Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH3:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O-:27])=[O:26].[OH-].[Na+].[Cl-].[Na+]>ClCCl>[CH3:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH2:32][C:31]1[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c2ccccc2c1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
In an ice water bath, into a reaction vessel were added trifluoroacetic acid (6.824 g, 60 mmol), triethylsilane (13.9 g, 120 mmol), dichloromethane 20 mL. After stirring for 5 min, a dichloromethane solution dissolving 2-methyl-1H-indole (5.24 g, 40 mmol) and p-nitro benzaldehyde (6.67 g, 44 mmol) was added dropwise slowly into the reaction vessel. After completion of dropwise addition, it was reacted maintaining this temperature for 1 h. It was adjusted to pH=8-9 with 2 M solution of sodium hydroxide. An aqueous solution of sodium chloride was added, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated to dryness to obtain a red brown solid, and washed with diethyl ether to obtain a yellow powdered solid 4.3 g, at a yield of 40.3%.
Reaction SMILES: N1C=CC=CC=1C1C2C(=O)N(CC(F)(F)F)C3C=CC=CC=3C=2N(C2CCCCO2)N=1.[Br:32][C:33]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:41][C:40]2[N:39]([CH2:49][C:50]([F:53])([F:52])[F:51])[C:38](=[O:54])[C:37]3[CH2:55][N:56](C4CCCCO4)[NH:57][C:36]=3[C:35]=2[CH:34]=1.[ClH:64].O>O1CCOCC1>[ClH:64].[Br:32][C:33]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:41][C:40]2[N:39]([CH2:49][C:50]([F:52])([F:53])[F:51])[C:38](=[O:54])[C:37]3[CH:55]=[N:56][NH:57][C:36]=3[C:35]=2[CH:34]=1
Reactant: O=c1c2c(c3cc(Br)c(-c4ccccn4)cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Agent: Cl
Agent: O=c1c2c(-c3ccccn3)nn(C3CCCCO3)c2c2ccccc2n1CC(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: O=c1c2cn[nH]c2c2cc(Br)c(-c3ccccn3)cc2n1CC(F)(F)F
Yield: 94 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. by treating 8-bromo-7-(pyrid-2-yl-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 8-bromo-7-(pyrid-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one with 4M HCl in dioxane, in the form of a white powder (hydrochloride, 0.4 H2O; yield 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:16]([N+:19]([O-])=O)[CH2:17][CH3:18])[CH:12]=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35].Cl>ClCCl.[Ni].O.CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[O:22][CH3:23])[CH2:15][CH:16]([NH:19][C:34](=[O:36])[CH3:35])[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccc(OC)c(OCc2ccccc2)c1)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCC(Cc1ccc(OC)c(OCc2ccccc2)c1)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.7 %

Procedure:
Raney-Nickel (3.82 g, 50% in water, ˜32.5 mmol) and a large heavy oval stirring bar were placed in a 500 mL RBF. The water was removed via pipette and the Raney-Nickel was washed with methanol (2×10 mL). Then methanol (100 mL) and 258 (7.88 g, 25.0 mmol) were added and the mixture was cooled to 0° C. Hydrazine hydrate (6.30 g, 126 mmol) was added dropwise via syringe. The reaction mixture was stirred for 30 min at 0° C., then for 7 h at 50° C. The mixture was passed through a sinter funnel with celite to remove the Raney-Nickel. The sinter was washed with methanol (4×20 mL). The combined filtrates were concentrated in vacuo to receive the crude amine as brownish green oil (7.72 g) which was used without further purification. The crude amine (7.41 g, max. 24.0 mmol) was dissolved in dichloromethane (80 mL) and cooled to 0° C. Triethylamine (3.68 g, 36.4 mmol) was added, then acetic anhydride (2.96 g, 29.0 mmol) added dropwise via syringe. The reaction mixture was stirred for 4 h. Water (40 mL) and hydrochloric acid (5M, 10 mL) were added and the layers separated. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (80 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (8.73 g, >99%) as beige solid. 1H NMR (270 MHz, CDCl3) δ 0.83 (3H, t, J 7.4, CH2CH3), 1.09-1.27 (1H, m, one of CH2CH3), 1.32-1.50 (1H, m, one of CH2CH3), 1.87 (3H, s, NCOCH3), 2.64 (2H, d, J 6.3, ArCH2CH), 3.85 (3H, s, OCH3), 3.89-4.07 (1H, m, ArCH2CH), 5.08 (1H, d, br, J 8.8, NH), 5.13 (2H, s, OCH2Ph), 6.63-6.72 (2H, m, 2×CH), 6.77-6.82 (1H, m, CH), 7.24-7.44 (5H, m, OCH2C6H5).
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)(C)=O.[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH:38]=[O:39])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]>CS(C)=O>[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH:38]4[CH2:1][O:39]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Reaction time: 0.08 h

