Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13]C(=O)[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].C[Al](C)C.[C:26]([O:29][C:30](=[O:32])[CH3:31])(=O)[CH3:27].O>O1CCOCC1.C1(C)C=CC=CC=1.[Cu]Br>[C:30]([O:29][C:26]1[CH:11]=[C:10]2[C@:15]([CH3:16])([C@@H:14]([CH3:13])[CH:27]=1)[C@@H:17]1[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH2:8][CH2:9]2)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cu]Br
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OC1=C[C@H](C)[C@@]2(C)C(=C1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
14.2 g (50 mmol) of androsta-1,4-diene-3,17-dione is dissolved in 100 ml of anhydrous dioxane under nitrogen atmosphere. 716 mg (5 mmol) of copper(I) bromide is added and the solution is heated to 25° C. Then 47 ml (55 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction so that the temperature does not rise above 35° C. Then it is stirred for 1.5 hours more at 35° C. 16.84 g (0.165 mol) of acetic anhydride is added at 35° C. and the reaction solution is stirred for 1 hour more at 30° C. For completion of the reaction it is then heated for 15 minutes to 60° C. After cooling of the solution to 20° C., 4 ml of water dissolved in 20 ml of dioxane is added to the reaction for the hydrolysis and the solution is stirred again for 15 minutes. The inorganic solid is suctioned off on diatomaceous earth and the solid is washed again with 50 ml of dioxane. After concentration by evaporation of the solution on a rotary evaporator, 18 g of crude product is obtained, that is chromatographed on silica gel with hexane and an increasing part of ethyl acetate as eluent. After concentration by evaporation of the fractions, 11.4 g of 3-acetoxy-1α-methyl-androsta-2,4-dien-17-one (70% of theory) is obtained as viscous material that can be recrystallized from diisopropylether.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:25][CH3:26])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClCCl.O1CCOCC1.O.C(#N)C>[CH2:27]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C@H:10]([O:25][CH3:26])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CO[C@H](CN1CCN(C(=O)OC(C)(C)C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H](CN1CCN(C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Tert-butyl 4-[(2S)-3-(dibenzylamino)-2-methoxy-propyl]piperazine-1-carboxylate 35b (4.36 g, 9.60 mmol) was dissolved in 30 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours. The resulting solution was concentrated under reduced pressure. The residue was added with 30 mL of acetonitrile, 30 mL of water and formaldehyde (0.58 g, 19.20 mmol) successively. The reaction solution was stirred for 0.5 hours, added with sodium triacetoxyborohydride (6.10 g, 28.80 mmol). The reaction solution was stirred for 1 hour. The resulting solution was added dropwise with aqueous ammonia to adjust pH to 9 to 10 and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2S)—N,N-dibenzyl-2-methoxy-3-(4-methylpiperazin-1-yl)propan-1-amine 38a (2.90 g, yield: 83.0%) as a brown oil.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:24]([C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([OH:26])=[O:25]>CO>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[CH3:13][O:25][C:24]([C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]1)=[O:26]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1
Yield: 453.8 %

Procedure:
1 g of p-toluenesulfonic acid monohydrate is added to a solution of 10 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 300 ml of MeOH and the reaction mixture is ref luxed for 3 days. It is concentrated under vacuum, the residue is taken up with acetone, and ether is added until precipitation occurs. 9.34 g of the expected product are obtained after wringing of the precipitate formed.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14](C3C=CC(OC)=CC=3)C[O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[O:36]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH2:14])=[C:11]([CH:10]=1)[O:16][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)cc1
Agent: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=Cc1ccc(OCc2ccccc2)cc1OCC(=O)c1ccc(OC)cc1

