Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Fe:1](Cl)Cl.[CH2:4]([O:16][S:17]([O-:20])(=[O:19])=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Na+]>>[CH2:4]([O:16][S:17]([O-:20])(=[O:19])=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Fe+2:1].[CH2:4]([O:16][S:17]([O-:20])(=[O:19])=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cl[Fe]Cl
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: [Fe+2]

Procedure:
Nano magnetic particles were prepared by chemical sedimentation. 500 ml of 1M aqueous solution of iron (II) chloride was placed into 250 ml of 0.1M aqueous solution of sodium dodecylsulfate (C12H25NaO4S), which is an anion surfactant, and then reacted under a nitrogen atmosphere for 12 hours. When an orange color suspension was formed, a salt was separated from the resultant by sedimentation at 2° C. The separated salt was subjected to water-washing with a 0.1 M aqueous solution of iron (II) chloride three to five times and then recrystallized in water held at 50° C., to obtain high-purity iron (II) dodecylsulfate salt (Fe(DS)2). Similarly, instead of iron (II) chloride, nickel (II) chloride and zinc (II) chloride were used in the reaction to obtain a nickel (II) dodecylsulfate salt (Ni(DS)2) and zinc (II) dodecylsulfate salt (Zn(DS)2), respectively. The critical micelle concentrations of these salts are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[OH:20])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]1[O:20][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[F:15])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(F)C(F)(F)F)ccc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)C(F)(F)c1ccc2oc(-c3ccncc3Cl)nc2c1
Reaction time: 1.8 h
Yield: 83.3 %

Procedure:
To a mixture of 0.24 g of 3-chloro-N-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide, 4 ml of tetrahydrofuran and 0.21 g of triphenylphosphine, 0.34 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 1.8 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of 2-(3-chloropyridin-4-yl)-5-(pentafluoroethyl)benzoxazole (hereinafter, referred to as “active compound 66”).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH2:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13][CH2:14][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=4)[CH2:18][CH2:17]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Reactant: COC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(C4CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of trans-2-(4-cyclopropylphenyl)cyclopropanamine (90 mg, 0.519 mmol) in methanol (2 mL) were added methyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (156 mg, 0.597 mmol) and acetic acid (8.92 μL, 0.156 mmol), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52.2 mg, 0.831 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with 10% NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using reverse-phase HPLC to give 120 mg of product as off-white solid. MS: (M+H)+=419.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.56-0.71 (m, 2H), 0.89-1.07 (m, 2H), 1.32-1.43 (m, 1H), 1.51-1.77 (m, 3H), 1.83-1.94 (m, 1H), 1.97-2.25 (m, 3H), 2.53 (ddd, J=10.11, 6.44, 3.41 Hz, 1H), 2.93-3.25 (m, 5H), 3.49-3.64 (m, 2H), 3.86-4.00 (m, 3H), 4.43 (s, 2H), 6.97-7.17 (m, 4H), 7.72 (d, J=8.08 Hz, 2H), 8.14 (d, J=8.08 Hz, 2H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:12])[CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:13]1([CH2:19][CH2:20]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Si:1]([O:8][C@H:9]([C@@H:10]([OH:11])[CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Reactant: BrCCc1ccccc1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccccc1

Procedure:
(2S,3S)-2-(tert-butyldimethylsilyloxy)-5-phenyl-pentan-3-ol was prepared from (S)-2-(tert-butyldimethylsilyloxy)propanal (Synthesis 1996, 652, 3.00 g) and 2-phenylethyl bromide.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([N:8]1[C:16]([Cl:26])=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[O:21]3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3c(Cl)n(Cc4ccccc4)nc3c2)OC1(C)C
Temperature: 40 °C
Yield: 81.7 %

Procedure:
To a solution of 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-Indazole (200 mg, 0.598 mmol) in THF (2 mL), was added N-chlorosuccinimide (95.9 mg, 0.718 mmol). The mixture was heated at 40° C. for 4 hr, cooled to rt then concentrated to dryness. The crude material was purified by ISCO® chromatography using a gradient of 1-7% EtOAc in hexane to afford the desired product (180.1 mg, 82%). 1H NMR (400 MHz, DMF-d6) δ 7.98 (s, 1H), 7.59 (d, 1H), 7.38-7.28 (m, 4H), 7.22-7.19 (m, 2H), 5.74 (s, 2H), 1.34 (s, 12H); LC-MS m/z [M+H]+ 369.2, RT 3.94 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Cl[C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:19][C:17]1[C:16]([C:20]([F:22])([F:21])[F:23])=[CH:15][N:14]=[C:13]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:18]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CP(C)(=O)c1ccc(N)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 494 %

