Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH:34]([NH:42][OH:43])[CH:35]=[C:36]3[CH2:41][CH2:40][S:39][CH2:38][CH2:37]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>O1CCCC1>[OH:43][N:42]([CH:34]([CH:35]=[C:36]1[CH2:37][CH2:38][S:39][CH2:40][CH2:41]1)[CH2:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:11])[CH:21]=2)=[CH:29][CH:28]=1)(=[O:31])=[O:32])[CH:1]=[O:2]
Reactant: O=CO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)CC(C=C3CCSCC3)NO)cc2)c2ccccc2n1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)CC(C=C3CCSCC3)N(O)C=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A mixture of formic acid (3.0 mL) and acetic anhydride (0.4 mL) premixed for 30 minutes at 0° C. was added to a solution of 0.28 g (0.58 mmol) of N-{2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]-1-(tetrahydrothiopyran-4-ylidenemethyl)ethyl}hydroxylamine (III-17) in tetrahydrofuran (4 mL) at 0° C., and stirred for another 2 hours at room temperature. After the reaction was completed, the solvent was removed under a reduced pressure, and then subjected to azeotropic distillation with toluene. The resulting residue was dissolved in a mixed solution of methanol (1 mL) and chloroform (3 mL) and stirred for 1 hour at room temperature. Then, the solvent was removed under a reduced pressure, and the obtained residue was subjected to medium pressure column chromatography on silica gel (developing solvent; chloroform:methanol=30: 1) to obtain 0.1 g (yield 34%) of the title compound as a white crystal. Its physical properties are shown below.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8]C.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(C)c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: Cc1cc(-c2sc3cc(O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)ccc1O
Yield: 63.8 %

Procedure:
By the method described in Example 2, the product of Example 6 (640 mg, 1.24 mmol), ethanethiol (0.45 mL, 6.18 mmol), and aluminum chloride (1.16 g, 8.70 mmol) were stirred in anhydrous CH2Cl2 (20 mL). After chromatography (silica gel, 5-10% methznol in CH2Cl2), the remnant crystallized from MeOH/CH2Cl2 to give 386 mg (64%) of the title product as a yellow solid: 1H NMR (DMSO-d6) d 1.34 (m, 2H), 1.44 (m, 4H), 2.37 (m, 4H), 2.60 (t, J=5.7 Hz, 2H), 4.05 (t, J=5.7 Hz, 2H), 6.64 (d, J=8.3 Hz, 1H), 6.82 (dd, J=2.1 Hz, 8.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.96 (dd, J=2.1 Hz, 8.3 Hz, 1H), 7.05 (d, J=1.8 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.30 (d, J=1.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 9.62 (br s, 1H), 9.75 (br s, 1 H); 13C NMR (DMSO-d6) d 15.7, 23.8, 25.4, 54.2, 57.0, 65.9, 107.0, 114.4, 114.8, 115.1, 123.2, 123.6, 124.3, 126.9, 129.5, 129.7, 130.6, 131.6 , 132.3, 139.1, 140.5, 155.3, 155.9, 162.7, 192.6; MS (FD) m/e 487 (M+); Anal. calc'd. for C29H29NO4S: C, 71.43; H, 6.00; N, 2.87. Found: C, 71.33; H, 6.05; N, 2.92.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH2:10]2)=[C:4]([F:25])[CH:3]=1.[Cu][C:27]#[N:28].CN(C)C=O.[OH-].[NH4+]>O>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH:11]1[CH2:12][CH2:13][CH:9]([C:5]2[C:4]([F:25])=[CH:3][C:2]([C:27]#[N:28])=[C:7]([F:8])[CH:6]=2)[CH2:10]1
Reactant: N#C[Cu]
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(c2cc(F)c(Br)cc2F)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(C2CCC(N3C(=O)c4ccccc4C3=O)C2)cc1F
Yield: 89.8 %