Procedure:
7-Benzyloxy-3-(4-methoxyphenyl)-2H-1-benzopyran can be prepared according to the following reaction scheme and protocols. Referring to Scheme 1,4-benzyloxy-2-hydroxybenzaldehyde (compound 1) was reacted with a mixture of methyl triphenyl phosphonium bromide (MTPPB) and potassium tert-butoxide (t-BuOK), followed by reaction with 2-bromo-4′-methoxyacetophenone to give 2-(5-benzyloxy-2-vinylphenoxy)-1-(4-methoxyphenyl)ethanone (compound 2a), which was subsequently reacted with a mixture of MTPPB and t-BuOK to give 4-benzyloxy-2-[2-(4-methoxyphenyl)allyloxy]-1-vinylbenzene (compound 2). Reaction of compound 2 with Grubbs' catalyst (II) gives 7-benzyloxy-3(4-methoxyphenyl)-2H-1-benzopyran (compound 3).
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][OH:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].Cl.C(O[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=N)C.C(N(CC)CC)C>O>[CH3:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C@H:3]2[O:4][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:1][C@@H:2]2[CH2:15][OH:16])=[CH:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1

Procedure:
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) (about 10 g, 0.04077 moles) is reacted at about 0° C. in a reaction vessel with 2,2-dichloro-ethanimidic acid ethyl ester hydrochloride (Compound IV hydrochloride wherein R2 is dichloromethyl and R4 is ethyl) (about 8.6 g, 0.0448 moles) in 1,2-dichloromethane (about 250 mL) containing triethylamine (about 4.1 g, 0.04077 moles). Next, water (about 125 mL) is added. The resulting solids are filtered, then dried to yield (4R,5R)-2-(Dichloromethyl)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is dichloromethyl).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2.C(N(CC)CC)C.[N:22]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.OP(O)(O)=O>ClCCCl.CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:25]1[CH2:26][CH2:27][N:22]([S:28]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]2=3)(=[O:30])=[O:29])[CH2:23][CH2:24]1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: COC(=O)c1cnc2c(c1)NCCO2
Agent: CN(C)c1ccncc1
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)N(S(=O)(=O)N1CCOCC1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
Methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (97 mg, 0.50 mmol) was suspended in 4 mL of DCE and sequentially treated with DMAP (61 mg, 0.50 mmol) and triethylamine (0.077 mL, 0.55 mmol). Morpholine-4-sulfonyl chloride (102 mg, 0.55 mmol) was added and the mixture was stirred at ambient temperature for 2 hours and then heated to 50° C. for 2 days. The mixture was cooled to ambient temperature and diluted with 10 mL of DCM and the whole solution poured into 15 mL of 1M aqueous H3PO4. The layers were separated and the aqueous layer was extracted with 10 mL of DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography (gradient elution 50% to 100% EtOAc/Hexanes) to provide 88 mg (51%) of the title compound as a thick tan oil. 1H NMR (CDCl3) δ 8.59 (d, 1H), 8.34 (d, 1H), 4.48 (m, 2H), 3.86 (s, 3H), 3.77 (m, 2H), 3.69 (m, 4H), 3.26 (m, 4H). LCMS (+ESI) m/z=344.1 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=O)[C:7]([OH:9])=[O:8])[CH:3]=[N:2]1.[OH-].[Mg+2].[OH-].[OH:14][NH:15]Cl>C(O)C.O>[OH:14][N:15]=[C:6]([C:4]1[CH:3]=[N:2][S:1][CH:5]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(=O)c1cnsc1
Reactant: ONCl
Agent: [Mg+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=NO)c1cnsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A suspension of 2-(isothiazol-4-yl)glyoxylic acid (240 mg.), magnesium hydroxide (290 mg.) and hydroxylamino hydrochloride (140 mg.) in a mixture of ethanol (2 ml.) and water (10 ml.) was stirred for 2 hours at ambient temperature and allowed to stand overnight at ambient temperature. Ethanol was distilled off and to the residue was added ethyl acetate. The mixture was adjusted to pH 1 with 10% hydrochloric acid and the ethyl acetate layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2-hydroxyimino-2-(isothiazol-4-yl)acetic acid (syn isomer) (0.20 g.), mp 159° to 161° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14](Cl)[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(Cl)Cl.[K+].[Br-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CNc1nc(Cl)nc(Nc2cc(OC)cc(OC)c2)n1
Reactant: Nc1ccc(O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Nc2ccc(O)cc2)nc(Nc2cc(OC)cc(OC)c2)n1
Yield: 80 %

