Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]([CH3:39])[S:27]([N:30]1[CH:34]=[CH:33][C:32]([Sn](C)(C)C)=[N:31]1)(=[O:29])=[O:28]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:32]2[CH:33]=[CH:34][N:30]([S:27](=[O:29])(=[O:28])[N:26]([CH3:25])[CH3:39])[N:31]=2)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
Reactant: CN(C)S(=O)(=O)n1ccc([Sn](C)(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)Nc1cc(-c2ccn(S(=O)(=O)N(C)C)n2)sc1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 66.5 %

Procedure:
To a stirred solution of 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (43 mg, 0.1 mmol) in toluene (3.0 mL) was sequentially added a solution of Pd(PPh3)4 (12 mg, 0.01 mmol) in toluene (1.0 mL) and 3-Trimethylstannanyl-pyrazole-1-sulfonic acid dimethylamide (prepared according to J. Med. Chem (1998), 41, p-2019) (75 mg, 0.2 mmol, 2.0 eq), and heated the resulting overnight at 80° C. It was then cooled to room temperature, the solvent was evaporated and the crude was purified on preparative TLC using EtOAc/hexane (1:5). 5-(1-Dimethylsulfamoyl-1H-pyrazol-3-yl)-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (35 mg, 66.5% yield) was isolated. 1H NMR (CDCl3, 400 MHz) 9.93 (s, 1H), 8.11 (d, J=0.7 Hz, 1H), 8.02 (dd, J=6.7, 1.32 Hz, 1H), 7.84 (d, J=0.7 Hz, 1H), 7.45 (dt, J=7.5, 1.3 Hz, 1H), 7.31 (t, J=8.2 Hz, 2H), 7.26 (d, J=1.0 Hz, 1H), 2.98 (s, 6H), 2.7 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: Cl.C(O[C:5](=[NH:7])[CH3:6])C.[F:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1>>[NH:7]=[C:5]([N:15]([C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=1)[NH2:16])[CH3:6]
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: CCOC(C)=N
Agent: Cl
Product: CC(=N)N(N)C(=O)c1ccc(F)cc1

Procedure:
Prepared from 7.2 g (58 mmol) ethylacetimidate hydrochloride and 5.00 g (32 mmol) 4-fluoro-benzoic acid hydrazide analogously to the method described for intermediate product 1, Step a).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH3:13].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)cnc1Cl
Temperature: 130 °C

Procedure:
To a solution of 2,5-dichloronicotinic acid (30 g, 0.16 mol) in toluene (100 ml) was added ethanol (50 ml) and cone, sulfuric acid (1 ml). The reaction mixture was heated at 130° C. for 3 days with stirring. Then the reaction mixture was cooled and poured into sat. sodium bicarbonate solution. The whole mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 34 g (quant.) of title compound:
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH2:15][CH3:16])=[N:13][O:14][C:8]=2[C:7]=1[OH:17])=[O:5])C.[NH2:18][CH2:19][C:20]([OH:22])=[O:21].[O-]CC.[Na+].Cl>CN(C=O)C.O.CCOC(C)=O>[CH2:15]([C:12]1[C:9]2[CH:10]=[N:11][C:6]([C:4]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:5])=[C:7]([OH:17])[C:8]=2[O:14][N:13]=1)[CH3:16]
Reactant: CCOC(=O)c1ncc2c(CC)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1noc2c(O)c(C(=O)NCC(=O)O)ncc12
Temperature: 25 °C
Yield: 50.3 %

Procedure:
3-Ethyl-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (80 mg, 0.42 mmol) was dissolved in 12 mL of DMF. Glycine (0.51 g, 6.78 mmol) and sodium ethoxide (0.35 g, 5.08 mmol) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and diluted with 60 mL of water. EtOAc (50 mL) was added and the resulting biphasic mixture was stirred vigorously as 4M hydrochloric acid was added dropwise until pH was 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. The solvent was evaporated and the solid residue was taken up in 50 mL of saturated sodium bicarbonate solution. The aqueous phase was washed with hexanes and EtOAc. The aqueous layer was then acidified to pH 2 by addition of concentrated hydrochloric acid and extracted with EtOAc (3×50 mL). The combined organic layer was dried over MgSO4 and concentrated to give 56 mg of the title compound. MS: (+) m/z 266.32 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1B(O)O>>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=4[N:7]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Reactant: OB(O)c1cc2ccccc2[nH]1
Product: CN(Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1)S(C)(=O)=O

