Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13]C)=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2]>CO.[OH-].[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cccc(CC(=O)O)c1
Yield: 103.4 %

Procedure:
A solution of methyl 3-ethoxyphenylacetate (92.6 g, 0.4 mole) in methanol (600 ml) and 6.25 N NaOH (400 ml) was stirred overnight at room temperature and then filtered and concentrated in vacuo to remove the methanol. The solution was adjusted to pH 1 with concentrated HCl, the resulting precipitate filtered, washed with ice water, and dried under high vacuum to give 3-ethoxyphenyl acetic acid (74.5 g). M.p=89-90° C. 1H NMR (DMSO-d6, 200 MHz) δ: 1.30 (6, J=7 Hz, 3H, CH3), 3.50 (s, 2H, ArCH2), 3.98 (q, J=7 Hz, 2H, ethylCH2), 6.75-6.80 (m, 3H, Ar), 7.14-7.23 (m, 1H, Ar). (Lit. ref.: J. Med. Chem, 1980, 23(4) 437-444.
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.Cl.N[C@@H](CCN1CC([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)C1)CO>>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:43][CH:44]=1
Reactant: N[C@H](CO)CCN1CC(Cc2ccc(F)cc2)C1
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Cc3ccc(F)cc3)C2)n(C)n1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(4-fluoro-benzyl)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:41]=[N:42][C:43](Br)=[CH:44][CH:45]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])=[CH:44][CH:45]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([C@H](Cc1ccccc1)N(Cc1ccc(Br)nc1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C([C@H](Cc1ccccc1)N(Cc1ccc(N2CCCC2=O)nc1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 120 °C
Yield: 41.3 %

Procedure:
In an inert atmosphere, N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(6-bromo-pyridin-3-ylmethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide (70 mg, 0.101 mmol), 2-pyrrolidinon (10.3 mg, 0.121 mmol), potassium carbonate (27.9 mg, 0.202 mmol), copper(I)iodide (1 mg, 0.005 mmol) and N,N-dimethylenediamine (1 mg, 0.01 mmol) were dissolved in dioxane (1 mL). The reaction mixture was heated to 120° C. for 12 h, then filtered over a plug of silicagel with EtOAc, concentrated and purified by perp. HPLC to give 29 mg (52%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-[6-(2-oxo-pyrrolidin-1-yl)-pyridin-3-ylmethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide. (LC-MS: tR=1.02 min; [M+H]+=688.46).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].O>CN1CCCC1=O>[CH2:9]([NH:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:13])[CH3:10]
Reactant: CCN=C=O
Reactant: Nc1ccc(O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCNC(=O)Nc1ccc(O)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
10 g of 4-aminophenol (Mw=109.13; 0.0916 mol) are suspended in 100 cm3 of anhydrous N-methylpyrrolidone, under an inert atmosphere. 6.5 g of ethyl isocyanate (Mw=71.08; 0.0914 mol) are then added dropwise. The reaction mixture is brought to a temperature of 60° C. with stirring for two hours. The mixture is poured into one litre of water and the precipitate is then filtered off and dried. After recrystallization from ethanol, 9 g of a white powder are obtained, which corresponds to a yield of 55%. The melting point of the product obtained is 173.4° C. The 200 MHz 1H NMR spectrum and the elemental analysis are in accordance with the expected product.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([O:43][CH3:44])[C:24]1=[O:45])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:46]([N-]C(C)C)([CH3:48])[CH3:47].[Li+].C(Br)C=C>C1COCC1>[CH2:48]([C@@:25]1([O:43][CH3:44])[CH2:26][C@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]1=[O:45])[CH:46]=[CH2:47]
Reactant: CC(C)[N-]C(C)C
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@@]1(OC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one (495 mg, 0.749 mmol; Example 203, Step B) in THF (7.49 mL) was sparged with argon for 5 minutes and cooled to 0° C. 1.0 M lithiumdiisopropylamide solution in THF (1.461 mL, 1.461 mmol) was added dropwise. The internal temperature did not rise above 2° C. After 30 minutes, allyl bromide (0.194 mL, 2.247 mmol) was added. The cooling bath was replaced with a room temperature water bath. After 70 minutes, the mixture was quenched with sat. aq. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (40 g column, eluent: 5 to 30% ethyl acetate/hexanes) to afford the title compound as the more polar diastereomer.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[CH:8]=[C:7]([CH:9]=O)[NH:6][CH:5]=1>>[CH2:1]([NH:3][CH2:9][C:7]1[NH:6][CH:5]=[N:4][CH:8]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1cnc[nH]1
Product: CCNCc1cnc[nH]1

