Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:9][C:10]([NH2:12])=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:14]([CH2:18][CH3:19])[C:15](O)=[O:16]>>[CH:1]1([NH:9][C:10]2[S:11][CH:14]([CH2:18][CH3:19])[C:15](=[O:16])[N:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(Br)C(=O)O
Reactant: NC(=S)NC1CCCCCCC1
Product: CCC1SC(NC2CCCCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-cyclooctyl-thiourea and 2-bromo-butyric acid according to Method C1.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH3:11])(=[O:9])=[O:8])#[N:2]>CO.[Pd]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH3:11])(=[O:9])=[O:8]
Reactant: CNS(=O)(=O)CCCCC#N
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)CCCCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-cyano-N-methylbutane-1-sulfonamide (Example 9; 91.2 mmol) and Pd/C (10 mol %, 1 g) in methanol/7N NH3 (180 ml) was put under a hydrogen atmosphere. The mixture was stirred overnight at room temperature. The mixture was filtered and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][C:12]([CH3:15])([OH:14])[CH2:11][CH:10]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:14][C:12]1([CH3:15])[CH2:13][CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH:10]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:11]1
Reactant: Cc1cccnc1C1CC(C)(O)CC(c2ncccc2C)N1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CC(C)(O)CC(c2ncccc2C)N1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of meso-2′β,6′β-[3,4′,3″-trimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridin-4′-ol (0.2499 g, 0.84 mmol) in DMF (9 mL) was added 2-(4-bromo-butyl)-isoindole-1,3-dione (0.2605 g, 0.92 mmol), KI (0.0142 g, 0.08 mmol), and DIPEA (0.29 mL, 1.68 mmol), and stirred at 60° C. for 24 hours. The mixture was concentrated, and saturated NaHCO3 (30 mL) was added and extracted with CH2Cl2 (3×35 mL). The combined organic extracts were washed with brine (2×20 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2—MeOH—NH4OH) provided 0.3144 g (75%) of meso-2′β,6′β-[2-[4-(4′-hydroxy-3,4′,3″-trimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′yl)-butyl]-isoindole-1,3-dione as a white solid. 1H NMR (CDCl3) δ 0.48 (s, 1H), 0.86 (s, 2H), 1.42 (s, 3H), 1.68-1.72 (m, 2H), 2.18-2.38 (m, 6H), 2.45 (s, 6H), 3.15 (t, 2H, J=6.0 Hz), 4.13 (d, 2H, J=12.0 Hz), 6.94-7.03 (m, 2H), 7.25-7.34 (m, 2H), 7.67-7.70 (m, 2H), 7.75-7.78 (m, 2H), 8.32-8.34 (m, 2H).
Reaction SMILES: COCCOC[N:7]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:8]1[CH3:30].Cl>CC(C)=O.O1CCCC1>[CH3:30][C:8]1[NH:7][C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:9]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COCCOCN1C(C)=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1

