Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[C:9]#[CH:10])=[C:4]([O:12][CH2:13][S:14][CH3:15])[CH:3]=1.Br[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1/[C:19](=[CH:27]/[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34])/[C:20](=[O:26])[NH:21]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[C:9]#[C:10][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2/[C:19](=[CH:27]/[C:28]2[NH:29][CH:30]=[CH:31][C:32]=2[O:33][CH3:34])/[C:20](=[O:26])[NH:21]3)=[C:4]([O:12][CH2:13][S:14][CH3:15])[CH:3]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc(Cl)cc1OCSC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(Cl)cc3OCSC)c21

Procedure:
Using Method D above, 3-(4-chloro-2-methylsulfanylmethoxy-phenyl)-3-hydroxy-1-propyne (158 mg, 0.65 mmol) (from Example 53 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (152 mg, 0.48 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (40 mg) (Aldrich) and CuI (22 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h, yielding rac-(Z)-4-[3-(4-chloro-2-methylsulfanylmethoxy-phenyl)-3-hydroxy-1-propynyl]-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 132 mg, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].[C:23]([C:27]1C=[C:31](C)[CH:30]=[C:29](C(C)(C)C)[C:28]=1O)(C)(C)[CH3:24].[NH4+:39].[OH-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][C:23]1[CH:27]=[C:28]([C:18]2[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([CH2:7][C:8]3[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)=[CH:16][C:17]=2[O:20][CH2:21][CH3:22])[CH:29]=[C:30]([CH3:31])[N:39]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [NH4+]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cc(C)nc(C)c1
Temperature: 140 °C
Reaction time: 24 h
Yield: 6.6 %