Procedure:
A suspension of 91.35 g (0.225 mol) of 2-[3-(4-bromo-2,5-difluorophenyl)cyclopentyl]-1H-isoindole-1,3-(2H)-dione, 22.4 g (0.25 mol) of copper (I) cyanide and 250 ml of N,N-dimethylformamide was stirred and heated in a nitrogen atmosphere at 170° for 18 hours. The cooled mixture was poured into a solution of 100 ml of concentrated ammonium hydroxide in 1 L of water. The aqueous mixture was extracted with ether (4×350 ml) and the combined ether layers were washed with water (3×300 ml), dried (MgSO4), and evaporated in vacuo to give 71.2 g of the title compound which was used as is for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:22])/[C:9](/[S:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:11])=[O:12])=[CH:28]\[C:27]2[CH:30]=[CH:31][C:24]([Br:23])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)c2ccc(Br)cc2)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: COc1ccc(CS(=O)(=O)/C(=C/c2ccc(Br)cc2)C(=O)c2ccc(Br)cc2)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 10. A solution of 1-(4-bromophenyl)-2-(4-methoxybenzylsulfonyl)ethanone (10 mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the procedure described as Method A in part C of Synthesis Example 10 and the product obtained was purified by column chromatography. m.p. 146-150° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[SH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH2:18][C@@H:19]([CH3:29])[N:20]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:21][CH:22]=2)[N:16]=1.O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:26]([O:25][C:23]([N:20]1[CH2:21][CH:22]=[C:17]([C:15]2[N:16]=[C:12]([S:11][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:13][CH:14]=2)[CH2:18][C@H:19]1[CH3:29])=[O:24])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@H](C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 0.58 ml, 0.58 mmol) was added at 0–5° C. to a solution of allyl (2R)-4-(2-mercapto-1,3-thiazol-4-yl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (172 mg, 0.58 mmol) in THF (2.0 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 2.21 g, 1.2 mmol) and the solution was allowed to stand in a refrigerator for 16 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/4→1/3) to give allyl (4R,5S,6S)-3-[(4-{(2R)-1-[(allyloxy)carbonyl]-2-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (137 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[C:8](=[CH:18]/[N:19](C)C)/[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=O)[CH:5]=[CH:4][N:3]=1.O.[NH2:23]N>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[N:23][NH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: CN(C)/C=C(\C(=O)c1cccc(Cl)c1)c1ccnc(Br)c1
Solvent: CCO
Solvent: O
Product: Clc1cccc(-c2n[nH]cc2-c2ccnc(Br)c2)c1
Yield: 31.5 %

Procedure:
A solution of the product from step 2 (650 mg, 1.8 mmol) and hydrazine monohydrate (100 mg) in ethanol (10 ml) was refluxed for 24 hours. Solvent was evaporated and the residue was chromatographed on silica gel using mixtures of ethyl acetate and toluene as eluents to give 2-bromo-4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine (190 mg, 31%) as an oil: Anal. Calc'd for C14H9BrClN3: C, 50.25; H, 2.71; N, 12.56. Found: C, 50.10; H, 2.60; N, 12.40.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:11]([CH3:10])[S:12]([CH3:15])(=[O:14])=[O:13])#[N:5]
Reactant: CNS(C)(=O)=O
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1C#N)S(C)(=O)=O
Temperature: 80 °C

Procedure:
To a round bottom flask was added 2-fluoro-benzonitrile (1.0 g, 8.2 mmol), N-Methyl-methanesulfonamide (1.0 g, 9.2 mmol), potassium carbonate (1.7 g, 12 mmol) and N,N-dimethylformamide (5 mL). The mixture was heated at 80° C. for 18 hours. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (75 mL). The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated to a waxy solid. The recovered solid was triturated with hexane, filtered and dried. N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a pale yellow solid (0.74 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72 (d, J=7.7 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 3.40 (s, 3H), 3.13 (s, 3H). MS=211 (MH)+.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[C:26]2[C:21](=[CH:22][N:23]=[CH:24][CH:25]=2)[S:20][CH:19]=1>>[S:20]1[C:21]2=[CH:22][N:23]=[CH:24][CH:25]=[C:26]2[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[CH:19]1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1csc2cnccc12
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3csc4cnccc34)N1C2
Yield: 68.2 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (10.1 g) and 3-aminothieno[2,3-c]pyridine (6.4 g) as the starting materials, (S)-3-[(thieno[2,3-c]pyrid-3-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (6.4 g) is obtained in the form of white crystals, m.p.=180° C.
Reaction SMILES: C([N:8]([CH2:32][CH2:33][O:34][CH3:35])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]1[C:22](=[O:31])[NH:23][C:24]3[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15]2)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH3:35][O:34][CH2:33][CH2:32][NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]1[C:22](=[O:31])[NH:23][C:24]3[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15]2
Reactant: COCCN(CCOc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1)Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCNCCOc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Reaction time: 18 h