Procedure:
hydrolyzing said (+)-1-(2-methoxyethoxymethyl)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine with 1N hydrochloric acid in acetone or tetrahydrofuran to produce (-)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([OH:17])=O)[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]1[NH:30][CH2:29][CH2:28][N:27]([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]#[N:38])[CH2:26]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:30]3[CH2:29][CH2:28][N:27]([C:31]4[N:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]#[N:38])[CH2:26][CH2:25]3)=[O:17])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: N#Cc1cccnc1N1CCNCC1
Product: N#Cc1cccnc1N1CCN(C(=O)C2CN(S(=O)(=O)c3ccccc3)C(=O)N2C2CCCCC2)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(2-(3-cyanopyridyl))piperazine to give the title compound as a colorless solid. MS: 523.3 ([M+H]+)
Reaction SMILES: [CH:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C:12]1[N:17]=[C:16]([C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][N:24]([C:28]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[CH:15]=[C:14]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[N:13]=1>>[NH2:11][C:12]1[N:17]=[C:16]([C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][N:24]([C:28]([O:30][CH:31]4[CH2:36][CH2:35][N:34]([S:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)(=[O:8])=[O:7])[CH2:33][CH2:32]4)=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[CH:15]=[C:14]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[N:13]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: O=S(=O)(Cl)C1CCCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(S(=O)(=O)C5CCCC5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from cyclopentanesulfonyl chloride (Aldrich, Cat. #656607) and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=584.2.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:21][NH2:22]>C(O)C>[NH:21]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)[NH2:22]
Reactant: NN
Reactant: CS(=O)(=O)c1nccc(-c2cccc(C(F)(F)F)c2)n1
Solvent: CCO
Product: NNc1nccc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
A solution of 6.0 g. of 2-methylsulfonyl-4-(m-trifluoromethylphenyl)pyrimidine in 75 ml. of absolute ethanol is treated with 1.9 g. of 95% hydrazine and is refluxed for 8 hours. Isolation as in the previous example gives the desired compound, m.p. 103°-106° C.; resolidifies and melts at 120°-122° C.
Reaction SMILES: [C-:1]#[N:2].Br[C:4]1[C:5]([Cl:16])=[CH:6][N:7]=[C:8]2[C:13]=1[N:12]=[C:11]([O:14][CH3:15])[CH:10]=[CH:9]2.[Cl-].[NH4+]>CN(C)C=O>[Cl:16][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:4]=1[C:1]#[N:2])=[N:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2
Reactant: [C-]#N
Reactant: COc1ccc2ncc(Cl)c(Br)c2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Cl)c(C#N)c2n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
CoppeeI cyanide (39.3 g, 0.44 mol, 1.2 eq) is added at room temperature to a stirred solution of 8-bromo-7-chloro-2-methoxy-[1,5]naphthyridine (100 g, 0.37 mol, 1.0 eq) in N,N-dimethylformamide (1.5 L). After 8 hours stirring at 130° C., the reaction mixture is cooled down to room temperature and treated with a saturated ammonium chloride aqueous solution (1.5 L). The aqueous layer is separated and extracted with ethyl acetate (2×1.5 L). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is washed with ethanol (20 mL) to afford 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbonitrile as an off-white solid (49.5 g, 62% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: O=C(Cl)c1ccco1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccco4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.068 mMol) 2-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 337(M+1)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([CH:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19][C:18]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:17]1=2)=O)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([CH:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19][C:18]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:17]1=2)=[S:41])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(C(=S)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Yield: 96.3 %

Procedure:
After 1.09 g of Compound 4 obtained in Example 4 was dissolved in 10 ml of toluene, 1.07 g of Lawesson's reagent was added to the solution. The mixture was heated under reflux for an hour. The reaction mixture was allowed to stand at room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: hexane-ethyl acetate (2:1)] to obtain 1.46 g of a crude product. The crude product was recrystallized from ethyl acetate-hexane to obtain 1.09 g of Compound 36.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10])([CH3:3])[CH3:2].[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26]O)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26][O:10][C:9](=[O:11])[CH2:8][O:7][C:6]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: Cc1cc(OCC(=O)O)cc(C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)cc(C(C)C)c2)cc1
Yield: 97.8 %

Procedure:
A mixture of 3-isopropyl-5-methylphenoxyacetic acid (prepared above, 6.0 g, 28.8 mmol), 2-(p-toluenesulfonyl)ethanol (5.77 g, 28.8 mmol), and p-toluenesulfonic acid hydrate (p-TsOH.H2O) (0.5 g) in 100 mL of toluene was refluxed with Dean-Stark trap for 3 h. Then water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution (2×), dried over MgSO4, and concentrated to give 3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 64, 11.0 g, 98%) as a light brown oil.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][C:3]=1OC1C=CC=CC=1.NC1[C:40]2[C:39](=[O:41])[C:38]3[C:33](=CC=CC=3)[C:32](=O)[C:31]=2C(O)=CC=1Br.C1(O)C=CC=CC=1>[OH-].[K+]>[O:41]([C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:39]1[CH:40]=[CH:31][CH:32]=[CH:33][CH:38]=1
Reactant: Nc1c(Br)cc(O)c2c1C(=O)c1ccccc1C2=O
Reactant: Nc1c(Oc2ccccc2)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Oc3ccccc3)cccc21

