Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.O=S(Cl)[Cl:25]>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([Cl:25])=[O:22])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (2.0 g, 6.825 mmol) in CHCl3 (6 mL) was added SOCl2 (10 mL) at 0° C. and the reaction mixture was stirred at RT for 2 h. The reaction was concentrated in vacuo and the residue was re-dissolved in ether (50 mL). The mixture was concentrated in vacuo again to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 95%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:17](OCC)=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reaction time: 0.17 h

Procedure:
A solution of 3.5 g (7.7 mmol) of ethyl 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanoate (example 2) in 105 ml methylene chloride is cooled to -78° and to it is added slowly added 15.2 ml (23.6 mmol) of 1.53M solution of diisobutylaluminium hydride in toluene. The solution is stirred at -78° for 10 min and then quenched by slow addition of 10.8 ml methanol. The solution is then allowed to warm to 0° by the removal of the cold bath, and then 350 ml of ether is added followed by 10.8 ml of saturated brine and 7.7 g finely powdered anhydrous sodium sulfate. The cloudy suspension is stirred vigorously at room temperature overnight. The salts are filtered off and washed with methylene chloride (10×20 ml). The filtrate is evaporated to give 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanal.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[S:22](Cl)(=[O:24])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:9]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[S:22]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:23])=[O:24])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1CCc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2sccc2CCc2ccccc2)c1Br
Yield: 48 %

Procedure:
3-Phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 3-phenethyl-2-thiophenesulfonyl chloride in 48% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].S(Cl)([Cl:12])(=O)=O>C(Cl)Cl>[Cl:12][C:2]1([CH3:1])[C:6](=[CH2:7])[O:5][C:4](=[O:8])[O:3]1
Reactant: Cc1oc(=O)oc1C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: C=C1OC(=O)OC1(C)Cl
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 50 g of 4,5-dimethyl-1,3-dioxolene-2-one (IV)(Synthesized by the method described in Tetrahedron Letters, 1701-1704 (1972)) in 350 ml of methylene chloride was added 65 g of sulfuryl chloride dropwise over 1 hour at 40°-42° C. The mixture was stirred for one hour at the same temperature and then evaporated in vacuo to remove the solvent. The resulting residue was distilled in vacuo to obtain 42.1 g (65% of theory) of 4-chloro-4-methyl-5-methylene-1,3-dioxolane-2-one (III) as a colorless oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Br:12])=[C:8](Br)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[SH-:14].[Na+].Cl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Br:12])=[C:8]([SH:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [SH-]
Reactant: CC(C)(C)n1ncc(Br)c(Br)c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)n1ncc(S)c(Br)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 30.4 %

Procedure:
To 200 ml of water were added 31.0 g of 2-tert.-butyl-4,5-dibromo-3(2H)-pyridazinone and 15.8 g of 70% sodium hydrosulfide. After stirring at 60° C. for 4 hours, the resulting mixture was allowed to cool to room temperature and incorporated with about 8 ml of concentrated hydrochloric acid to lower the pH of the liquid to not higher than 2. The resulting solid was filtered off, washed with water, dried and then recrystallized from benzene/n-hexane to give 8.0g of the intended product as white crystals of m.p. 107°-110° C. (yield: 30.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:27][O:28][C:29]1[N:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[C:32]2[CH:39]=[O:40]>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH:6]1[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)[CH:39]([OH:40])[C:32]1[C:31]2[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[N:30]=2)[N:35]=[CH:34][CH:33]=1)[CH3:2]
Reactant: COc1ccc2nccc(C=O)c2n1
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C1CCC2(CC1)OCCO2)C(O)c1ccnc2ccc(OC)nc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid ethyl ester (3.6 g, 15.77 mmol) in THF (50 mL) cooled to −78° C. was added LiHMDS (1M in THF, 18.1 mL) under argon. The resulting solution was stirred for 1 h at −40° C., then recooled to −78° C. 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (3.56 g, 18.92 mmol; prepared according to WO 2006/032466) was added portionwise and stirring was continued for 30 min at −78° C. The reaction mixture was quenched by the addition of aq. NH4Cl. The two layers were separated and the aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (Hept-EA 1-2→EA) to afford a diastereoisomeric 1:1 mixture of the title compound as a pale yellow oil (4.44 g, 68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:36]>[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[O:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: O=C(CCl)Nc1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)Nc3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.1 %