Procedure:
prepared by reaction of ethylamine with 3H-imidazole-4-carbaldehyde
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[C:5]=1[CH:14]=O)[CH3:2].Cl.[CH3:17][O:18][NH2:19]>>[CH3:17][O:18][N:19]=[CH:14][C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4]=1[S:3][CH2:1][CH3:2]
Reactant: CCSc1c(C=O)c(=O)n(C)c(=O)n1C
Reactant: CON
Agent: Cl
Product: CCSc1c(C=NOC)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method A was followed. 6-(Ethylthio)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (Example 23, Step 1) (0.148 mg, 0.65 mmol) and methoxyamine hydrochloride (0.072 mg, 0.86 mmol) were used to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:17]3=[N:18][C:19](S(C)=O)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])[C:13]2=[O:37])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:38][NH2:39].O1CCCC1>O1CCOCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:17]3=[N:18][C:19]([NH:39][CH3:38])=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])[C:13]2=[O:37])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CN
Reactant: CCOC(=O)C1CCC(N2C(=O)N(c3c(F)c(OC)cc(OC)c3F)Cc3cnc(S(C)=O)nc32)CC1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(N2C(=O)N(c3c(F)c(OC)cc(OC)c3F)Cc3cnc(NC)nc32)CC1

Procedure:
To a 100-mL round-bottomed flask was added Ethyl-4-[3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-cyclohexanecarboxylate (820 mg, 1.52 mmol), dioxane(60 mL), then a 2 M solution of methylamine in tetrahydrofuran (7.6 mL, 15.2 mmol), and the solution was heated to 60° C. under an atmosphere of nitrogen for 5 hours. The solution was then concentrated in vacuo, and reacted further without purification: LRMS: 506.2 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:29]O)([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=3[OH:28])[C:9]2=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:32]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][C:18]=4[O:28][CH2:29]3)[C:9]2=[O:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1ccc(OC(F)(F)F)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(hydroxymethyl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one (17.3 mmol) in anhydrous THF (200 mL) was added triphenylphosphine (6.34 g, 24.2 mmol) followed by diethyl azodicarboxylate (4.39 mL, 24.2 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h, quenched with saturated ammonium chloride (40.0 mL). The aqueous mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/4) to give the title compound (6.00 g, 71%): 1H NMR (300 MHz, CDCl3) δ 7.45-6.51 (m, 18H), 5.08 (d, 1H), 4.81 (d, 1H); MS (ES+) m/z 488 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15](=[O:38])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:17]=3[F:37])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[OH-].[Li+].Cl>O1CCCC1>[F:37][C:17]1[C:18]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]([C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([CH2:5][CH2:4][C:3]([OH:39])=[O:2])[CH:7]=2)[NH:12][CH:13]=1)=[O:38]
Reactant: COC(=O)CCc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c2c1
Temperature: 50 °C