Procedure:
Ya. B. Shteinberg and S. S. Tkachenko, Zh. Prikl. Khim. 49 (1976) 4, 904-905, describe a process for the preparation of 1-amino-2-phenoxy-4-hydroxyanthraquinone in an aqueous medium. In this process, 1-amino-2-bromo-4-hydroxyanthraquinone is reacted with phenol in aqueous potassium hydroxide solution in the presence of dispersants at 150° C. The authors claim yields of 87-90%. On repeating this process with various dispersants, we were unable to obtain a phenoxyanthraquinone derivative which could be used as a dye. In every case, the content of 1-amino-2-phenoxy-4-hydroxyanthraquinone in the products was less than 80%.
Reaction SMILES: C[O:2][C:3](=[O:52])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20]([S:24]([NH:27][C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O:33]C)=[O:32])(=[O:26])=[O:25])=[CH:19][C:18]([S:38]([NH:41][C:42]2[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=2)[C:45]([O:47]C)=[O:46])(=[O:40])=[O:39])=[CH:17]3)(=[O:13])=[O:12])[CH:5]=1.[OH-].[Na+:54].C(O)(=O)C>C(O)C>[Na+:54].[Na+:54].[Na+:54].[C:20]1([S:24]([NH:27][C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O-:33])=[O:32])(=[O:26])=[O:25])[C:21]2[C:16](=[CH:15][C:14]([S:11]([NH:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([O-:52])=[O:2])(=[O:12])=[O:13])=[CH:23][CH:22]=2)[CH:17]=[C:18]([S:38]([NH:41][C:42]2[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=2)[C:45]([O-:47])=[O:46])(=[O:40])=[O:39])[CH:19]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cccc(C(=O)OC)c4)cc(S(=O)(=O)Nc4cccc(C(=O)OC)c4)cc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C([O-])c1cccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cccc(C(=O)[O-])c4)cc(S(=O)(=O)Nc4cccc(C(=O)[O-])c4)cc3c2)c1
Reaction time: 0.75 h

Procedure:
A mixture of 12.0 g of the product of Example 11 and 62.0 ml of 2N sodium hydroxide is stirred for 45 minutes. The solution is neutralized with 3.6 ml of glacial acetic acid and diluted with 400 ml of ethanol. The solvent is concentrated in vacuo to a small volume. Then it is diluted again with ethanol with the separation of an oil. The solvent is decanted off, and the oil is triturated with fresh ethanol to produce a yellow solid. The solid is separated, washed with ethanol and ether, and dried at 70° C to yield 7.3 g of the product of the Example.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=1.Cl[CH2:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C(N(CC)CC)C>C(O)C>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[CH2:13][NH:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: CCc1cc(N)c(=O)[nH]c1C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(NCc2nc3ccccc3s2)c(=O)[nH]c1C
Yield: 77.8 %

Procedure:
A solution of 3-amino-5-ethyl-6-methyl-2-(1H)-pyridinone (152 mg, 1.0 mmol), 2-chloromethyl-1,3-benzthiazole (184 mg, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) in absolute ethanol (5 mL) was stirred at reflux for 24 hours. After filtering and concentrating under reduced pressure, the residue was flash chromatographed over silica gel. Elution with 4% MeOH- 96% CHCl3 gave 233 mg of product. Recrystallization from EtOH-water gave 77 mg of analytically pure product, mp 209°-210° C. Anal. Calcd for C16H17N3OS: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.71; H, 6.03; N, 14.70.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](OCC)=[O:7].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][OH:7]
Reactant: CCOC(=O)C(C)(CCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCBr)c1ccccc1
Yield: 98.2 %

Procedure:
According to the procedure given for the synthesis of 206e, 205b (23.70 g, 79.21 mmol) was reduced with LiBH4 (3.45 g, 158.4 mmol) and methanol (5.24 g, 163.5 mmol) in anhydrous CH2Cl2 (150 mL) to give 206b (20.0 g, 98%) as an oil. 1H NMR (CDCl3): δ 7.34-7.14 (m, 5H), 3.60 (m, 1H), 3.48 (m, 1H), 3.29 (t, 2H, J=6.0), 1.96-1.44 (m, 5H), 1.32 (s, 3H). 13C NMR (CDCl3): δ 144.25, 128.59, 126.71, 126.41, 72.44, 43.15, 37.06, 34.64, 27.58, 21.61. HRMS (LSIMS, nba): Calcd for C12H16Br (MH+-H2O): 239.0435, found: 239.0444.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:8]([C:20]#[N:21])=[C:7]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.[C:36]1([CH3:45])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.[F-].[Cs+]>COCCOC.CO.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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:45])[C:7]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[C:8]2[C:20]#[N:21])=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(Br)c32)cc1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(-c4ccccc4C)c32)cc1