Procedure:
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-N-(4-fluorophenyl)acetamide (96 mg, 0.53 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure, to obtain 20 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-fluorophenyl)acetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 5 00 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)OCO4)nc12
Reactant: CS(=O)(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine (100 mg, 0.24 mmol) in 5 mL of dry DMF was added N-(2-bromoethyl)methanesulfonamide (150 mg, 0.7 mmol) and Cs2CO3 (150 mg, 0.46 mmol). The resulting mixture was stirred at a temperature of about 25° C. for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound WS35 as white solid (35 mg, 27% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[I-:24].[K+].II>N.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:6][C:7]=1[I:24]
Reactant: [I-]
Reactant: CCOC(=O)c1cccc(-c2ccc(O)cc2)c1
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccc(O)c(I)c2)c1
Reaction time: 1 h

Procedure:
The product from Example 143A (7.71 g, 31.8 mmol) was dissolved into N,N-dimethylformamide (30 mL), diluted with concentrated aqueous ammonia (320 mL), and treated with a solution of potassium iodide (27.72 g, 167 mmol) and iodine (8.48 g, 33.4 mmol) in water (100 mL) all at once. After the mixture was stirred for one hour, the ammonia was removed under reduced pressure on a rotary evaporator. The remaining solution was neutralized to pH 7 with aqueous hydrochloric acid, diluted with EtOAc (200 mL), worked up as usual, dried (Na2SO4), concentrated, and chromatographed on silica with a 33 to 100% gradient of CH2Cl2/hexanes to provide the title compound as a white microcrystalline solid (37% yield). 1HNMR (300 MHz, d6-DMSO) δ 1.35 (t, 3 H), 4.35 (q, 2H), 7.00 (d, 1 H), 7.53-7.60 (m, 2 H), 7.84-7.91 (m, 2 H), 7.97 (d, 1 H), 8.08 (dd, 1 H), 10.55 (bs, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6](=N)[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][O:23][CH3:24].C(Cl)Cl.CC(C)=[O:31]>>[CH3:1][C:2]1([CH3:25])[C:6](=[O:31])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:18])([F:17])[F:19])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][O:23][CH3:24]
Reactant: CC(C)=O
Reactant: COCCN1C(=S)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=N)C1(C)C
Solvent: ClCCl
Product: COCCN1C(=S)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C