Procedure:
5-(3,5-Diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (414 mg; 1 mmol), 2,6-dimethyl-4-trimethyltin-pyridine (404 mg; 1.5 mmol), bis(triphenyl-phosphine)palladium dichloride (20 mg) and a few crystals of 2,6-di-tert-butyl-4-methylphenol are dissolved in dimethylformamide (5 ml) and the solution is stirred for 24 hours at 140° C. while gassing with argon. The reaction mixture is concentrated, a little water is added to the residue obtained, the pH is adjusted to 8 by addition of NH4OH conc. and the entire mixture is filtered with suction. The mother liquor is concentrated and the residue is chromatographed over silica gel (30 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05). 26 mg (6.6%) 5-[4-(2,6-dimethyl-pyridin-4-yl)-3,5-diethoxy-benzyl]-pyrimidine-2,4-diamine are obtained as a yellow powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[N+:32]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39])([O-:34])=[O:33]>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4cccc([N+](=O)[O-])c4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 86 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (40 mg, 0.1 18 mmol) (from Example 5 supra) and Et3N (33 μL , 0.237 mmol) in 3 mL of chloroform was cooled to −78° C. and then treated with 3-nitrobenzoyl chloride (24 mg, 0.129 mmol) (Aldrich). The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 7 h. The reaction mixture was then concentrated in vacuo. The resulting yellow solid was dissolved in ethanol, and re-precipitated by the addition of distilled water to yield pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-3-nitrobenzamide (yield: 50 mg, 94%) as a yellow solid (mp 265-266° C.).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].[NH2:9][C:10]([NH2:12])=[O:11].C1C=CC=CC=1>C(OCC)(=O)C>[C:10]([N:12]1[CH2:7][CH2:6][CH:2]([Br:1])[C:3]1=[O:4])(=[O:11])[NH2:9]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: NC(N)=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: NC(=O)N1CCC(Br)C1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
A solution of 30 g of 2,4-dibromobutyryl chloride (J. Med. Chem., p1995, 30. 1987) and 13.63 g of urea dissolved into 150 ml of benzene was heated at 90° C. with stirring for 3 hours. The reaction mixture was cooled to room temperature, then a very excessive amount of ethyl acetate was added thereto. The layer of ethyl acetate was washed with an aqueous solution of sodium bicarbonate and saturated brine, then the resulting solution was dried over magnesium sulfate and evaporated. The obtained residue (28 g) was dissolved into 30 ml of tetrahydrofuran (THF) and cooled. To this mixture was added 4.7 g of NaH (55% in mineral oil) bit by bit, then the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to make the amount of the solution about 50 ml, then which was poured into ethyl acetate. The layer of ethyl acetate was washed with water and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was washed well with n-hexane, whereby 15.7 g of the objective compound was obtained in 66% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:14])[CH2:12]O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Br)(Br)[Br:16].O>C(OC(C)C)(C)C>[Br:16][CH2:12][C:11]([CH3:14])=[CH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: BrP(Br)Br
Reactant: CC(=Cc1ccc(C(C)C)cc1)CO
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(=Cc1ccc(C(C)C)cc1)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 136.4 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-2-methyl-2-propen-1-ol (6.30 g, 33.1 mmol) in isopropyl ether (50 ml) was added under ice cooling phosphorus tribromide(5.98 g, 22.1 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction mixture and the product was extracted with isopropyl ether. The organic layer was washed with water and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 7.63 g (91% yield) of the oily title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH2:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH:60]=2)[CH:55]=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([NH:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:64])[CH3:65])[CH:60]=2)[CH:55]=[CH:54][CH:53]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cccc(N)c2c1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
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: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)methionine (27.3 g, 109 mmol) in dry CH2Cl2 (45 mL) at 0° C., under argon, were added PYBOP (57 g, 109 mmol), 1-amino-7-(tert-butyldimethylsilyloxy)naphthalene hydrochloride, as described above in Step C above (13.6 g, 44 mmol), and N,N-diisopropylethylamine (26.7 mL, 153 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 4 hours, then partitioned between 10% aqueous citric acid (400 mL) and CH2Cl2 (1 L). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—10% to 25% EtOAc to yield the titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[Li]CCCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[NH4+].[Cl-]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1cccc(CO)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1c(CO)cccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
2.00 g (14.5 mmol) of 3-methoxybenzyl alcohol were dissolved in 40 ml of dry benzene. At 0° C., 19.91 ml (31.9 mmol, 2.2 eq.) of a 1.6 molar n-BuLi solution were slowly added dropwise, where the white suspension formed after addition of one equivalent of n-BuLi changed its color to dark red during the addition of the second equivalent. Stirring at RT was continued for another 2 hours, and 5.1 ml (18.8 mmol, 1.3 eq.) of tributyltin chloride were then added at 0° C. The mixture was stirred at RT overnight, and 40 ml of saturated NH4Cl solution were then added and the mixture was extracted three times with 70 ml of EA. After washing of the organic phase with saturated NaCl solution and drying over MgSO4, the solvent was removed. The crude product was purified by column chromatography (reversed-phase silica RP-18, MeCN), which gave 4.83 g (11.3 mmol, 78%) of 3-methoxy-2-(tributylstannyl)benzyl alcohol as a colorless oil. In a further experiment, a yield of 60% was obtained.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.S(=O)(=O)(O)O.[OH-].[Na+].[C:29](=O)([O-])O.[Na+]>CO>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:29])=[O:11]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reaction time: 30 h
Yield: 90 %

Procedure:
To 10 g (33.8 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid are added 75 mL of methanol and then 10 mL of sulfuric acid dropwise over 30 minutes. After 30 hours, the reaction medium is basified to pH 8-9 by adding aqueous 10N sodium hydroxide solution followed by saturated sodium hydrogen carbonate solution. The organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then filtered, and the solvents are evaporated off. 6.36 g of methyl (S)-2-amino-3-(4-methoxyphenyl)propionate in the form of a brown oil are obtained in a yield of 90%.
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(OCC)(=O)C.C1C=CC=CC=1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1cc(C)c(-n2c(C)c(C)c3c(Cl)nc(C)nc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCO
Product: Cc1cc(C)c(-n2c(C)c(C)c3c(-c4ccccc4C(F)(F)F)nc(C)nc32)c(C)c1