Procedure:
N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 194. NMR: (400 MHz, DMSO) 2.83 (s, 3H), 3.02 (s, 3H), 3.85 (t, J=4.7, 4H), 3.99 (t, J=4.7, 4H), 4.64 (s, 2H), 7.19 (t, J=7.7, 1H), 7.43 (m, 2H), 7.51 (m, 2H), 8.12 (d, J=7.3, 1H), 11.20 (s br, 1H) MS: (ESI+)[M+H]+ 458.01
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:2]2[CH:3]=[CH:4][CH:8]=[CH:9][CH:10]=2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 189.3 %

Procedure:
Under ice-cooling, to a solution of 3-bromobenzoyl chloride (9.50 g, 43.3 mmol) in benzene (30 mL) was added aluminum chloride (III) (6.93 g, 52.0 mmol) by small portions, and the mixture was heated to 50° C. and stirred for 2 hrs. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-5% ethyl acetate/hexane) to give the title compound (10.7 g, yield 95%) as pale-red crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].[Br:14]Br>CC(O)=O>[C:1]([C:4]1[CH:9]=[C:8]([Br:14])[CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1ccccc1C(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)cc1C(C)=O
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
Under N2, a pale yellow suspension of crude N-(2-acetylphenyl)acetamide (28 g, 158 mmol) in AcOH (300 mL) was stirred for about 5 min, and Br2 (12.95 mL, 253 mmol) was added within 1 h at room temperature. The resulting mixture was then stirred at room temperature for 75 min. After the reaction went to completion as monitored by LC-MS, the reaction mixture was quenched with H2O (200 mL). The mixture was filtered through Buchner funnel, and the solid was collected as N-(2-acetyl-4-bromophenyl)acetamide (35 g, yield 86%). MS (m/z): 216 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([N+]([O-])=O)[CH:6]=2.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1COCC1.CN(C1C=CN=CC=1)C.CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])n1cc2ccc(Br)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2n[nH]c3cc(Br)ccc23)CC1
Reaction time: 24 h
Yield: 35.5 %

Procedure:
A solution of 6-bromo-2-nitro-2H-indazole (50 mg) and 1,1-dimethylethyl 1-piperazinecarboxylate (107 mg) in THF (1 ml) was stirred at reflux for 18 h. Additional 1,1-dimethylethyl 1-piperazinecarboxylate (107 mg) and DMAP (˜10 mg) were added and heating was continued for 24 h. The mixture was diluted with methanol then purified by reverse phase preparative HPLC to give the title compound as a yellow oil (28 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:27]=[C:25]([OH:26])[C:23]([OH:24])=[CH:22][CH:21]=1)[C:16]([OH:18])=[O:17])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[CH2:28]([O:26][C:25]1[CH:27]=[C:20]([CH2:19][C@H:15]([NH:14][C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C:16]([O:18][CH2:19][C:20]2[CH:27]=[CH:25][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:21]=[CH:22][C:23]=1[O:24][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Temperature: 55 °C
Yield: 163.3 %