Procedure:
Using the procedure of Example 71, the product of Example 78 was reacted to obtain the expected product melting at 98°-99° C. with a Rf=0.32 (eluant: methylene chloride--acetone (99-1))
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[N:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C=CC=CC=1.[O:28]=[CH:29][C:30]([Cl:33])([Cl:32])[Cl:31].C(=O)([O-])[O-].[K+].[K+].OOS([O-])=O.[K+].OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1.CCCCCC>[Cl:31][C:30]([Cl:33])([Cl:32])[CH:29]1[O:28][N:8]1[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: O=S([O-])OO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Temperature: 120 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
20.0 g (53.0 mol) of triphenyl(t-butoxycarbonylimino)phosphorane was suspended in 80 mL of toluene, mixed with 8.84 g (60.0 mmol) of anhydrous chloral and heated at 120° C. for 4 hours under reflux. After cooling to room temperature, 300 mL of hexane was added, and the resulting white solid was separated by filtration. The filtrate was concentrated under reduced pressure. The resulting brown liquid was dissolved in 200 mL of chloroform, and simultaneous addition of 3.74 g (50.0 mmol) of potassium carbonate in 20 mL of ice-cold water and 4.94 g (15 mmol) of OXONE (2KHSO5.KHSO4.K2SO4, supplied from Du Pont) in 40 mL of ice-cold water and 1 hour of stirring under cooling with ice were repeated three times. After removal of the aqueous layer, simultaneous addition of aqueous potassium carbonate and aqueous OXONE (2KHSO5.KHSO4.K2SO4, supplied from Du Pont) and 1 hour of stirring under cooling with ice were repeated three times, similarly. After removal of the aqueous layer, simultaneous addition of aqueous potassium carbonate and aqueous OXONE and 1 hour of stirring under cooling with ice were repeated three times, similarly. After removal of the aqueous layer, 11.2 g (150 mmol) of potassium carbonate in 60 mL of ice-cold water and 14.8 g (45 mmol) of OXONE in 120 mL of ice-cold water were added simultaneously, and the reaction solution was stirred for 1 hour of stirring under cooling with ice. After removal of the aqueous layer, aqueous potassium carbonate and aqueous OXONE were simultaneously added, the reaction solution was stirred for 1 hour of stirring under cooling with ice, similarly. After removal of the aqueous layer, aqueous potassium carbonate and aqueous OXONE were simultaneously added, the reaction solution was stirred for 1 hour of stirring under cooling with ice, similarly. After removal of the aqueous layer, the chloroform layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate {100:0 (volume ratio, hereinafter the same applies) to 80:20} as the eluent to give 10.3 g of the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH2:10].C([O:19][C@@H:20]1[C@H:24]([O:25]C(=O)C2C=CC=CC=2)[C@@H:23]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:22][C@H:21]1[N:44]1[CH:52]=[N:51][C:50]2[C:45]1=[N:46][C:47]([Cl:54])=[N:48][C:49]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:54][C:47]1[N:48]=[C:49]([NH:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:50]2[N:51]=[CH:52][N:44]([C:45]=2[N:46]=1)[C@@H:21]1[O:22][C@H:23]([CH2:34][OH:35])[C@@H:24]([OH:25])[C@H:20]1[OH:19]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: COc1ccccc1CN
Agent: N
Product: COc1ccccc1CNc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 45.9 %

Procedure:
The title compound was prepared by reacting (2-methoxyphenyl)methylamine (0.55 g, 4.0 mmol) with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.01 g, 1.6 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro- N-[(2-methoxyphenyl)methyl]adenosine (0.31 g, 45%)(after column chromatography) as a solid, mp 116°-119° C., 1H NMR (DMSO-d6)δ 3.51-3.60 (1H, m, H-5'a), 3.61-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, m, H-3'), 4.52 (1H, q, H-2'), 5.06 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 6.83-7.25 (4H, 2t, 2d, Ar--H), 8.43 (1H, s, H-8), 8.72 (1H, t, N--H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1.[OH-].[NH4+:26]>O1CCOCC1>[NH2:26][C:9]1[C:10]2[C:2]([Br:1])=[CH:3][N:4]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(Cl)ncnc32)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(N)ncnc32)CC1
Temperature: 100 °C
Yield: 112.6 %

Procedure:
To 1,1-dimethylethyl 4-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (313 mg, 0.753 mmol) was added ammonium hydroxide (2 mL, 51.4 mmol) and 1,4-Dioxane (1 mL) to a 5 mL microwave vial and heated in microwave for 20 min. at 100° C. After total of 35 min. reaction was completed. The reaction was concentrated to give 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (336 mg), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
3.00 g (14.3 mmol) 2,6-dichloropyridine-4-carboxylic acid chloride, 1.80 g (11.0 mmol) 4-methyl-3H-benzoxazol-2-one and 9.47 g (71.0 mmol) aluminium trichloride were combined and heated for 2 h to 125° C. with stirring. Then the mixture was decomposed with ice water and EtOAc and the phases were separated. The aqueous phase was extracted several times with EtOAc. The organic phases were combined, dried on sodium sulphate, filtered and the filtrate was evaporated down i. vac. The residue was triturated with diethyl ether, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[C:10]2[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[C:4]2[NH:21][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:23][C:3]1=2.[CH2:28](O)[CH2:29][OH:30].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:12]=[C:11]1[C:10]2[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[C:4]2[NH:21][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:23][C:3]=2[C:2]21[O:30][CH2:29][CH2:28][O:1]2
Reactant: COC(=O)c1cc(C(=O)OC)c2c(n1)C(=O)C(=O)c1cc(C(=O)OC)[nH]c1-2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)c1cc(C(=O)OC)c2c(n1)C(=O)C1(OCCO1)c1cc(C(=O)OC)[nH]c1-2
Temperature: 25 °C

