Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1.Cl>C(O)CCC>[NH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(N)c1
Reactant: Clc1cc(Nc2cccc(Oc3ccccc3)c2)ncn1
Agent: Cl
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3cccc(Oc4ccccc4)c3)ncn2)c1
Yield: 33.8 %

Procedure:
A solution of 6-chloro-N-(3-phenoxyphenyl)pyrimidine-4-amine (0.25 g, 0.8 mmol), 1,3-diaminobenzene (0.36 g, 3.3 mmol), n-butanol (10 mL) and conc. HCl (61 mg, 1.6 mmol) was subjected to microwave irradiation (160° C., 15 min). The reaction mixture was cooled, was concentrated under reduced pressure and the residue was taken in EtOAc (10 mL). The EtOAc solution was washed with water (5 mL) and brine (5 mL), and was dried over Na2SO4. Concentration under reduced pressure gave a residue that was purified by column chromatography (SiO2, 60-120, hexane/ethyl acetate, 6/4) to give N4-(3-aminophenyl)-N6-(3-phenoxyphenyl)pyrimidine-4,6-diamine (0.1 g, 32%) as a brown solid.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[N:15]([CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.Cl>C(#N)C>[CH:13]12[N:15]([CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[CH:10]([CH2:11][CH2:12]1)[CH2:9][NH:8][CH2:14]2
Reactant: N#Cc1ccc(OCC(O)CN2C3CCC2CN(Cc2ccccc2)C3)cc1
Agent: Cl
Solvent: CC#N
Product: N#Cc1ccc(OCC(O)CN2C3CCC2CNC3)cc1
Reaction time: 0.25 h
Yield: 36.2 %

Procedure:
To a cold solution of 4-[3-(3-benzyl-3,8-diazabicyclo[3.2.1.]oct-8-yl)-2-hydroxypropoxy]benzonitrile (5.74 g, 15.2 mmol; from step (a) above) in acetonitrile (100 mL) there was added 12 M HCl (3.2 mL). The reaction mixture was stirred for 15 minutes, concentrated in vacuo and dried under high vacuum overnight. The resulting hydrochloride salt was added to a suspension of 10% Pd/C (700 mg) in methanol (500 mL). The reaction was then stirred under hydrogen (1 atmosphere of pressure) for 90 minutes. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was partitioned with saturated sodium bicarbonate (100 mL) and CH2Cl2 (150 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the crude product. Flash chromatography on silica gel, eluting with CH2Cl2:CMA (4:1), gave 1.58 g (38%) of the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH:4]([CH2:15][OH:16])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.C(N1C=CN=C1)(N1C=CN=C1)=[O:19].C1COCC1>C(N(CC)CC)C>[C:1]1(=[O:19])[N:5]2[C:6]3[C:7]([NH:12][C:15](=[O:16])[CH:4]2[CH2:3][O:2]1)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: COC(=O)C(CO)Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2N2C(=O)OCC12
Reaction time: 6 h

Procedure:
To 3-hydroxymethyl-1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 286, 21.35 g), 1.00 g of carbonyldiimidazole, and 30 ml of THF are added 1.64. ml of triethylamine. The reaction is stirred at 20°-25° for 6 hr, then at 80° for 18 hr, at which time an additional 0.11 g carbonyldiimidazole are added. Heating is continued for another 6 hr, at which time the reaction mixture is cooled and the solvent is removed under reduced pressure. The residue is partitioned between methylene chloride and water, the organic layers are dried over sodium sulfate and concentrated. The residue is crystallized from methanol/dichloromethane to give the title compound, mp 230°-231°; MS (m/z) at 204; NMR (CDCl3) 4.60, 4.78, 6.93, 7.19, 7.82 and 8.48 δ.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[C:30]([OH:35])(=[O:34])[CH:31]([CH3:33])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH:31]([C:30]([OH:35])=[O:34])[CH3:33])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and allowed to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:39])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)[CH3:10]>>[CH2:9]([O:11][C:12](=[O:39])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:33]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)/[C:24](=[C:25](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)/[C:23]2=[O:32])=[CH:17][CH:16]=1)[CH3:10]
Reactant: CCOC(=O)COc1ccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc1
Reactant: Clc1ccc(I)cc1
Product: CCOC(=O)COc1ccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and (4-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-phenoxy)-acetic acid ethyl ester. 1H NMR (300 Hz, CDCl3): δppm 1.28 (t, 3H), 4.26 (q, 2H), 4.57 (s, 2H), 4.84 (s, 2H), 6.51 (d, 1H), 6.67-6.71 (m, 2H), 6.83 (d, 2H), 7.08 (t, 1H), 7.24-7.42 (m, 11H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[CH:20]=[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]3=[CH:17][C:16]=2[C:15]2=[N:26][N:27](C(OC(C)(C)C)=O)[C:28]([CH3:29])=[C:14]2[C:13]1=[O:37])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[CH:20]=[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]3=[CH:17][C:16]=2[C:15]2=[N:26][NH:27][C:28]([CH3:29])=[C:14]2[C:13]1=[O:37]