Procedure:
The title compound was synthesized from 2-(3,5-dimethoxyphenylamino)-4-methylamino-6-chloro-1,3,5-triazine and 4-aminophenol using a similar procedure to the one used in 7. Yield: 80%; Tg 81° C.; FTIR (CH2Cl2/KBr) 3401, 3288, 3133, 3003, 2958, 2915, 2840, 1587, 1507, 1481, 1450, 1427, 1400, 1360, 1294, 1264, 1234, 1205, 1177, 1153, 1106, 1082, 1065, 1014, 980, 927, 834, 808, 737, 703, 682, 661 cm−1; 1H NMR (300 MHz, DMSO-d6, 298 K): δ 9.02 (s, 1H), 8.95 (br s, 0.5H), 8.82 (br s, 1H), 8.64 (br s, 0.5H), 7.49 (br s, 2H), 7.09 (br d, 2H), 6.86 (br s, 1H), 6.66 (d, 3J=8.8 Hz, 2H), 6.08 (s, 1H), 3.69 (s, 6H), 2.81 (br s, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 166.0, 164.1, 163.8, 160.2, 152.4, 142.1, 131.6, 122.3, 114.7, 98.0, 93.7, 54.9, 27.3 ppm; HRMS (EI) calcd. for C18H20N6O3 (m/e): 368.1597. found: 368.1609.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[N:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:3][CH2:2]1>C(O)C.O1CCCC1.[OH-].[Na+]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[N:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCC4CC4)cc3c2C)C(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)nc2)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Ethyl 3-[{[5-({1-[5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate (280 mg) synthesized in Example A212 was dissolved in ethanol (1.0 mL)-tetrahydrofuran (1.0 mL), 1N aqueous sodium hydroxide solution (1.1 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, water (2.0 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (1.1 mL) under ice-cooling, and stirred for 30 min. The resulting precipitate was collected by filtration, and dried to give the title compound (238 mg, 90%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[N:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:19]2[CH2:21][CH2:20]2)[N:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Br)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(C2CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Combine [1-(6-bromo-pyridin-2-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (250 mg, 1.16 mmol), cyclopropyl boronic acid (129 mg, 1.5 mmol), potassium phosphate (920 mg, 4.0 mmol), toluene (4.8 mL) and water (0.24 mL). Mix vigorously. Add 1M tricyclohexyl phosphine in toluene (120 μA, 0.12 mmol); degas the mixture, purge with nitrogen, and add palladium acetate 13 mg, (0.06 mmol) and heat at 100° C. for 6 hours, then stir at room temperature overnight. Filter the reaction and purify the filtrate over silica (80 g) eluting with 0% to 25% EtOAc:hexanes to give [1-(6-cyclopropyl-pyridin-2-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (157 mg, 49%). MS (m/z): 277.3 (M+H)+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:45])[C:18](=[O:44])[C:19]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:34]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37]=[CH:36][CH:35]=4)[CH:28]=[N:27][C:20]=3[N:21]([CH:24]3[CH2:26][CH2:25]3)[C:22]=2[N:23]=1>C(Cl)Cl.C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:45])[C:18](=[O:44])[C:19]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:34]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N+:37]([O-:9])=[CH:36][CH:35]=4)[CH:28]=[N:27][C:20]=3[N:21]([CH:24]3[CH2:26][CH2:25]3)[C:22]=2[N:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1C(=O)c2cc(CCOc3ccnc4ccccc34)cnc2N(C2CC2)c2nc(Cl)ccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(=O)c2cc(CCOc3cc[n+]([O-])c4ccccc34)cnc2N(C2CC2)c2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.3 %