Procedure:
A mixture of 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine (425 mg, prepared as described by Y. L. Chen in Patent Application WO94/13676), 2-(trifluoromethyl)phenylboronic acid (310 mg) tetrakis(triphenylphoshine)palladium(0) (50 mg), 1M aqueous sodium carbonate (2 mL), ethanol (0.75 mL) and benzene (6 mL) was refluxed for 6 hr. The cooled mixture was diluted with ethyl acetate and the aqueous layer was removed. The organic layer was washed with 1N aqueous sodium hydroxide, and brine, dried, and concentrated in vacuo. The crude reaction product was chromatographed on silica gel using ethyl acetate/hexanes (1:3) as eluent. The title compound was obtained as a glass (300 mg) that crystallized on trituration with ether to give crystals, mp 176.5-177.5°. Elemental Analysis: Calcd. for C22H24N3F3 : C, 70.91: H, 5.71; N, 9.92. Found: C, 70.69; H, 5.72; N, 9.84.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]12(CC(O)=O)[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.ON1C2C=CC=CC=2N=N1.C(N1CC[O:46][CH2:45][CH2:44]1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.CN(C)C=O>[CH2:2]([O:9][C:10](=[O:16])[C@:11]1([C:45](=[O:46])[CH3:44])[CH2:15][CH2:14][CH2:13][N:12]1[C:17]12[CH2:26][CH:21]3[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]3)[CH2:24]1)[CH2:18]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)[C@@]1(C(=O)OCc2ccccc2)CCCN1C12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
A mixture of 4.8 g (0.02 m) of L-proline benzyl ester hydrochloride, 3.88 g (0.02 m) of α-(1-adamantyl)acetic acid, 5.4 g (0.04 m) of 1-hydroxybenzotriazole, 2.56 ml of N-ethylmorpholine, 60 ml of dimethylformamide and 4.16 g (0.02 m) of dicyclohexylcarbodiimide was stirred overnight at 25°. The mixture was filtered and the tetrahydrofuran removed in vacuo from the filtrate to leave a residue which was taken up in 200 ml of ethyl acetate. The resulting extract was acidified with dilute hydrochloride acid. The layers were separated. The organic layer was extracted several times with ethyl acetate. The organic extracts were combined and washed with dilute acid, water, bicarbonate solution and brine then dried and evaporated to give an amber syrup of N-(1-adamantyl)-ethanoylproline benzyl ester, m/e=381. A second run on a 0.04 m scale gave 16.2 g of ester.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.C[C:20]1([CH3:60])[C:46]2[C:41](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=[CH:44][CH:45]=2)[O:40]C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O.C(=O)([O-])[O-:63].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:45]([C:46]1[C:41](=[O:63])[O:40][CH2:60][C:20]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 60 °C

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 4-ethyl-5-oxo-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (246 mg, 0.944 mmol), Xantphos (45.5, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 60° C. for 16 h. After filtration through CELITE®, the filtrate was concentrated and the residue was purified on silica gel using ethyl acetatehexane to give the title compound. LC/MS: (M+1)+: 365.19.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9]1)(C)(C)C.C([Cl:23])(=O)C>CO>[ClH:23].[ClH:23].[F:18][C:15]([F:16])([F:17])[CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([NH2:7])[CH2:9]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(CC(F)(F)F)C1
Solvent: CO
Product: Cl
Product: N[C@@H]1CCCN(CC(F)(F)F)C1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 101.5 %

Procedure:
In a 250 mL round-bottomed flask, [(R)-1-(2,2,2-trifluoro-ethyl)-piperidin-3-yl]-carbamic acid tert-butyl ester (1.20 g, 4.25 mmol) was combined with MeOH (100 ml) to give a colorless suspension. The reaction mixture was place under a nitrogen atmosphere and cooled in an ice bath. Acetyl chloride (6.04 ml, 85.0 mmol) was added slowly. The reaction mixture was stirred at 5° C. for an additional 10 min then warmed to room temperature. After stirring at room temperature for 17 h, the reaction mixture was concentrated to dryness to afford 1.10 g (quantitative) of (R)-1-(2,2,2-trifluoroethyl)piperidin-3-amine dihydrochloride as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 8.27 (br. s., 3H), 3.39 (q, J=10.2 Hz, 2H), 3.15-3.27 (m, 1H), 3.10 (dd, J=11.3, 3.0 Hz, 1H), 2.83 (app d, J=11.7 Hz, 1H), 2.56 (d, J=10.2 Hz, 1H), 2.45 (d, J=9.8 Hz, 1H), 1.83-2.04 (m, 1H), 1.62-1.83 (m, 1H), 1.45-1.62 (m, 1H), 1.25-1.45 (m, 1H).
Reaction SMILES: [OH:1]O.[Se](=O)=O.[NH2:6]/[C:7](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1>O.CO>[NH2:6]/[C:7](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1=[O:1]
Reactant: OO
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Agent: O=[Se]=O
Solvent: CO
Solvent: O
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 1.1 ml (10.8 mmols) of 30% hydrogen peroxide and 1.1 gm (10 mmols) of selenium dioxide in 5 ml of water was added dropwise, while stirring, to a solution of 2.53 gm (10 mmols) of (E)-2-[(amino)phenylmethylene]-benzo[b]thiophen-3(2H)-one in 20 ml of methanol. The reaction temperature was not allowed to exceed +25° C. After 20 minutes, the reaction mixture was diluted with 100 ml of water, the reaction product was separated by suction filtering and recrystallized from ethanol/ethyl acetate (1:1 v/v) using activated charcoal.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[NH:4][CH:3]=1.[CH3:12]N(C)C=O.[H-].[Na+].CI>C(OCC)(=O)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ncnc2c(Br)c[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1cc(Br)c2ncnc(Cl)c21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (147 mg), N,N-dimethylformamide (10 mL) was added, and NaH (36 mg) was further added thereto, followed by stirring for 30 min. Subsequently, methyl iodide was added thereto, and the reaction mixture was heated to 50° C. and stirred for 2 hours. After completion of the reaction, the reaction mixture was mixed with ethyl acetate and washed with water. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CS(C)=O>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:22][CH:23]=1)#[N:26]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Temperature: 80 °C
Yield: 79 %