Reactant: Cc1c2c(=O)n(CCCNC(=O)OC(C)(C)C)c3cc4ccccc4cc3c2nn1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]nc2c1c(=O)n(CCCN)c1cc3ccccc3cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 5-{3-[(tert-butoxycarbonyl)amino]propyl}-3-methyl-4-oxo-4,5-dihydro-2H-benzo[g]pyrazolo[4,3-c]quinoline-2-carboxylate (1-7) (0.14 g, 0.28 mmol, 1.0 equiv) in CH2Cl2 (6 ml) was added trifluoroacetic acid (3 ml) and the reaction was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure and the residue was dissolved DMSO/NH4HO and purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.05% NH4OH present) to yield 5-(3-aminopropyl)-3-methyl-2,5-dihydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-8) as a white solid. 1H NMR (500 MHz, MeOH-d4, TFA Salt) δ 8.65 (s, 1H), 8.00 (m, 2H), 7.97 (s, 1H) 7.57 (t, 1H), 7.52 (t, 1H), 4.57 (t, 2H), 3.06 (t, 2H), 2.69 (s, 3H), 2.26 (t, 2H). LRMS m/z (M+H) 307.5 found, 307.2 required.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[C:18]=2S(C)(=O)=O)[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH2:4]1)[CH3:2].CN1CCCC1=[O:32].[OH-].[Na+]>O>[CH2:1]([C:3]1([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[C:18]=2[OH:32])[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH2:4]1)[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCC1=CC(CC)(c2c(S(C)(=O)=O)c(C)nn(C)c2=O)CC(CC)=C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1=CC(CC)(c2c(O)c(C)nn(C)c2=O)CC(CC)=C1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a 1 L volume four-necked flask, 4-(1,3,5-triethylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-40) (98.5 g) and N-methyl-2-pyrrolidone (383 ml) were added at room temperature. Sodium hydroxide (43.5 g) dissolved in water (118 ml) and a container washing solution (39 ml of water×2) were added at room temperature. The mixture was heated to 70±2° C., and stirred for 6 hours. To the mixture, toluene (300 ml) and water (500 ml) were added. After the mixture was stirred vigorously, additional toluene (300 ml) was added. The organic layer was removed and ice-water (500 ml) was added to the aqueous layer. pH was adjusted to 1-2 with 20 w/w % of sulfuric acid below 20° C. The precipitated solids were collected by filtration and washed with water. After air-drying, the solids were dissolved in ethyl acetate, and dried over anhydrous sodium sulfate. The insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The resulting crude product was purified by recrystallization (ethyl acetate-hexane) to give 78.0 g of 4-(1,3,5-triethylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-40).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][CH2:17][S:18]([N:21]2[CH2:37][CH2:36][C:24]3([N:28]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34])[NH:26][C:25]3=[O:35])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[C:11]([CH3:38])[CH:10]=1)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:15][C:13]1[CH:14]=[C:9]([NH:7][CH3:6])[CH:10]=[C:11]([CH3:38])[C:12]=1[CH2:16][CH2:17][S:18]([N:21]1[CH2:22][CH2:23][C:24]2([N:28]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34])[NH:26][C:25]2=[O:35])[CH2:36][CH2:37]1)(=[O:19])=[O:20]
Reactant: C=CCCCCC1=NC2(CCN(S(=O)(=O)CCc3c(C)cc(N(C)C(=O)OC(C)(C)C)cc3C)CC2)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCCCC1=NC2(CCN(S(=O)(=O)CCc3c(C)cc(NC)cc3C)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
{4-[2-(2-Hex-5-enyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-ethyl]-3,5-dimethyl-phenyl}-methyl-carbamic acid tert-butyl ester (820 mg, 1.46 mmol) was dissolved in methylene chloride (16 ml). Trifluoroacetic acid (10 ml) was added and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated, and a saturated aqueous sodium bicarbonate solution was added to the residue. This mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 8-[2-(2,6-dimethyl-4-methylamino-phenyl)-ethanesulfonyl]-2-hex-5-enyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (686 mg) as a crude compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a suspension of crude 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (423 mg, 1.5 mmol) in N,N-dimethylformamide (3 mL) is added 4-(4-Methyl-piperazin-1-yl)-phenylamine (290 mg, 1.5 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to room temperature and addition of 2 mL of water, the product precipitated out. The precipitate is then filtered off, washed with water, and dried to yield 0.5 g of crude 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione, which is used as such for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.