Procedure:
n-Butyllithium (1.6M in hexanes, 2.30 mL, 3.69 mmol) was placed in a flask along with DMSO (8 mL) and the solution was placed under N2 atmosphere. Trimethyl sulfoxonium iodide (0.963 g, 4.29 mmol) was added and stirred for 5 minutes. 1-[4′-(4-Formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.46 g, 1.23 mmol) in DMSO (8 mL) was then added and the reaction was stirred. After 40 minutes the reaction was quenched with ice then submitted to standard aqueous workup and purified on silica gel (0-40% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]3[C:11]([I:20])=[N:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[C:21]([Si:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)Cl)([CH3:24])([CH3:23])[CH3:22]>N1C=CC=CC=1>[Si:25]([CH:7]([OH:8])[C@H:5]1[O:6][C@@H:1]([N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]3[C:11]([I:20])=[N:10]2)[CH2:2][C@@H:3]1[OH:4])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ncnc2c1c(I)nn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COc1ncnc2c1c(I)nn2[C@H]1C[C@H](O)[C@@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Reaction time: 72 h
Yield: 89.6 %

Procedure:
In a 500 mL flask was suspended 2 (3.6 g, 9.2 mmol) in anhydrous pyridine (60 mL), then tert-butyldiphenylchlorosilane (2.78 g, 10 mmol) was added and the mixture stirred for 72 hours. The suspension was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with 10% citric acid, brine, dried over MgSO4, and concentrated to a white foam. The crude product was purified by flash chromatography with 25-33% ethyl acetate in hexanes to obtain 3 as a white foam (5.2 g, 90% yield).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=O)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH:16]=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[NH2:28])=[CH:21][CH:20]=1)[CH3:18])([O:14][CH3:15])=[O:13]>>[C:12]([CH:16]=[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([NH:28][CH2:10][CH:8]([OH:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([CH3:30])[CH3:29])=[CH:23][CH:24]=1)[CH3:18])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C=C(C)c1ccc(CCC(C)(C)N)cc1
Reactant: O=CC(=O)c1ccccc1
Solvent: O
Product: COC(=O)C=C(C)c1ccc(CCC(C)(C)NCC(O)c2ccccc2)cc1
Yield: 64.6 %

Procedure:
This was prepared in an identical manner to the compound described in Example 13 using phenylglyoxal monohydrate (1.34 g) and 3-{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1, 1-dimethylpropanamine (2.61 g). The title compound (2.17 g) m.p. 98°-102° C. (benzene-hexane) was obtained after chromatography on Kieselgel 60 eluting with 1% methanolchloroform. τ(CDCl3) 8.85 (6H, s), 8.1-8.7 (2H, m), 6.8-7.8 (9H, m), 6.2 (3H, s), 5.3 (1H, dd), 3.82 (1H broad), 2.65 (9H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:16][C:17]2[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(Cn2ccc(OCc3ccccc3)cc2=O)cc1