Procedure:
K2CO3 (21.0 g, 150 mmol) was added to a solution of Boc-L-dopa (10.0 g, 33 mmol) in acetonitrile (100 mL) followed by addition of benzyl bromide (21.0 g, 123 mmol). The suspension was heated at 50-60° C. for 4 h and then cooled to ambient temperature. The mixture was filtered and the filtration cake was washed with acetonitrile (50 mL). The filtrate and washings were combined and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc=20:1) to afford (S)-benzyl 3-(3,4-bis(benzyloxy)phenyl)-2-(tert-butoxycarbonylamino)propanoate (15.3 g, yield 80%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: OB(O)c1cncnc1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide (Stage 179.1) and pyrimidin-5-ylboronic acid to afford a white crystalline solid. HPLC (Condition 4) tR=5.02 min, UPLC-MS (Condition 3) tR=0.96 min, m/z=450.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H) 3.38-3.65 (m, 4H) 4.67 (t, J=5.08 Hz, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 8.13 (d, J=2.35 Hz, 1H) 8.75 (d, J=1.56 Hz, 1H) 8.95 (s, 2H) 9.17 (s, 1H) 10.22 (s, 1H).
Reaction SMILES: [Cl:1][CH:2]=[CH:3]Cl.N#N.[Li]CCCC.[CH3:12][C:13](=[O:34])[C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C@@H:21]([CH2:22][C:23](=[O:33])[CH2:24][CH2:25]2)[CH2:20][CH2:19]3)[CH2:16][CH2:15]1>C1COCC1>[Cl:1][C:2]#[C:3][C@@:23]1([OH:33])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:31]2([CH3:32])[C@H:17]3[CH2:16][CH2:15][C@@H:14]2[C:13](=[O:34])[CH3:12])[CH2:22]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: ClC=CCl
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@](O)(C#CCl)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
An attempt was also made to prepare the organometallic reagent with 1,2-dichloroethylene. A 100 mL three-neck flask equipped with a N2 gas bubbler, a thermometer, and a dropping funnel was charged with 1,2-dichloroethylene (cis, Aldrich, 0.16 mL, 2 mmol, mw=97, d=1.28). Dry THF (7 mL) was added, and the solution was cooled to -10° C., n-BuLi (2.5M in THF, 1.6 mL, 4 mmol) was added dropwise over a period of 10 min. The mixture was stirred at -30° C. for 20 min and then at 0°-5° C. for 10 more min. The resulting reagent was then recooled to -30° C. and was treated dropwise with a solution of 5β-pregnan-3,20-dione, 20-ketal (360 mg, 1 mmol) in THF (15 mL). The cooling bath was removed and the mixture was stirred at room temp. for 30 min. (100% conversion as detected by TLC). The cooling bath was removed and the resulting solution was quenched with sat. NH4Cl solution (1 mL). The solvent was removed and the residue was dissolved in acetone (30 mL). After adding 2N HCl (5 mL) the solution was stirred at ambient temperature for 1.5 h. The mixture was neutralized with dil. NaOH solution (pH 5-6). The precipitated solid (429 mg) was collected by filtration, washed with water, and dried. The crude product was then purified by column chromatography over silica gel (toluene acetone 95:5) to yield 3β-chloroethynyl-3α-hydroxy-5β-pregnan-20-one (130 mg); TLC-Rf 0.33 (toluene:acetone 95:5), NMR (CDCl3) δ 0.59 (s, 3H, Me), 0.97 (s, 3H, Me), 2.11 (s, 3H, Me), 2.55 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].C(O)=O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Temperature: 50 °C
Reaction time: 22 h

Procedure:
A solution of Intermediate Ab (161 g, 624 mmol) in DMF (2 L) was vacuum degassed with Argon. [N-[(1R,2R)-2-(Amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium (CAS: 192139-92-7, 9.95 g, 15.6 mmol) was then added. Formic acid (57.5 g, 1.25 mol) was added slowly to ice cold triethylamine (126 g, 1.25 mol) with stirring, this was then added to the DMF solution. The resulting reaction mixture was heated to 50° C. (internal temperature) for 41 h with stirring. LCMS analysis of the reaction indicated it was incomplete, therefore a solution of formic acid (14.4 g, 313 mmol) was added slowly to ice cold triethylamine (31.6 g, 312 mmol), this was then added to the reaction mixture. Heating was continued for an additional 22 h. After cooling, the mixture was concentrated in vacuo to give an orange residue. The residue was diluted with ethyl acetate (1.5 L) and the solution washed with brine (2×0.5 L). The organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (Silica, 3 Kg, 0-50% ethyl acetate in cyclohexane) gave Intermediate Ac (118 g, 73%). 97.5 d.e. % determination by LCMS (Method 4): Rt 3.37 min, M-H=258 (93.7%, desired); Rt 3.25 min, M-H=258 (1.2%, trans isomer). 1H NMR (400 MHz, CDCl3): 1.88-1.92 (1H, d, J=4.8 Hz), 1.98-2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H, br s), 7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)[CH:16]=2)[C:11]([CH3:37])([CH3:36])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)[CH:16]=2)[C:11]([CH3:36])([CH3:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(C#Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(C#Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A solution of 7-[3-(4-methoxycarbonyl-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.035 g, 0.07 mmole) in 5 mL of a 4:1 THF/methanol mixture was treated with a solution of 0.1 g of lithium hydroxide monohydrate in 2 mL of water and stirred at 40° C. for 2 hours. The mixture was diluted with 5 mL of water and the pH adjusted to 2 with 2N HCl solution. The mixture was extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 0.03 g of 7-[3-(4-carboxy-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a yellow oil
Reaction SMILES: [CH3:1][C:2]1([O:15][CH2:16][CH2:17]/[CH:18]=[CH:19]/[C:20](=[O:22])[CH3:21])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(=O)/C=C/CCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 5 h
Yield: 92.9 %

