Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15](=O)[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)C.Cl>C(OCC)(=O)C.O>[F:23][C:22]([F:24])([F:25])[C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=1)[C:15]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:14]
Reactant: O=C1CCc2sccc21
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 41 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one in 13 mL of THY was treated with NaH (60 percent, 1.1 g, 27 mmol). After the addition of 3,5-Bis-trifluoromethyl-benzoic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(3,5-Bis-trifluoromethyl-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.07 g, 4.1 mmol) as yellow solid in 41% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].CN(C)C=O.CS(O[CH:27]1[CH2:31][CH2:30][O:29][CH2:28]1)(=O)=O>C(OCC)(=O)C>[O:29]1[CH2:30][CH2:31][CH:27]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:28]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(C3CCOC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), sodium hydride (31 mg, 0.77 mmol) in N,N-dimethylformamide (1 mL, 10 mmol) was stirred at r.t. for 10 min, then, tetrahydrofuran-3-yl methanesulfonate (86 mg, 0.52 mmol) was added. The resulting mixture was stirred at 110° C. for 2 hours. After cooling it was diluted with ethyl acetate, washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 95 mg of product which was directly used in the next step reaction without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][CH2:39][C:40]#[N:41])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:42]>CS(C)=O>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][CH2:39][C:40]([NH:2][OH:3])=[NH:41])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:42]
Reactant: NO
Reactant: Cc1cc(F)ccc1-c1nc(NCCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NCCC(=N)NO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 45 %

Procedure:
Under Ar, a soln of hydroxylamine hydrochloride (119 mg, 1.72 mmol) and triethylamine (0.26 mL, 1.89 mmol) in 5 mL of DMSO was stirred at room temperature for 5 min, the product of Example 206, 3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-propionitrile (150 mg, 0.34 mmol) was added. The resulting mixture was heated to 80° for 16 h. Preparative hplc, followed by recrystallization from ethanol and hexane, gave the desired product 80 mg (45%). LC-MS: 469.2 (MH+, m/z), 1.52 (Rt, min).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[C:34](=[O:35])[N:33]([CH2:36][CH3:37])[CH2:32][CH2:31][N:30]([CH2:38][CH3:39])[C:29]=3[CH:40]=2)[C:21]([Cl:41])=[CH:20][N:19]=1>>[Cl:41][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[C:34](=[O:35])[N:33]([CH2:36][CH3:37])[CH2:32][CH2:31][N:30]([CH2:38][CH3:39])[C:29]=3[CH:40]=2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(Nc3nc(Cl)ncc3Cl)ccc2C1=O
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc5c(c4)N(CC)CCN(CC)C5=O)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and 8-(2,5-Dichloro-pyrimidin-4-ylamino)-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one in an analogous manner to example 712. Product was isolated as a tan solid (0.080 g, 40%). Mp 100-106° C.; LCMS (m/e) 563 (M); 1H-NMR (DMSO, 400 MHz) δ 9.27 (s, 1H), 8.90 (s, 1H), 8.23 (s, 1H), 7.52-49 (d, 1H, J=8.59 Hz), 7.46-44 (d, 1H, J=8.33 Hz), 7.31-23 (s, 2H), 7.20-18 (d, 1H, J=7.84 Hz), 7.01-6.96 (d, 1H, J=8.34 Hz), 3.67-60 (br, 1H), 3.60-55 (q, 1H, J=6.82 Hz), 3.48-42 (t, 1H, J=5.06 Hz), 3.38-31 (s, 2H), 3.31-29 (t, 1H, J=6.57 Hz), 3.16-06 (q, 1H, J=6.82 Hz), 3.10-2.96 (m, 3H), 2.84-80 (br, 1H), 2.56-40 (br, 2H), 1.21-16 (t, 3H, J=7.07 Hz), 1.18-08 (m, 9H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[O:9])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O>[CH:44]1[C:45]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:43]=1[O:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[O:9])[CH2:4]1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(OCc1cscn1)N1CCC(CO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1cscn1)N1CCC(COc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.5 %