Procedure:
4-Benzyloxy-2(1H)-pyridone (3.0 g, 0.015 mol), 4-methylbenzyl bromide (3.15 g, 0.17 mol), and potassium carbonate (3.0 g, 0.022 mol) were heated at 80° C. for 2 hours. Contents were allowed to cool, diluted with water and a solid (5.52 g) was filtered. FABHRMS m/z 306.1494 (M+H, C20H20NO2 requires 306.1494). 1H NMR (CDCl3/300 MHz): 7.50-7.40 (m, 5H); 7.20-7.05 (m, 5H); 6.07-6.00 (m, 1H); 5.95-5.90 (m, 1H); 5.05 (s, 2H); 5.00 (s, 2H); 2.32 (s, 3H).
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH3:14][O:15]C(Cl)Cl.Cl.CCOC(C)=O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([CH:14]=[O:15])[CH:8]=1
Reactant: COC(Cl)Cl
Reactant: COC(=O)Oc1ccc(OC)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Oc1ccc(OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirred solution of 4-methoxyphenyl methyl carbonate (5, 16.5 g. 91 mmol) in CH2Cl2 (205 mL) at 0° C. was added dropwise TiCl4(23.5 mL, 210 mmol) in CH2Cl2 (20 mL) over 30 min. Then MeOCHCl2 (9.3 mL, 104 mmol) in CH2Cl2 (20 mL) was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction material was poured into a mixture of ice (210 g) and concentrated HCl (8.5 mL). EtOAc (200 mL) was added and the mixture was stirred vigorously for 30 min. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from EtOAc/hexanes to afford the title compound (16.6 g, 87%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H), 7.63 (d, J=3.1 Hz, 1H), 7.37 (dd, J=9.0, 3.1 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H); ESI MS m/z 228 [M+H2O]+.
Reaction SMILES: C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(OP(N=C=S)(OCC)=O)C.[CH3:24][C:25]1([CH3:47])[S:29][C@@H:28]2[C@H:30](NC([C@H](N)C3C=CC=CC=3)=O)[C:31](=[O:32])[N:27]2[C@H:26]1[C:44]([OH:46])=[O:45]>ClCCl>[CH3:24][C:25]1([CH3:47])[S:29][C@@H:28]2[CH2:30][C:31](=[O:32])[N:27]2[C@H:26]1[C:44]([OH:46])=[O:45]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCOP(=O)(N=C=S)OCC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Temperature: 20 °C

Procedure:
0.75 ml (about 3 mmol) of N,O-bis(trimethylsilyl) acetamide was added under anhydrous conditions, to a suspension of 1.05 g (3 mmol) of D(-) 6-α-amino-benzylcarbonamidopenicillanic acid (anhydrous D(-) ampicillin) in 50 ml of dry dichloromethane and after 30 minutes stirring at about 20°C, a clear solution was obtained. Then, a solution of 0.6 g (3 mmol) of diethoxyphosphinylisothiocyanate [(C2H5O)2P(O)NCS] in 10 ml of dichloromethane was added at 0°-5°C over a period of 10 minutes and as the reaction did not cause a rise in temperature, the reaction mixture was further stirred at 5°C for 150 minutes. A small amount of precipitate was formed and according to thin-layer chromatograms, ampicillin was no longer present in the reaction mixture. The reaction mixture was poured into 75 ml of ice-water and the pH was brought to 7.0. The layers were separated and as the organic layer did contain part of the desired penicillin, the aqueous layer was extracted once with 75 ml of ethyl acetate at pH 7.0. The organic layers were combined, concentrated to some extent in vacuo in order to remove dichloromethane, and subsequently treated with n-hexane until a precipitate was formed, which was vacuum filtered off, washed with n-hexane and dried in vacuo to constant weight to obtain 0.5 g (30%) of D-6-[α-{3-diethoxyphosphinyl)-thioureido}benzylcarbonamido]-penicillanic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[N:13]=[N:14][C:9]2=[N:8][CH:7]=1)=[CH2:5])C.Cl.C([O-])(O)=O.[Na+]>C(#N)C>[N:22]1[C:23]2[C:18](=[CH:17][C:16]([CH2:15][N:12]3[C:10]4[C:9](=[N:8][CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[N:11]=4)[N:14]=[N:13]3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 104.1 %