Procedure:
15.1 g of 1-(4-hydroxyphenyl)piperazine, 9.4 g of lithium carbonate and 10.4 g of 4-fluorobenzonitrile in 250 ml of dimethyl sulfoxide were reacted at 80° C. for 4 hours under a nitrogen atmosphere. After fresh addition of 3.0 g of 4-fluorobenzonitrile, the mixture was heated at 80° C. for a further 4 hours and the precipitated product was filtered out with suction after cooling the reaction mixture. To separate the co-precipitated lithium carbonate, the crude product was then stirred with aqueous citric acid. After filtering out with suction and drying in a vacuum oven at 60° C., 18.7 g of 4-[4-(4-cyanophenyl)-1-piperazinyl]phenol were obtained, m.p.=258°-262° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][O:18][CH2:19][CH2:20][OH:21].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:21][CH2:20][CH2:19][O:18][CH3:17]
Reactant: COCCO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COCCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-methoxyethanol and DBU in dioxane. ES-MS m/e (%): 316 (M{81Br}+H+, 96), 314 (M{79Br}+H+, 100), 258 ([M{81Br}+H-MeOCH═CH2]+, 70), 256 ([M{81Br}+H-MeOCH═CH2]+, 75).
Reaction SMILES: [C:1]1([N:11]([CH2:15][CH2:16][CH3:17])[C:12]([NH2:14])=[S:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH:19]([CH3:31])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[Cl:30])=O>CO>[Cl:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[C:20]1[N:14]=[C:12]([N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:16][CH3:17])[S:13][C:19]=1[CH3:31]
Reactant: COc1ccc(C(=O)C(C)Br)c(Cl)c1
Reactant: CCCN(C(N)=S)c1cccc2ccccc12
Solvent: CO
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cccc2ccccc12
Yield: 73.5 %

Procedure:
A solution containing 0.5 g of N-naphth-1-yl-N-propylthiourea and 0.5 g of 2-bromo-1-(2-chloro-4-methoxyphenyl)propan-1-one in 15 ml of methanol is heated at reflux for 6 hours. The reaction mixture is then evaporated to dryness and then, successively, the residue is taken up in water, basified with 33% sodium hydroxide and extracted with ethyl acetate and the organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. The residue is then purified on a column of silica gel eluted with ethyl acetate, to provide 0.56 g of a yellow oil. 1H NMR (CDCl3): 0.97 (t, J=7.7, 3H, --CH2 --CH3), 1.73 (sex, 2H, --CH2 --CH3), 2.04 (s, 3H, --CH3), 3.82 (s, 3H, --OCH3), 3.90 (m, 2H, --CH2 --CH2 --CH3), 6.89 (dd, J=1.8, J=8.0, 1H, H5arom) 7.02 (d, J=1.8, 1H, H3arom), 7.50-7.70 (m, 4H, H2, H3, H8 and H6arom), 7.85-8.10 (m, H, H6, H7, H4 and H5).