Procedure:
0.25 g (1.03 mmol) of thiazol-4-ylmethyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate is dissolved in 8 ml of toluene. 0.35 g (1.34 mmol) of triphenylphosphine and 0.16 g (1.13 mmol) of naphth-2-ol are added and then the medium is cooled to 0° C. for slow addition of a solution of 0.27 g (1.34 mmol) of diisopropyl azodicarboxylate in 2 ml of toluene. The medium is stirred at ambient temperature for 14 hours. The residue obtained is taken up in water and extracted twice with dichloromethane. The combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified by chromatography on silica gel, elution being carried out with a 99/1 to 98/2 mixture of dichloromethane and methanol. 0.15 g of the expected product is obtained in the form of a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.[C:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].O>C(Cl)(Cl)Cl.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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:31]([C:30]2[CH:34]=[CH:35][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)=[O:32])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Cc3ccc(Br)cc3)c2cc1OC
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Cc3ccc(C(=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Reaction time: 15 h
Yield: 8.7 %

Procedure:
6,7-Dimethoxy-4-tri-n-butylstanniophenylmethyl)quinoline (82 mg) obtained in Example 162, commercially available 4-t-butylbenzoyl chloride (31 mg) and a catalytic amount of commercially available bis(triphenylphosphine)palladium(II) chloride were dissolved in chloroform (3 ml), and the admixture was stirred for 15 hours under reflux with heat. After the addition of water, the admixture was extracted with methylene chloride, and the organic layer was washed with brine and saturated aqueous potassium fluoride and then dried with anhydrous sodium sulfate. After removing the solvent by distillation, the resulting residue was purified by thin layer chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to obtain 6 mg of the title compound (yield: 10%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([O:10][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cnc1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ncc(Br)cc1C
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 83.3 %

Procedure:
To a solution 5-bromo-3-methylpyridine-2-carboxylic acid (2.6 g, 12 mmol) in N,N-dimethylformamide (20.0 mL) was added potassium carbonate (4.99 g, 36.1 mmol) and methyl iodide (1.50 mL, 24.1 mmol) and the reaction was stirred 80° C. for 40 min. The reaction mixture was partitioned with EtOAc and water. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2.3 g (83% yield) of the desired product as a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[NH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:20][C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccsc1
Agent: Cl
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccsc1
Yield: 82.2 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 400 mg of 3-aminothiophene hydrochloride in place of the 2,4-difluoroaniline. 252 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(thiophen-3-yl)acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:32])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[O:31]=[C:25]1[CH:24]([N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:10])=[O:9])[C:18]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: Cc1ccccc1N=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
o-Tolyl isocyanate (0.4 g, 3.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.8 g, 2.3 mmol) and triethylamine (0.3 g, 3.2 mmol) in THF (40 mL) at 5° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with hot acetone (15 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-o-tolyl-urea (0.7 g, 72%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.19 (s, 3H), 2.49-2.65 (m, 2H), 2.84-2.98 (m, 1H), 4.73 (d, J=5.9 Hz, 2H), 5.13-5.20 (dd, J=5.4 and 12.7 Hz, 1H), 6.85-7.19 (m, 4H), 7.77-7.92 (m, 5H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 13.90, 17.99, 26.93, 34.68, 44.86, 116.73, 117.88, 118.14, 122.03, 123.05, 123.18, 126.06, 127.61, 129.69, 130.75, 133.93, '36.25, 151.47, 163.00, 163.56, 165.83, 168.76; Anal. calcd. for C22H20N4O5: C, 62.85; H, 4.79; N, 13.33. Found: C, 62.76; H, 4.75; N, 13.12.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:24])[CH2:15][C:16]2[CH:17]=[N:18][C:19](Cl)=[C:20]([CH3:22])[CH:21]=2)=[CH:11][CH:12]=1.[CH3:25][C:26]1[CH:31]=[C:30]([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH:28][N:27]=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.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([C:30]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:25])[CH:31]=3)=[N:18][CH:17]=2)=[CH:11][CH:12]=1
Reactant: Cc1cc(CC(=O)Nc2ccc(-c3ccccn3)cn2)cnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ncc(CC(=O)Nc3ccc(-c4ccccn4)cn3)cc2C)ccn1
Temperature: 118 °C