Procedure:
To a solution of the 6-[6-(1-ethoxy-vinyl)-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl]-quinoline (1.0 g, 3.00 mmol) in ACN (50 mL), was added 2 N HCl dropwise. The reaction was refluxed for 1 hour, and then neutralized with NaHCO3. The solution was extracted with EtOAc (3×100 mL) to give the product 1-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-ethanone (950 mg, 99% yield).
Reaction SMILES: [C:1]1([C:7]2[N:20]=[N:19][C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(COC)OC>[C:1]1([C:7]2[N:20]=[N:19][C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:10][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: c1ccc(-c2cc3ncc4ccccc4c3nn2)cc1
Solvent: COCCOC
Product: c1ccc(-c2cc3nc(N4CCCC4)c4ccccc4c3nn2)cc1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
3-Phenyl-pyridazino-[4,3-c]isoquinoline (5.83 g, 0.02 mol) and dimethoxyethane (100 ml) are heated to reflux temperature with stirring in a 250 ml flask. Pyrrolidine (3.1 g, 0.044 mol) is added to the obtained solution and heating is continued for further 2 hours. When the reaction is completed, the reaction mixture is concentrated to dryness under reduced pressure and the residue is taken up with water (200 ml), a solid is recovered by filtrating the obtained suspension which is dried yielding 6.1 g of a crude 3-phenyl-6-(1-pyrrolidinyl)pyridazino[4,3-c]isoquinoline. Crystallization from ethyl acetate gives 5.6 g of the pure product of the title. (Yield 85%) M.p. 174°-176° C.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:26]C(=O)OC(C)(C)C)([CH2:8][N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:26][C:5]([CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=2)[CH2:10]1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCCCCCCc1ccc2c(c1)CN(CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1)C2
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Product: CCCCCCCCc1ccc2c(c1)CN(CC(N)(CO)CO)C2
Yield: 70 %

Procedure:
When the product of Step F was substituted for tert-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 70% yield. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.94 Hz); 1.25 (m, 10H); 1.56 (m, 2H); 2.56 (tr, 2H, J=7.86 Hz); 2.66 (broad m, 4H); 2.89 (s, 2H); 3.57 (s, 4H); 4.07 (s, 4H); 6.98 (s, 1H); 7.0 (d, 1H, J=7.6 Hz); 7.06 (d, 1H, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13][CH2:12][C:11](=[O:15])[N:10]2[CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1.C[OH:28]>OO.Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13](=[O:28])[CH2:12][C:11](=[O:15])[N:10]2[CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CO
Reactant: O=C(CN1C(=O)CSC[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Agent: Cl
Agent: OO
Product: O=C(CN1C(=O)CS(=O)C[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of benzyl [(3R)-3-(3,5-difluorophenyl)-5-oxothiomorpholin-4-yl]acetate (151 mg, 0.399 mmol, from Step A.) in MeOH (10 mL) was added aqueous hydrogen peroxide (30 drops, ˜0.8 mL, 30% by weight), and aqueous HCl (5 drops, 3 M HCl). This mixture was then heated to 40° C. for 2.5 hours. After cooling to ambient temperature, the bulk of the MeOH was removed in vacuo, and the residue was partitioned between 50 mL of water and 100 mL of diethyl ether. The organics were washed with saturated brine, then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography eluting with a gradient of Hexanes:EtOAc-1:1 to 100% EtOAc, to yield 24.5 mg of the minor sulfoxide isomer and 93.6 mg of the major sulfoxide isomer. MS: m/z=394 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH2:39][CH3:40])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31]CC3C=CC=CC=3)=[O:30])[CH2:24]2)[O:12]1>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH2:39][CH3:40])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24]2)[O:12]1
Reactant: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Temperature: 50 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
To a solution of Benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(ethyl)amino)cyclobutyl)propanoate (2.6 g, 4.73 mmol) in MeOH (40 mL) was added 10% Pd/C (2.3 g) and the mixture was stirred under H2 atmosphere at 50° C. for 20 h. The mixture was filtered and the filtrate was concentrated to obtain the target (2 g, yield: 92%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.27 (s, 1H), 8.25 (s, 1H), 6.30 (s, 1H), 5.52-5.49 (m, 1H), 5.14-5.12 (m, 1H), 4.51-4.47 (m, 1H), 3.43-3.36 (m, 2H), 3.22-3.15 (m, 1H), 2.94-2.89 (m, 2H), 2.28-2.05 (m, 4H), 1.96-1.80 (m, 2H), 1.74-1.69 (m, 1H), 1.65-1.59 (m, 5H), 1.41-1.36 (m, 4H), 1.03-0.99 (m, 3H) ppm; ESI-MS (m/z): 461.3 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13]([CH:15]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:16]1)=O.C(=O)(O)[O-].[Na+]>C(O)(=O)CC>[CH2:22]([O:21][C:19]([N:17]1[CH2:18][CH:15]([C:13]2[O:1][C:2]3[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=3[N:12]=2)[CH2:16]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cccc(NC(=O)C2CN(C(=O)OCc3ccccc3)C2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(=O)O
Product: COC(=O)c1cccc2nc(C3CN(C(=O)OCc4ccccc4)C3)oc12
Yield: 35.9 %