Procedure:
To 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester (P-0033, 215 mg, 0.38 mmol) dissolved in tetrahydrofuran (30 mL) was added 1 N lithium hydroxide solution (15 mL). The mixture was heated at 50° C. for 2 hrs, then acidified to pH˜1-2 with 6 N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine dried over anhydrous magnesium sulfate, filtered and concentrated to provide an off-white solid (P-0034, 202 mg, 96%). MS(ESI) [M+H+]+=554.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10](/[CH:14]=[CH:15]/[CH:16]([C:21]3[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[C:23]([Cl:29])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[F:30][C:31]([F:37])([F:36])[CH2:32][C:33](O)=[O:34].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:27][C:25]1[CH:26]=[C:21]([CH:16]([C:17]([F:19])([F:20])[F:18])/[CH:15]=[CH:14]/[C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:33](=[O:34])[CH2:32][C:31]([F:37])([F:36])[F:30])[CH:6]=[CH:7]3)[CH:22]=[C:23]([Cl:29])[C:24]=1[F:28]
Reactant: O=C(O)CC(F)(F)F
Reactant: NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a stirred solution of (E)-2-amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl) ethanone (0.04 g, 0.09 mmol) in CH2Cl2 (5.0 ml) was added 3,3,3-trifluoropropanoic acid (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135 mmol) and DIPEA (29 mg, 0.225 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer was washed with water and saturated brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; 10% ethyl acetate/petroleum ether) to afford the title compound as an off-white solid (30 mg, 60%): mp 121-126° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (br, 1H), 7.59 (s, 1H), 7.45 (m, 4H), 6.72 (d, J=3.6 Hz, 3H), 6.39 (m, 1H), 4.71 (t, J=7.2 Hz, 2H), 4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m/z 553.06 ([M−H]−).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH3:16])[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[C:10](=[O:25])[NH:9][C:8]1=[O:26].[H-].[Na+].[C:29]([O:32][C@@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37]Br)(=[O:31])[CH3:30].C(OCC)(=O)C>CS(C)=O>[C:29]([O:32][C@@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37][N:9]1[C:10](=[O:25])[C:11]2[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21])[C:13]([CH3:16])=[N:14][C:15]=2[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:26])(=[O:31])[CH3:30]
Reactant: CC(=O)O[C@@H](C)CCCCBr
Reactant: Cc1nc2c(c(=O)[nH]c(=O)n2Cc2ccco2)n1COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(nc(C)n2COC(=O)C(C)(C)C)n(Cc2ccco2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a stirring solution of 3-(2-Furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.65 g, 1.8 mmol) in dimethyl sulfoxide (20 ml) was added sodium hydride in one portion. After 30 minutes, (S)-5-acetoxy-1-bromohexane (0.48 g, 2.16 mmol) was added neat. After stirring at ambient temperature for 20 hours, the reaction was quenched by addition of water (70 ml) and then extracted with ethyl acetate (3×35 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over sodium sulfate and concentrated to give a yellow oil. Flash chromatography on silica gel eluting with ethyl acetate gave (S)-1-(5-Acetoxyhexyl)-3-(2-furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.43 g) as a yellow oil. The product oil was dissolved in methanol (20 ml) and treated with a sodium methoxide solution (25 wt. % in MeOH, 0.98 ml, 4.3 mmol). After stirring at ambient temperature for 48 hours, the solution was diluted with ethyl acetate (40 ml) and quenched with water (20 ml). The organic phase was washed with saturated aqueous sodium chloride solution (20 ml), dried over sodium sulfate and concentrated to give a yellow solid. Column chromatography on silica gel eluting with 10% methane ethyl acetate gave (S)-3-(2-furylmethyl)1-(5-hydroxyhexyl)-8-methylxanthine CT2412S (80 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+].CCCCCC>C1COCC1>[OH:17]/[C:11](=[CH:9]\[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10])/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(=O)c1cncc(C)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(O)=C/C(=O)c1cncc(C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-2 (0.5 g, 3.70 mmol) and diethyl oxalate (1.010 ml, 7.40 mmol) in THF (15 ml) was added sodium ethoxide (3.45 ml, 21% wt. in ethanol, 9.25 mmol). The resulting mixture was heated at 60° C. for 1 h followed by stirring at rt overnight. The reaction mixture was poured into cold hexane and the desire product 1-3 was collected as a light yellow solid: ESI+ MS [M+H]+ C12H14NO4=236.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH:8]=[O:9].[CH3:15][O:16]C1C(OC)=CC(C=O)=C(O)C=1>>[CH3:15][O:16][C:4]1[C:3]([O:2][CH3:1])=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:11][CH2:12][O:13][CH3:14])[CH:5]=1
Reactant: COc1cc(O)c(C=O)cc1OC
Reactant: COCOc1ccc(OC)cc1C=O
Product: COCOc1cc(OC)c(OC)cc1C=O