Procedure:
To a reaction tube were added 5 N-(2,3′-bipyridin-6′-yl)-2-(6-chloro-5-methylpyridin-3-yl)acetamide 124-2 (52 mg, 0.15 mmol), 2-methyl-4-(tributylstannyl)pyridine (115 mg, 0.3 mmol), and Pd(PPh3)4 (35 mg, 0.03 mmol). The tube was subjected to vacuum and back filled with argon. DMF (1.0 ml) was added and the mixture was heated in 118° C. oil bath overnight. After cooled to room temperature, the mixture was filtered through celite, washed and diluted with ethyl acetate (30 ml) and extracted with 0.1 N HCl solution (30 ml). The acidic aqueous phase was treated with Na2CO3 to have pH around 9 and extracted with ethyl acetate (3×20 ml). The combined organic phase was dried over Na2SO4 and concentrated by evaporation. The residue was subjected to silica gel column chromatography with 5% MeOH in DCM as eluent to give N-(2,3′-bipyridin-6′-yl)-2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)acetamide 124 as white solid. MS m/z 396.3 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.93-8.89 (m, 1H), 8.72-8.67 (m, 1H), 8.59 (d, 1H), 8.51 (d, 1H), 8.37-8.29 (m, 2H), 8.23 (bs, 1H), 7.76 (m, 1H), 7.71 (m, 1H), 7.65 (d, 1H), 7.33 (bs, 1H), 7.30-7.24 (m, 1H), 3.81 (s, 2H), 2.63 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[CH:12][CH:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCCl>[CH3:31][N:9]([CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(NCCc2ccccc2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: C[N+](C)(C)C
Solvent: ClCCCl
Product: CN(CCc1ccccc1)c1ccc(C(=O)Nc2cnc3ccccc3c2)cc1

Procedure:
A mixture of 4-phenethylamino-N-quinolin-3-yl-benzamide (0.213 g, 0.57 mmol), paraformaldehyde (0.17 g, 5.8 mmol) and tetramethylammonium triacetoxyborohydride (0.37 g, 1.42 mmol) in 1,2-dichloroethane (˜10 mL) was heated at reflux for 6 hours. The resultant solution was washed with saturated aqueous sodium bicarbonate and applied to a flash silica gel column. The product was eluted with ethyl acetate (40%) in hexanes to give the product, 0.2 g (92%). MS: m/z 382 (MH+). 1H NMR (DMSO-d6): 2.90 (t, 2 H), 2.93 (s, 3 H), 3.66 (t, 2 H), 6.73 (d, 2 H), 7.21-7.35 (m, 5 H), 7.53 (d of t, 1 H), 7.63 (d of t, 1 H), 7.80-7.87 (m, 3 H), 8.05 (m, 1 H), 8.85 (d, 1H) and 8.91 (d, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1.[O:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:41][C:38]4[CH:39]=[CH:40][O:36][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1
Reactant: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 0 °C
Yield: 86.8 %