Procedure:
A mixture of benzyl 3-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)azetidine-1-carboxylate (820 mg, 2.13 mmol) in propionic acid (20 ml) was stirred at reflux for 2 days. Then the mixture was adjusted pH=7 by sodium bicarbonate. The mixture was extracted with ethyl acetate. The extraction was washed with sodium bicarbonate, brine, dried with sodium sulfate. The residue was removed in vacuum. The crude was purified by chromatography (silica gel, petroleum ether/ethyl acetate=5:1). 280 mg of methyl 2-(1-(benzyloxycarbonyl)azetidin-3-yl)benzo[d]oxazole-7-carboxylate as a solid was obtained, yield 39%. LC-MS (ESI) m/z: 367 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:37])[C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][C@H:15]2[NH:25][C:26]([C:28]2[N:33]=[CH:32][C:31]3[CH2:34][NH:35][CH2:36][C:30]=3[CH:29]=2)=[O:27])=[O:12])=[N:7][CH:8]=1.[CH2:38]=O>>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:37])[C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:23])[CH3:24])=[O:21])[CH2:16][C@H:15]2[NH:25][C:26]([C:28]2[N:33]=[CH:32][C:31]3[CH2:34][N:35]([CH3:38])[CH2:36][C:30]=3[CH:29]=2)=[O:27])=[O:12])=[N:7][CH:8]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)C(=O)Nc2ccc(Cl)cn2)[C@H](NC(=O)c2cc3c(cn2)CNC3)C1
Reactant: C=O
Agent: Cl
Product: CN1Cc2cnc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)C(=O)Nc3ccc(Cl)cn3)cc2C1

Procedure:
In a manner similar to that employed in Example 18, the title compound was prepared from the compound obtained in Example 339 and formalin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)O)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:8]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:10]3[CH:11]=[N:12][CH:13]=[N:14][C:15]=32)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cncnc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc(C2c3ccc(Cl)cc3-c3ncncc32)cc1
Yield: 51.6 %

Procedure:
A solution of 4.0 g of α, α-bis(4-chlorophenyl)-5-pyrimidinemethanol in 25 ml of methanesulfonic acid was stirred under a nitrogen atmosphere for 18 hours. The solution was poured into a sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Recrystallization from ethyl acetate/isooctane provided 1.95 g of the desired title product, m.p. 158°-163° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:20](=[O:25])[C:21]([O:23]C)=[O:22])=[CH:15][N:16]3[CH3:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O.Cl>CO>[CH3:19][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:9][CH:8]=3)[CH:18]=2)[C:14]([C:20](=[O:25])[C:21]([OH:23])=[O:22])=[CH:15]1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(C(=O)C(=O)O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.4 %

Procedure:
The mixture of methyl 2-[6-(4-trifluoromethoxyphenyl)-1-methyl-1H-indol-3-yl]-2-oxoacetate (0.120 g, 0.318 mmol), and sodium hydroxide (1N, 1 mL, 1.0 mmol) in methanol (10 mL), was stirred at room temperature for 2.5 hours. The mixture was poured into excess water and acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The organic phase was evaporated to dryness and dried under vacuum at 55° C. for 12 hours to yield the title compound as a yellow solid (0.0686 g, 59.1%), mp: 233-235° C. (dec). Mass spectrum (+APCI, [M+H]+) m/z 364; 1HNMR (400 MHz, DMSO-d6): δ13.8-14.0 (br s, 1H), 8.55 (s, 1H), 8.25 (d, 1H, J=8.3 Hz), 7.95 (d, 1H, J=1.1 Hz), 7.85-7.95 (m, 2H), 7.65 (dd, 1H, J=8.2 and 1.6 Hz), 7.45 (dd, 2H, J=8.8 Hz and 0.88 Hz), add 4.0 ppm (s, 3H). Elemental Analysis for C19H14F3NO4: Calculated: C, 59.51; H, 3.33; N, 3.86. Found: C, 59.39; H, 3.38; N, 3.71.