Procedure:
To a solution of (E)-tert-butyl 4-methyl-4-((5-oxohex-3-en-1-yl)oxy)piperidine-1-carboxylate (6.2 g, 19.91 mmol) in MeOH (100 mL) was added 10% Pd/C (2.119 g, 1.991 mmol) and the flask was three times evacuated and released to H2, then left under balloon H2 atmosphere for 5 h. Then, filtered and concentrated to give tert-butyl 4-methyl-4-((5-oxohexyl)oxy)piperidine-1-carboxylate (5.8 g, 18.50 mmol, 93% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 3.77-3.70 (m, 2H), 3.32 (t, J=6.3 Hz, 2H), 3.13 (t, J=11.2 Hz, 2H), 2.48 (t, J=7.3 Hz, 2H), 2.16 (s, 3H), 1.77-1.62 (m, 4H), 1.59-1.53 (m, 2H), 1.48 (s, 9H), 1.45-1.37 (m, 2H), 1.16 (s, 3H). LCMS (M+Na)=336.4.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[O:1]
Reactant: COC(=O)CCc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.1 %

Procedure:
A suspension of methyl 4-hydroxymethylhydrocinnamate (2.34 g) and manganese dioxide (21.0 g) in 40 ml dichloromethane was stirred at room temperature for 17 hours. Manganese dioxide was filtered off onto Celite. The filtrate was evaporated and dried under reduced pressure to give methyl 4-formylhydrocinnamate (2.11 g, 91%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][S:27](=[O:30])[CH2:26][CH2:25]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:14]1([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][S:27](=[O:30])[CH2:26][CH2:25]4)[C:5]=3[N:11]=[CH:10][N:9]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4cccc5ccccc45)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4cccc5ccccc45)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(1-naphthylmethyl-thio)-4-(1-oxidothiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 212°-215° C.) and piperazine.
Reaction SMILES: [CH3:1][C:2]1[N:3](NS(C2C=CC(C)=CC=2)(=O)=O)[C:4]([C:15]2[C:20]([CH3:21])=[N:19][CH:18]=[CH:17][N:16]=2)=[C:5]([C:11]([O:13][CH3:14])=[O:12])[C:6]=1[C:7]([O:9][CH3:10])=[O:8]>CO.[Ni]>[CH3:1][C:2]1[NH:3][C:4]([C:15]2[C:20]([CH3:21])=[N:19][CH:18]=[CH:17][N:16]=2)=[C:5]([C:11]([O:13][CH3:14])=[O:12])[C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1c(C(=O)OC)c(-c2nccnc2C)n(NS(=O)(=O)c2ccc(C)cc2)c1C
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1c(C)[nH]c(-c2nccnc2C)c1C(=O)OC

Procedure:
A solution of 4.57 g of 31C in 20 ml of methanol was added to a mixture of 15 g of Raney nickel in 30 ml of methanol. The mixture was heated at reflux overnight, cooled and the methanol phase was decanted. The catalyst was washed with 100 ml of 1:1 mixture of methylene chloride and methanol. The washings were combined with the methanol phases, and the resulting mixture was stripped of the solvents. The residue was dissolved in a mixture of 20 ml of water and 100 ml methylene chloride. The mixture was acidified to pH=2 with 6N hydrochloric acid, and the solution was neutralized with solid sodium bicarbonate to pH=7. The organic phase was separated, dried (Na2SO4), and stripped of solvent, and the residue was flash chromtographed on silica gel, with a 7:3 v:v mixture of methylene chloride and ethyl acetate as solvent. The product was triturated with ether and the solid product was collected to give 31, as a white solid, m.p.: 155°-156° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[C:11]1([C:2]2[CH:8]=[C:7]([C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=3)[CH:6]=[C:5]([F:10])[C:3]=2[NH2:4])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1c(F)cc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1c(F)cc(-c2ccccc2)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 159.5 %

Procedure:
2,4-dibromo-6-fluoroaniline (10 mmol), benzeneboronic acid (24 mmol), tetrakis(triphenylphosphine)palladium(0) (1 mmol) and potassium carbonate (12 g) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL) and H2O (10 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 2,4-diphenyl-6-fluoroaniline (2.1 g) is yielded.