[CH3:25][O:26][C:27]1[CH:48]=[CH:47][C:30]([CH2:31][O:32][C:33]2[CH:38]=[C:37]([Sn](C)(C)C)[N:36]=[C:35]([S:43]([CH3:46])(=[O:45])=[O:44])[N:34]=2)=[CH:29][CH:28]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:37]1[CH:38]=[C:33]([O:32][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:48][CH:47]=2)[N:34]=[C:35]([S:43]([CH3:46])(=[O:45])=[O:44])[N:36]=1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Reactant: COc1ccc(COc2cc([Sn](C)(C)C)nc(S(C)(=O)=O)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Yield: 88.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (347 mg, 0.788 mmol) and 4-(4-methoxybenzyloxy)-2-(methylsulfonyl)-6-(trimethylstannyl)pyrimidine (360 mg, 0.788 mmol) in DMF (3 mL) followed by Pd(PPh3)4 (45.5 mg, 0.039 mmol) and CuI (31 mg, 0.158 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The mixture was diluted with DCM and washed with water, brine, dried with MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-30% EtOAc in Hexanes) to give 5-(2,6-difluorophenyl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (422 mg, 0.696 mmol, 88% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 606.5 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:15])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[NH:20][CH2:19][CH2:18]2>>[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[N:20]([C:1]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[CH2:19][CH2:18]2
Reactant: O=C(Cl)Oc1ccccc1-c1ccccc1
Reactant: C1CN2CCC(CC2)N1
Product: O=C(Oc1ccccc1-c1ccccc1)N1CCN2CCC1CC2
Yield: 14.7 %

Procedure:
Biphenyl-2-yl carbonochloridate (83.0 mg, 0.358 mmol) was treated with 1,4-diazabicyclo[3.2.2] nonane (113 mg, 0.896 mmol) using the same procedure reported in example 46 to afford the title compound as an off-white solid (17 mg, 15%). Purity: >99% UPLCMS (210 nm); retention time 0.75 min; (M+1) 323.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[C:4](=[O:18])[N:3]1[CH2:19][C:20]([OH:22])=[O:21].S(=O)(=O)(O)O.[C:28](=O)(O)[O-].[Na+]>CO>[CH3:28][O:21][C:20](=[O:22])[CH2:19][N:3]1[C:4](=[O:18])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)[C:2]1=[O:1]
Reactant: O=C(O)CN1C(=O)c2ccc(Sc3ccccc3)cc2C1=O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CN1C(=O)c2ccc(Sc3ccccc3)cc2C1=O
Reaction time: 18 h

Procedure:
A mixture of 20 ml of methanol, 6.27 g of (1,3-dioxo-5-phenylsulfanyl-1,3-dihydro-isoindol-2-yl)-acetic acid (20 mmol) and 0.3 ml of concentrated sulfuric acid was refluxed with stirring for 18 h. Then 100 ml of concentrated aqueous sodium bicarbonate solution were added and the mixture was extracted with 100 ml of ethyl acetate. The organic phase was dried over MgSO4 and evaporated in vacuo. 6.54 g of the title compound were obtained; MS-(+)-ion: M+1=328.0.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:7]=[C:8]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])[CH2:37][NH:36][C:35]2=[S:40])[N:29]=[CH:28]1.N1CCCCC1>ClCCl>[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])/[C:37](=[CH:17]/[C:15]3[O:16][C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=4)=[CH:13][CH:14]=3)/[NH:36][C:35]2=[S:40])[N:29]=[CH:28]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(C=O)o2)c1
Reactant: O=C1CNC(=S)N1CCc1c[nH]cn1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\NC(=S)N(CCc4c[nH]cn4)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
5-(3-(Tributylstannyl)phenyl)furan-2-carbaldehyde (65 mg, 0.14 mmol) synthesized by the same method as in Example 4 and 3-(2-(1H-imidazol-4-yl)ethyl)-2-thioxoimidazolidin-4-one (32 mg, 0.15 mmol) synthesized by the same method as in Example 3 were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform/methanol (9/1 (volume ratio)) as an eluent, to give labeling precursor 3 in a yield of 42 mg (yield 45.9%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:14]1([CH3:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:14]1([CH3:21])[CH2:19][CH2:18][CH:17]([NH2:29])[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(NC(=O)OCc1ccccc1)C1(C)CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(NC(=O)OCc1ccccc1)C1(C)CCC(N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
2.10 g (6.92 mmol) of the ketone (78) were dissolved in 21 mL of absolute methanol, then 5.34 g (69.2 mmol) of ammonium acetate and 435 mg (6.92 mmol) of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated, the residue dissolved in 50 mL of 1N aqueous sodium hydroxide and extracted twice with 100 mL of dichloromethane. The combined organic layer was dried over magnesium sulphate, filtered, and evaporated to give 1.70 g of the title compound 79 in a purity sufficient to be used directly in the next step. Rt=0.75 min (Method P). Detected mass: 305.2 (M+H+).