Procedure:
A suspension of trimethyl 4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylate, 1 (1.2 g, 3.22 mMol) in benzene (200 mL) was treated with ethylene glycol (10 mL) and p-toluensulfonic acid (60 mg, 0.32 mMol). The resulting mixture was heated at reflux under a Dean-Stark trap and reflux condenser for 14 hours. The orange suspension became a yellow solution. The heat was turned off, the trap was removed, and the condenser was replaced. To the hot solution, a mixture of benzene (75 mL) and DCM (75 mL) was cautiously added. The resulting solution was allowed to cool to room temperature, and then washed with 5% aqueous NaHCO3 (100 mL). The organic layer was separated and washed with water (100 mL). The organic layer was separated, dried over Na2SO4, and filtered. Evaporation of solvent at reduced pressure gave a yellow solid. Flash chromatography on silica gel (40 g), eluting with EtOAc-DCM-Hexane (50:25:25) gave purified 2 (1/02 g, 74.4%) as a yellow solid upon evaporation of solvent. 1H-NMR (CDCl3, δ) 12.31 (s, 1H, NH), 8.77 (s, 1H, H-8), 7.15 (d, 1H, H-3), 4.35 (m, 2H, OCH2), 4.30 (m, 2H, OCH2), 4.11 (s, 1H, CO2CH3), 4.07 (s, 1H, CO2CH3), 3.93 (s, 1H, CO2CH3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[C:8](=O)[CH2:9][CH3:10].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[C:8](=[N:24][OH:25])[CH2:9][CH3:10]
Reactant: CCC(=O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NO)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of 1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-one (330 mg, 1.11 mmol), hydroxylamine hydrochloride (230.4 mg, 3.33 mmol), and sodium acetate (273 mg, 3.33 mmol) in ethanol (25 ml) was stirred at room temperature over a weekend. The mixture was concentrated to dryness, then diluted with water, and extracted with chloroform. The organic layer was separated, dried over sodium sulfate and concentrated to dryness to give 306 mg of a mixture of the title (E) and (Z)-isomers as a white solid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[Cl:18])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:26][O:27][C:28]([C:30]1[CH2:31][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:33][CH2:34][C:35]=1OS(C(F)(F)F)(=O)=O)=[O:29].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:26][O:27][C:28]([C:30]1[CH2:31][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:33][CH2:34][C:35]=1[C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[Cl:18])=[CH:4][CH:3]=1)=[O:29]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(Br)cc2)c(Cl)c1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
1-[2-(4-Bromo-phenoxy)-ethoxy]-2,6-dichloro-4-methyl-benzene (16.6 g, 44.2 mmol) was dissolved in THF (150 mL), and the sol. was cooled to −78° C. BuLi (1.6M in hexane, 31.4 mL, 50.3 mmol) was added, and the mixture was stirred at −78° C. for 30 min. ZnCl2 (1M in THF, 56.0 mL, 56.0 mmol) was added, and the mixture was allowed to warm up to rt. The mixture was stirred at rt for 1 h. A sol. of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957; 14.3 g, 36.7 mmol) in THF (30 mL), and then a sol. of Pd(PPh3)4 (1.23 g, 1.06 mmol) in THF (30 mL) were added. The mixture was stirred at 50° C. over 20 min, and cooled to 0° C. Aq. 10% NH4Cl was added. The mixture was extracted with EtOAc. The org. extracts were washed with aq. 10% NH4Cl, water, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→EtOAc) yielded the title compound (19.7 g, quantitative yield). LC-MS: tR=1.20 min; ES+: 536.77.