Procedure:
To a RBF was added perfluorophenyl 1-(5-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.92 g, 10.27 mmol) and THF (103 ml). Isoxazol-3-amine (0.950 g, 11.36 mmol) was added, and the reaction was cooled to 0° C. Lithium bis(trimethylsilyl)amide (1.0M in THF) (21.57 ml, 21.57 mmol) was added drop wise (reaction turned from clear solution to bright yellow suspension) and the reaction was allowed to stir in the ice bath for 1 h. The reaction was warmed to RT, and 1N HCl was added. The product was extracted with EtOAc (×3), and the resulting organics were dried with MgSO4 and concentrated in vacuo. The resulting light yellow solid was triturated in diethyl ether and filtered over a fine frit, rinsing with minimal ether, to yield 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (4.245 g, 8.91 mmol, 87% yield) as an off-white solid. MS (ESI, pos. ion) m/z: [M+1] 476.1
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)[N:7]=1)([O-:5])=[O:4].[CH3:19]I>C(Cl)Cl>[CH3:19][O:18][CH2:17][C:15]1[N:16]=[C:12]([CH2:11][N:8]2[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)[S:13][CH:14]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cnn(Cc2nc(CO)cs2)n1
Agent: N#N
Solvent: ClCCl
Product: COCc1csc(Cn2ncc([N+](=O)[O-])n2)n1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazol-4-yl)methanol (672 mg, 2.79 mmol) in CH2Cl2 (15.0 mL) was added to a suspension of Ag2O (968 mg, 4.18 mmol) and MeI (0.52 mL, 8.36 mmol). The resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. LC-MS-conditions 07: tR=0.66 min, [M+H]+=226.27.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:9][CH:10]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[N:17]=2)[CH:12]=1)=[O:6]>O.O1CCOCC1>[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[N:17]=[C:13]([C:11]3[CH:12]=[C:7]([C:5]([OH:6])=[O:4])[C:8]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N+:32]([O-:34])=[O:33])=[CH:9][CH:10]=3)[S:14][CH:15]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(F)c(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3ccc(F)c(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
Sodium hydroxide (100 mg, 2.5 mmol) was added to a suspension of 4-[4-(3-chloro-4-fluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid methyl ester (100 mg) in a mixture of water (2 mL) and dioxane (4 mL). The reaction mixture was stirred at 50° C. for 2 h. An additional portion of water (2 mL) was added and the reaction mixture was stirred at 50° C. for a further 2 h. The reaction mixture was evaporated to dryness and water (5 mL) was added. The mixture was filtered and the filtrate was made acidic to pH 3-4 by the addition of concentrated HCl. The precipitate was collected by filtration and dried to give 4-[4-(3-chloro-4-fluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (60 mg, 41% for two steps). 1H NMR (300 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.27 (d, J=8.3 Hz, 1H), 8.08-8.16 (m, 2H), 7.79 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.9 Hz, 1H), 7.41-7.58 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28]C)=[O:27].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COCCOCOc1c(C/C=C(\C)CCC(=O)OC)c(OC)c(C)c2c1C(=O)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOCOc1c(CC=C(C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To methyl (E) 6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (76.0 g) in methanol (300 ml) was added 1N aqueous sodium hydroxide (300 ml). After 11/2 hours the solution was diluted with water, washed twice with ether, then acidified with dilute hydrochloric acid. The acidified solution was extracted with ether, and the extract was dried and evaporated to give (E) 6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, m.p. 77°-82° C. (etherhexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.CO[C:15]1C(OC)=C[C:18]2[NH:19][C:20](CCCNC)=N[C:17]=2[CH:16]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:15]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])=[N:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Product: CNCCCc1nc2cc(C(=O)OC)ccc2[nH]1

Procedure:
Prepared from 3,4-diamino-benzoic acid methyl ester (Eur. J. Med. Chem. 2004, 39(3), 291-298) in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([NH:8][C:9]2[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:53][C@H:52]([CH2:51][O:50][C:47]1[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=1)[CH2:54][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]2[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(Nc2ncccc2NC(=O)c2ccccc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1)c1ccccc1
Yield: 32.8 %

Procedure:
N-{2-[4-(2-Aminoethyl)anilino]-3-pyridinyl}benzamide (0.1 g, 0.30 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.107 g, 0.265 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.064 g, 0.087 mmol).