Reaction SMILES: [S:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1.[CH:8]1([CH2:14][CH2:15][Mg]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1.C(OCC)C>[S:1]1[C:5]([CH:6]([OH:7])[CH2:15][CH2:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1cncs1
Reactant: Br[Mg]CCC1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(CCC1CCCCC1)c1cncs1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A solution of thiazole-5-carboxaldehyde (2.31 g, 20.4 mmol) in 20 mL of in THF was added to a cold (0° C.) solution of 2-cyclohexylethylmagnesium bromide (prepared from 2-bromoethylcyclohexane (7.88 g) and magnesium turnings (1.22 g)) in 30 mL of ethyl ether and the mixture stirred 30 minutes. The cold bath was removed and the mixture stirred for 2 hours more and then quenched by the addition of 3N aqueous HCl. The solution was stirred until 2 clear phases resulted and then the layers were separated. The pH of the aqueous phase was adjusted to 4 with 2M aqueous sodium carbonate and then extracted with 3 portions of ethyl acetate. All the organic phases were combined and washed with brine, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (125 g, 50% ethyl acetate/hexanes) to provide 2.69 g (58%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([O:22][Si](C)(C)C)=[C:19](C)[CH3:20].C([O-])([O-])=O.[K+].[K+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:19]([CH3:20])[C:18]([O:17][CH3:16])=[O:22])=[CH:4][CH:3]=1
Reactant: OC(c1cccc(F)c1)c1ccc(Br)s1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(C)C(c1cccc(F)c1)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (5-bromo-thiophen-2-yl)-(3-fluoro-phenyl)-methanol (2 g, 6.96 mmol) and (1-methoxy-2-methyl-propenyloxy)-trimethyl-silane (2.23 g, 13.92 mmol) in dichloromethane (20 ml) at 0° C. was added a solution of titanium tetrachloride in dichloromethane (1M solution, 7.7 ml, 7.66 mmol) slowly. After being stirred at 0° C. for 10 minutes and room temperature overnight, the reaction mixture was poured into an iced aqueous solution of K2CO3. The solution was extracted with dichloromethane. The organic layer was washed, dried (MgSO4) and concentrated to give the crude product. The crude product was purified by silica gel flash chromatography using 10% ethyl acetate in hexanes to give methyl 3-(5-bromothiophen-2-yl)-3-(3-fluorophenyl)-2-methyl-propanoate as a viscous yellow oil (1.74 g, 70% yield). HPLC Rt: 3.97 min.
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[CH3:15][NH:16][CH3:17]>O>[CH3:15][N:16]([CH3:17])[C:7]1[C:6]([F:14])=[C:5]([F:4])[N:10]=[C:9]([F:11])[C:8]=1[F:12]
Reactant: CNC
Reactant: Fc1nc(F)c(F)c(F)c1F
Solvent: O
Solvent: ClCCl
Product: CN(C)c1c(F)c(F)nc(F)c1F
Reaction time: 0.5 h

Procedure:
To methylene chloride (50 mL) cooled in an ice bath was added pentafluoropyridine (2.0 g, 11.8 mmol) and dimethylamine (2.97 mL of a 40% solution in water, 24 mmol). After stirring for 30 minutes the solution was washed with water, and dried over basic alumina. The solvent was removed in vacuo to give 4-dimethylamino-2,3,5,6-tetra-fluoropyridine; NMR (CDCl3) 3.13 (m,6) ppm.