Procedure:
To a mixture of EXAMPLE 581C (300 mg) and o-tolylboronic acid (93 mg) in 1,2-dimethoxyethane (10 ml) and methanol (5 ml) was added tetrakis(triphenylphosphine)palladium(0) (33 mg) and CsF (260 mg). The mixture was stirred at reflux under nitrogen for 4 hours. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (300 mL) and water (100 ml). The aqueous layer was further extracted with ethyl acetate and the combined extracts were washed with water, brine and dried over Na2SO4. After filtration, concentration of the solvent and column purification (5 to 10% ethyl acetate in hexane) gave EXAMPLE 581D.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([C:29]1[CH:28]=[CH:24][CH:23]=[C:22]([Br:21])[CH:30]=1)=[O:5])[CH3:9]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To potassium ethyl malonate (3.25 g, 19.13 mmol) in acetonitrile (50 mL) was sequentially added triethyl amine (4.1 mL, 29.16 mmol) and magnesium chloride (2.16 g, 22.78 mmol) at room temperature. After stirring the reaction mixture at room temperature for 2 hours, 3-bromobenzoyl chloride (2.0 g, 9.11 mmol) was added and the mixture was heated at 60° C. for 18 hours, concentrated under reduced pressure and partitioned between ethyl acetate (100 mL) and 1N HCl (25 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (2.45 g, 99 %). 1H NMR (CDCl3): δ 8.1 (s, 1H), 7.85 (d, 1H), 7.7 (d, 1H), 7.35 (t, 1H), 4.3 (m, 2H), 3.4 (s, 1H), 1.3 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[C:11]([F:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:30]([Si:33](Cl)([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:33]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:30]([CH3:32])[CH3:31])[CH:15]=2)=[C:11]([F:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Cc2c[nH]c3ncccc23)c(F)cc1OCc1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine (656, 0.877 g, 2.42 mmol) was dissolved in N,N-dimethylformamide (30 mL). Sodium hydride (60% dispersion in mineral oil, 140 mg, 3.6 mmol) was added at room temperature. After 20 minutes, triisopropylsilyl chloride (513 μL, 2.42 mmol) was added dropwise. The reaction was stirred for four hours. The reaction was poured into water and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate and brine. The organic portion was dried over anhydrous sodium sulfate and filtered. The filtrate was adsorbed onto silica gel and purified by silica gel chromatography using 20-80% ethyl acetate/hexane. The resulting material was purified a second time with 5-30% gradient ethyl acetate/hexane to provide the desired compound (657, 831 mg, 66%). MS (ESI) [M+H+]+=519.4.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]([F:15])([F:14])[F:13])C.[OH-].[Na+].Cl>C(O)C>[F:14][C:12]([F:13])([F:15])[S:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)c1ccccc1SC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1SC(F)(F)F

Procedure:
A solution of 5.0 g. of ethyl-o-(trifluoromethylthio)benzoate, 30 ml. of ethanol and 20 ml. of 10% sodium hydroxide was refluxed for 1.5 hrs. After cooling, the solution was acidified with 6N hydrochloric acid. The product was collected by filtration, dried, and recrystallized from a mixture of 60% hexane-40% benzene to give o-(trifluoromethylthio)benzoic acid, m.p. 119°-121° .
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=NC2C=C(F)C=C3C=2C=CC(=O)N3)[C:9](O)([CH2:14][O:15]C)[C:10]([F:13])([F:12])[F:11])=[C:4]([O:31][CH3:32])[C:3]=1[F:33].B.[Na].C[OH:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2([C:10]([F:11])([F:12])[F:13])[CH2:14][O:15]2)=[O:37])=[C:4]([O:31][CH3:32])[C:3]=1[F:33]
Reactant: COCC(O)(C(=Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Reactant: CO
Agent: B
Agent: [Na]
Product: COc1c(C(=O)C2(C(F)(F)F)CO2)ccc(Cl)c1F

Procedure:
285 mg (0.95 mmol) (4-Chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone are stirred with 622 mg (1.9 mmol) caesium carbonate in 6.7 ml methanol. The reaction is quenched by addition of water after one day. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 262 mg 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one. To 27 mg (0.15 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 50 mg (0.15 mmol) 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one in 0.45 ml toluene and 0.13 ml 1,4-dioxane are added 33 μl acetic acid and 0.12 ml tetra butyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethyl acetate. The combined organic phases are concentrated to yield quantitatively 5-{[1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethylpropylidene]amino}-7-fluoro-1H-quinolin-2-one. The raw imine in 4.2 ml methanol is cooled to 5° C. and 120 mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (acetone in methylene chloride, 30%) yields 9.5 mg of the title compound.