Procedure:
Solid mCPBA (177 mg, 0.82 mmol) was added to a solution of 2-chloro-11-cyclopropyl-5,11-dihydro-5-methyl-8-{2-(4-quinolinyloxy)ethyl}-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (143 mg, 0.30 mmol) in CH2Cl2 (3 mL) and THF (3 mL). The mixture was stirred at room temperature for 14 h then was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), the solution was successively washed with aqueous 10% Na2S2O3 (3×10 mL), aqueous saturated NaHCO3 (3×10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was partially purified by flash chromatography (EtOAc:MeOH, 95:5 to CH2Cl2:MeOH, 9:1). The impure compound was further purified by reverse phase HPLC (CombiPrep ADS-AQ 50×20 mm, 5 μ, 120 A, 5-100% MeCN+0.10% TFA/water+0.10% TFA in 25 min). The pure fractions were treated with aqueous saturated NaHCO3, extracted with EtOAc and the solution was dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (28.3 mg, 19%) as a white solid: MS (ESI) m/z 488/490 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1>C(#N)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(O)c(CNC(=O)OC(C)(C)C)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(CNC(=O)OC(C)(C)C)c1
Temperature: 82 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-hydroxyphenyl)acetate (200 mg, 0.677 mmol) was diluted with ACN (2 mL) followed by the addition of K2CO3 (206 mg, 1.49 mmol) and 1-fluoro-4-nitrobenzene (0.103 mL, 0.948 mmol). The reaction mixture was heated to reflux (at about 82° C.) and stirred for 5 hours. The reaction mixture was then diluted with ethyl acetate and water. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40S eluting with hexanes/ethyl acetate (3:1) to yield 242 mg of methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-nitrophenoxy)phenyl)acetate as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1
Reactant: CCc1cc(NCCCCCCO)nc(Cl)n1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCCCCCNc1cc(CC)nc(Cl)n1
Yield: 38.2 %

Procedure:
In 10 ml of dichloromethane were dissolved 0.70 g of dl-5-chloro-6-ethyl-4-(6-hydroxyhexyl)aminopyrimidine and 0.30 g of ethyl chloroformate, and under stirring, 0.40 g of triethylamine and a catalytic amount of 4-dimethylaminopyridine were added to the solution and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane and washed with water. Then, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=4:1) to give 0.30 g of the title compound as pale yellow oily product. nD18.7 1.5138.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)[CH3:2].O[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CO)cc1
Reactant: O=Cc1cccc(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(COc2cccc(C=O)c2)cc1
Temperature: 25 °C

Procedure:
Mix 4-ethoxybenzyl alcohol (3.35 g. 22 mmol), 3-hydroxybenzaldehyde (2.69 g, 22 mmol), triphenylphosphine (5.8 g, 22 mmol) and diethylazadicarboxylate (3.83 g, 22 mmol) in tetrahydrofuran (25 mL). Stir at room temperature under anhydrous atmosphere until the reaction is done. Concentrate the solution in vacuo and dilute with a small quantity of ethyl ether. Filter any precipitate and concentrate the filtrate in vacuo. Purify by silica gel chromatography to give 3-(4-ethoxybenzyloxy)benzaldehyde.
Reaction SMILES: N[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[CH2:10][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8](=[O:18])[C:6]=2[N:7]=1.O.Cl.N([O-])=[O:23].[Na+]>>[CH2:11]([N:9]1[CH2:10][C:5]2[C:4]([OH:19])=[N:3][C:2]([OH:23])=[N:7][C:6]=2[C:8]1=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(O)c2c(n1)C(=O)N(Cc1ccccc1)C2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1c2nc(O)nc(O)c2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-amino-6-benzyl-4-hydroxy-5H-pyrrolo[3,4-d]pyrimidin-7(6H)-one (8.721 g, 0.03403 mol) and water (510.7 mL, 28.35 mol) were mixed and the mixture was heated at 100° C. Conc. HCl was added slowly until the sample dissolved. The mixture was cooled at 90° C. then sodium nitrite (7.044 g, 0.1021 mol) in water (68.05 mL, 3.778 mol) was added dropwise. The reaction mixture was stirred at 90° C. for 1 hour then vacuum filtered hot to provide the product cv (3.187 g, 36%).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:4].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:12]=1
Reactant: OCCCCCCCl
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 90 °C
Reaction time: 32 h
Yield: 71.9 %

Procedure:
Methyl 4-hydroxy cinnamate (40 g, 225 mmol) was dissolved in 300 ml of NMP. 6-Chlorohexanol (269 mmol, 36.8 g), anhydrous potassium carbonate (37.2 g, 269 mmol) and a catalytic amount of potassium iodide were added. The batch was stirred at 90° C. for 32 hours. Water was added to the cooled solution, which was subsequently extracted with 3×200 mls of ethyl acetate. The combined organics were washed with 10% KOH (2×100 mls), brine solution and then dried over magnesium sulfate. The concentrated product was then recrystallized from a 1:1 mixture of ethyl acetate/hexane to give 45 g (72% yield) of an off-white solid.