl3) δ7.30 (5H, m); 7.00 (1H, t); 6.83 (1H, d); 6.70 (1H, d. d.); 5.10 (2H, m); 4.30 (1H, m); 4.05 (2H, t); 3.90 (1H, m); 3.79 (2H, t); 3.05 (1H, m); 2.75 (2H, m); 2.30 (1H, m); 2.15 (2H, m); 1.00˜1.80 (10H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of (2S,3S)-N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1B) (4.90 g, 20.0 mmol) in DMF (20 mL) at rt was added imidazole (3.41 g, 50.1 mmol), and then tert-butydimethylsilyl chloride (3.91 g, 25.9 mmol). After stirring at rt overnight, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 0-20% EtOAc/hexane to yield (2S,3S)-3-(tert-butyldimethylsilanyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (6.86 g).
Reaction SMILES: [Cl:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH:9]=[CH2:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)(Cl)Cl>[Cl:1][C:2]([F:7])([F:6])[C:3]([O:5][CH2:10][CH:9]=[CH2:8])=[O:4]
Reactant: O=C(O)C(F)(F)Cl
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCOC(=O)C(F)(F)Cl

Procedure:
In a 1.5 liter sulfonation flask with a water separator, 294.0 g (2.25 mol) of chlorodifluoroacetic acid (pure, from Fluka AG) and 228.0 g (3.93 mol) of allyl alcohol are dissolved in 1 liter of chloroform and kept under reflux for 17 hours in the presence of 11.25 g of p-toluenesulfonic acid (0.06 mol), 41 ml of H2O separating out. The yellow reaction solution is washed twice with H2O and 3 times with saturated aqueous NaHCO3 solution, dried over MgSO4 and distilled under normal pressure through a Vigreux column. Yield: 306.0 g (80%) of a colourless oil of boiling point 98°-100° C./988 mbar.
Reaction SMILES: [N:1]([CH:4]([CH:17]([F:19])[F:18])[CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N+]=[N-].[BH4-].[Na+].[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24]>C1COCC1.[Co](Cl)Cl>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[NH2:1][CH:4]([CH:17]([F:18])[F:19])[CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [N-]=[N+]=NC(CNC(=O)OCc1ccccc1)C(F)F
Agent: Cl[Co]Cl
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: NC(CNC(=O)OCc1ccccc1)C(F)F
Reaction time: 2 h

Procedure:
To a solution of benzyl (2-azido-3,3-difluoropropyl)carbamate (305 g, 1.13 mol) (1500 mL) and cobalt chloride (60 g, 460 mmol) in THF was added dropwise sodium borohydride (2.44 M solution in water, 2000 mL, 4.87 mol) over a period of 2 hours. After 2 hours, the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (2×2000 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and diluted with oxalic acid (1.22 M solution in ethyl acetate, 1500 mL, 1.83 mol). After 2 hours, the mixture was filtered to afford benzyl (2-amino-3,3-difluoropropyl)carbamate oxalic acid salt. The material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH3:29]>C(#N)C>[CH2:28]([O:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH3:29]
Reactant: CCI
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(OC)ccc(-c2ccc3c(c2)COC3=O)c1OC
Temperature: 80 °C
Yield: 57 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and ethyl iodide (130 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (50 mg, 57%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[N:6][N:5]2[C:10]=1[C:11]1[S:15][C:14]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1>CS(C)=O.O>[CH3:20][C:16]1[C:14]2[S:15][C:11]([C:10]3[N:5]4[N:6]=[C:7]([NH:33][C@H:34]5[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]5)[CH:8]=[CH:9][C:4]4=[N:3][CH:2]=3)=[CH:12][C:13]=2[CH:19]=[CH:18][CH:17]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1cccc2cc(-c3c(Cl)nc4cccnn34)sc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc2cc(-c3cnc4ccc(N[C@H]5CC[C@H](O)CC5)nn34)sc12
Temperature: 100 °C

Procedure:
To a solution of -chloro-3-(7-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.168 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (23 mg, 0.168 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.840 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 32 mg of the yellow solid, 48%.