Procedure:
10% Pd/C (840 mg) was added to a solution (150 mL) of 3-(5-{2-[Benzyl-(2-methoxyethyl)-amino]-ethoxy}-1H-indol-2-yl)-2(1H)-quinolinone, Compound 1-27, (840 mg, 1.8 mmol) in EtOAc (150 mL), and the resulting mixture was stirred under a hydrogen balloon for 18 h. The catalyst was removed by filtration and the filtrate concentrated to a yellow solid which was purified by chromatography on a silica column. Elution with EtOAc to 25% NH3-EtOH/EtOAc gave 3-(5-{2-[(2-methoxyethyl)amino]ethoxy}-1H-indol-2-yl)-2(1H)-quinolinone (2-1) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.05 (s, 1H), 9.65 (br s, 1H), 8.32 (s, 1H), 7.67 (d, 1H, J=8 Hz), 7.51 (t, 1H, J=8 Hz), 7.34 (d, 1H, J=8 Hz), 7.29 (t, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 7.09 (s, 1H), 6.96 (s, 1H), 6.90 (dd, 1H, J=8, 2 Hz), 4.15 (t, 2H, J=5 Hz), 3.55 (t, 2H, J=5 Hz), 3.38 (s, 3H), 3.07 (t, 2H, J=5 Hz), 2.91 (t, 2H, J=5 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][NH2:30].O>CCO>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([NH:29][NH2:30])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NN)no1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
A solution of ethyl 5-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-1,2,4-oxadiazole-3-carboxylate (preparation 170) (1.14 g, 2.89 mmol) in EtOH (20 ml) was treated with NH2NH2.H2O (280 μl, 5.78 mmol) and stirred at room temperature for 45 minutes. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc and H2O/brine. The organic solvent was removed under reduced pressure to afford the title compound (1.06 g, 90%).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:9]([CH2:18]O)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:23][CH2:18][C:9]1[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:21])([CH3:20])[CH3:1])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: C[Si](C)(C)CCOCOc1cc2ccccc2cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[Si](C)(C)CCOCOc1cc2ccccc2cc1CBr
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
400 mg (1.30 mmol) of [3-(2-trimethylsilylethoxy-methoxy)-naphthalen-2-yl]-methanol and 462 mg (1.81 mmol) of carbon tetrabromide were dissolved in 5 ml of absolute acetonitrile and the solution was cooled to 0° C. A solution of 446 mg (1.68 mmol) of triphenylphosphine in 6 ml of absolute acetonitrile was added dropwise thereto at 0° C. within 10 minutes and thereafter the mixture was stirred at 0° C. for a further 30 minutes. Subsequently, the solvent was distilled off under reduced pressure and, for purification, the crude product was chromatographed, without further working up, on silica gel using a 2:3 mixture of methylene chloride and hexane as the eluent. There were obtained 314 mg (65% of theory) of 2-bromomethyl-3-(2-trimethylsilylethoxymethoxy)-naphthalene as a light yellow oil; MS: 366, 368 (M)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([N:21]=[C:22]=[S:23])[CH:20]=1>C(Cl)(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([NH:21][C:22](=[S:23])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:20]=1
Reactant: COc1ccc(Cl)cc1N=C=S
Reactant: NCC(N)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of glycinamide hydrochloride (5.5 g), triethyl amine (5.05 g), 5-chloro-2-methoxyphenyl-isothiocyanate (9.95 g), and chloroform (500 mL) were heated at reflux for 3 hours. The mixture was then cooled to ambient temperature and washed with water (300 mL). The organic phase was separated. Precipitate formed upon standing. The solid was collected by filtration, washed with water, then with diethyl ether and air dried to give 2-[3-(5-chloro-2-methoxyphenyl)-thioureido]acetamide (12.8 g), m.p. 166°-169° C. (dec.). This compound was used without further purification for the preparation of the title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=C(N[C:29](=[O:39])[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:30]1[C:29](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:38][CH:31]1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CC1C(=O)c2ccccc2OC1c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and flavanone (II), MS (m/e) 524, 479, 302 and 165; IR (neat) 2983, 1683, 1607, 1580, 1499, 1474, 1464 and 1257 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[Cl:31][C:32]1[N:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[CH:34][N:33]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:38]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([Cl:31])[N:37]=3)=[O:39])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)c3ccnc(Cl)n3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Yield: 40.4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 2-chloropyrimidine-4-carboxylic acid, to afford the title compound (8.3 mg, 40.4%). Data: UPLC (C) Rt: 1.64 min; m/z 540.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[N:8]([CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21](O)=[O:22])[CH2:16]3)[C:7](=[O:24])[C:6]=12.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:56]([NH2:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C)C=O>[CH2:56]([NH:63][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[N:11][CH:10]=3)[C:5]3=[N:4][O:3][C:2]([CH3:1])=[C:6]3[C:7]2=[O:24])[CH2:16]1)=[O:22])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(C(=O)O)C1)c1cnccc21
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc2c1c(=O)n(C1CCCC(C(=O)NCc3ccccc3)C1)c1cnccc21
Yield: 96 %