Procedure:
4,5-dimethoxy-2-methoxymethoxybenzaldehyde (F2) was prepared in a similar manner for the preparation of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) by using 4,5-dimethoxy-2-hydroxybenzaldehyde (1.75 g, 14.9 mmol) instead of 2-hydroxy-5-methoxybenzaldehyde in 76% (2.56 g): 1H-NMR (500 MHz, CDCl3) δ3.55 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 5.26 (s, 2H), 6.77 (s, 1H), 7.32 (s, 1H) 10.35 (s, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13]OC(=O)C)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.[BrH:18]>>[BrH:18].[Br:18][CH2:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[CH:6]2
Reactant: CC(=O)OCc1ccc2c(cnn2C(C)=O)c1
Agent: Br
Product: BrCc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A suspension of 1-acetyl-5-(acetoxymethyl)indazole (106) (3.0 g, 13 mmol) in aqueous hydrobromic acid (15 mL, 226 mmol) was stirred at room temperature for 25 hours. The solid was collected on a Buchner funnel and dried under vacuum for 12 hours. The filtrate was stirred at room temperature for additional 24 hours and more solid was collected. After drying under vacuum, title compound was obtained as a yellow solid (107, 3.48 g, 92%) which was used in the next synthesis step without further purification. 1H NMR (CDCl3) δ 4.88 (s, 2H), 7.43 (d, 1H, J=8.8), 7.56 (d, 1H, J=8.8 Hz), 7.87 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:25]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][CH:12]1[O:14][CH:13]1[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:25]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][CH:12]([OH:14])[CH2:13][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C2OC2CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC(O)CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of methyl 4-[3-((3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-phenoxypentyl)oxiran-2-yl]benzoate from step D (410 mg, 0.7 mM) in 15 ml of methanol was added 100 mg of palladium on carbon (10%) and the suspension was set under 40 PSI of hydrogen gas and shaken for 2 h on the Parr shaker. The catalyst was filtered and the filtrate concentrated under reduced pressure to afford 378 mg of the title compound which was directly used for next step. LC-MS: m/z (ES) 488.21 (M-Boc+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[NH:18][C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[NH:18][C:12]2=[N:13][CH:14]=[C:15]([C:6]([O:5][CH3:1])=[O:19])[CH:16]=[C:11]2[N:10]=1)=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(Br)cnc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2[nH]c(CNC(=O)OC(C)(C)C)nc2c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 160.6 %

Procedure:
To a MeOH 25 mL solution of tert-butyl[(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)methyl]carbamate (Priepke, H.; Pfau, R; Gerlach, K.; Gillard, J.; Bauer, E.; Wienen, E.; Wolfgang, H.; Sandra N. H. WO 2004056784, 2004.) (1.2 g, 3.66 mmol) were added Et3N (1.11 g, 11 mmol), Pd(dppf)Cl2 (263 mg, 0.366 mmol). The reaction mixture was stirred at 80° C. under CO atmosphere (50 psi) for 24 hr. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated, chromatographed on silica gel eluting with DCM: MeOH: TEA (50:1:0.01, v/v/v) to give the title compound (0.9 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:22][C:23]1([CH3:26])[CH2:25][O:24]1.[I-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][C:23]3([CH3:26])[CH2:25][O:24]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: CC1(CCl)CO1
Agent: [I-]
Agent: [K+]
Product: CC1(CN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)CO1

Procedure:
In analogy to the procedure described for example 166, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 2-chloromethyl-2-methyloxirane with 0.3 equivalent of potassium iodide gave the intermediate 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-methyl-oxiranylmethyl)-[1,4]diazepan-5-one which was reacted with no work up with piperidine in ethanol to give the title compound as light yellow waxy solid. MS: 468.2 (MH+, 2Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:28][CH2:29]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:32][CH2:29][CH2:28][CH:9]1[CH2:10][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCO
Reactant: BrC(Br)(Br)Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In methylene chloride (50 ml) was dissolved 1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(2-hydroxylethyl)piperazine (1.00 g), followed by the addition of carbon tetrabromide (1.46 g) and triphenylphosphine (1.15 g). The resulting mixture was stirred at room temperature for 30 minutes. After the addition of a saturated aqueous solution of sodium sulfite, the organic layer was collected from the mixture. The organic layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column [hexane:ethyl acetate=10:1 to 6:1], whereby the title compound (990 mg) was obtained as a colorless foam.