Procedure:
Combine 3-(3-methyl-4-oxo-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexanecarboxylic acid (50 mg, 0.15 mmol) with 1-[3-(dimethyl-amino)propyl]-3ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), 1-hydroxy-7-azabenzo-triazole (23 mg, 0.17 mmol), N,N-diisopropylethyl amine (44 mg, 3.4 mmol), and benzylamine (18 mg, 0.17 mmol) in N,N-dimethyl-formamide (4 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry the combined extracts over sodium sulfate. Concentrate and elute over silica gel using methanol/dichloromethane to give 60 mg (94%) of the desired product as a white solid. MS(ES): (M+1)+ 417.3, 418.3 m/z.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:6]([CH:20]=[O:21])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]=[C:10]([O:16][CH3:17])[C:9]([O:18][CH3:19])=[N:8]2.[Cl-].[NH4+]>O1CCCC1>[Cl:4][C:5]1[C:6]([CH:20]([OH:21])[CH3:1])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]=[C:10]([O:16][CH3:17])[C:9]([O:18][CH3:19])=[N:8]2
Reactant: COc1nc2cc(Cl)c(Cl)c(C=O)c2nc1OC
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(Cl)c(C(C)O)c2nc1OC
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Methylmagnesium bromide (2.3 mL, 1M in di-n-butylether, 2.3 mmol) was added to a suspension of 6,7-dichloro-2,3-dimethoxy-5-formylquinoxaline (600 mg, 2.09 mmol) in dry tetrahydrofuran (30 mL) under nitrogen at room temperature. After 30 minutes, saturated ammonium chloride (20 mL) was added, and the product was extracted into ethyl acetate (2×30 mL). The combined extracts were dried (MgSO4) and concentrated under reduced pressure to give 6,7-dichloro-2,3-dimethoxy-5-(1-hydroxyethyl)quinoxaline (577 mg, 91%), as a creamy coloured solid.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[C:9]([C:12]1[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([S:24][C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])[CH:21]=[CH:22][CH:23]=2)=[C:14]([CH3:36])[C:13]=1[OH:37])(=[O:11])[CH3:10].Cl>O.CO>[C:9]([C:12]1[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([S:24]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])=[O:2])[CH:21]=[CH:22][CH:23]=2)=[C:14]([CH3:36])[C:13]=1[OH:37])(=[O:11])[CH3:10]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(=O)c1ccc(OCc2cccc(Sc3cncc(C(=O)O)c3)c2)c(C)c1O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(OCc2cccc(S(=O)c3cncc(C(=O)O)c3)c2)c(C)c1O
Temperature: 25 °C
Reaction time: 36 h
Yield: 14.6 %

Procedure:
Add a 0.5 M solution of potassium peroxymonosulfate (0.61 g, 1.00 mmol) in water (2.0 mL) to a solution of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio)nicotinic acid (205 mg, 0.50 mmol) in methanol (7.5 mL) at 0° C. Allow the solution to warm to room temperature and stir for 1.5 d. Add water and 2.2 mL of 2.0 M HCl to the mixture. Extract the mixture with EtOAc. Dry, filter and concentrate. Recrystallize the residue from a mixture of CH2Cl2 and hexanes to give a light yellow solid. Purify the yellow solid by flash chromatograhpy on silica gel eluting with a mixture of acetone, hexanes, and acetic acid (50:50:1 to 90:10) to afford the title compound (31 mg, 15%): 1H NMR (d6-DMSO) δ 2.01 (s, 3H), 2.58 (s, 3H), 5.33 (s, 2H), 6.67 (d, J=9.0 Hz, 1H), 7.61-7.63 (m, 2H), 7.77 (d, J=9.0 Hz, 1H), 7.81-7.83 (m, 1H), 7.88 (s, 1H), 8.49 (t, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 9.12 (d, J=2.0 Hz, 1H), 12.84 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 424 (M−H, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:38]4[CH:37]=[N:36][C:35]([NH2:34])=[CH:40][CH:39]=4)[CH:7]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.56) (0.25 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a light brown solid (0.21 g, 77%). MS (ISP) 560.0 [(M+H)+]; mp 223° C.