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, was allowed to stirred at room temperature for 15 minutes until a clear solution was obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) was added in four portions over 5 minutes. The reaction mixture was stirred at 60 degrees for 1 hour. The reaction mixture was cooled to room temperature and filtered to obtain a white solid. The white solid was washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid was dried under vacuum to yield desired product (3.8 g, 49% yield). MS/ES+: m/z=350.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][OH:9])[S:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([Si:23]([CH3:25])([CH3:24])[O:9][CH2:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: Cc1csc(CCO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1csc(CCO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 2-(4-methylthiophen-2-yl)ethanol (3.0 g, 21.1 mmol) and diisopropylethylamine (4.1 g, 31.7 mmol) in dry DCM (50 mL) at 0° C. was added TBSCl (4.8 g, 32.0 mmol) in dry DCM (20 mL) dropwise and the mixture was then warmed to room temperature gradually. After the alcohol was consumed completely, water (10 mL) was added. The resulting mixture was extracted with DCM (3×100 mL), washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.1 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2nccn2Cc2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1

Procedure:
A mixture of 5 mmol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours in a Parr hydrogenator at 35 psi of hydrogen. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography to give the desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][CH:15]=[N:14][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[C:8]1([C:7]2[N:6]=[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]3=[N:3][C:2]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1nc2cccnc2nc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
2-Chloro-3-phenylpyrido[2,3-b]pyrazine (step 3) (175 mg, 0.724 mmol) in dry dioxane (4 ml) under nitrogen was treated with p-tolylboronic acid (108 mg, 0.797 mmol), potassium carbonate (200 mg, 1.448 mmol) in water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (41.8 mg, 0.036 mmol). The resulting mixture was heated using microwave radiation at 150° C. for 1 hour. After cooling to RT, the mixture was diluted with water (100 ml) and extracted with DCM (×3). The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica eluting with 0-30% EtOAc in iso-hexane to afford the titled compound as a yellow solid;
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: c1ccncc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole), pyridine (158 mg, 2 mmoles) in dimethylsulfoxide (DMSO) (1 ml) was stirred for 1 hour at room temperature. To the mixture was added ethyl acetate (20 ml) to precipitate a solid (620 mg), which was added to formic acid (6 ml) containing sodium bisulfite (60 mg). The mixture was stirred for 30 minutes at 40° C. and concentrated to dryness. The residue was dissolved in H2O (40 ml) and some insolubles were removed. The aqueous solution was charged on a column of reverse phase (PrepPAK-500/C18, 100 ml) eluting with H2O (300 ml) and 5% aqueous CH3OH (800 ml), and the eluate was monitored by uv (254 nm) and HPLC. The fractions (5% aqueous CH3OH) containing the desired product were combined, concentrated to a small volume and lyophilized to yield 40 mg (8%) of the title compound (I-1B), melting at >200° C. (dec.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]OP(C=[N+]=[N-])(=O)OC.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[CH:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COP(=O)(C=[N+]=[N-])OC
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A solution of 1-BOC-3-formylpiperidine (1.46 g, 6.85 mmol) and (diazomethyl) phosphonic acid dimethyl ester (1.79 g, 11.94 mmol) in 50 mL methanol was stirred at ice-bath for 10 min, K2CO3 (1.96 g, 14.2 mmol) was added to the above mixture and stirred at ice-bath for 2 hrs, then stirred at rt overnight. The mixture was evaporated in vacuo, to the residue was added EtOAc and water, the organic layer was separated and water layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine successively, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo to give 1.44 g product as colorless oil (100.0%). 1H NMR (300 MHz, CDCl3) δ: 3.90 (1 H, brs), 3.70-3.75 (1 H, m), 2.95-3.02 (2 H, m), 2.40-2.47 (1 H, m), 2.05 (1 H, d, J=2.1 Hz), 1.94-1.99 (1 H, m), 1.69-1.73 (1 H, m), 1.50-1.63 (2 H, m), 1.46 (9 H, s).
Reaction SMILES: [CH2:1]([C:3]1[N:7](CCC)[N:6]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])=[CH:14][CH:13]=2)[C:4]=1[C:32]([O:34][CH3:35])=[O:33])[CH3:2].[C:36]1(OC)[CH:41]=CC=C[CH:37]=1.CCOC(C)=O>FC(F)(F)C(O)=O>[NH2:27][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:5]2[N:6]([CH2:37][CH2:36][CH3:41])[N:7]=[C:3]([CH2:1][CH3:2])[C:4]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:13][CH:14]=1)(=[O:26])=[O:25]
Reactant: CCCn1nc(Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(C(=O)OC)c1CC
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCn1nc(CC)c(C(=O)OC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of the compound obtained in example 43 (2.65 g, 5.3 mmol) in trifluoroacetic acid (58 mL) was added anisole (1 mL) and the mixture stirred under an argon atmosphere for 18 h. The solvent was concentrated and the residue purified by chromatography on silica-gel (hexane-EtOAc mixtures) to give a 1:1 mixture of regioisomers, from which the title compound was obtained as a white solid by recrystallization from EtOAc (1.34 g, 57%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26][C:25]=2[CH:32]=1.C(O)(C)C>Cl>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26][C:25]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CCC(=O)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(=O)CC3)ncc1Cl
Yield: 43.6 %

Procedure:
Into a microwave vial was placed 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (50 mg, 0.0002 mol) and 2-amino-5,6,8,9-tetrahydro-benzocyclohepten-7-one (38 mg, 0.00022 mol) in isopropyl alcohol (5 mL, 0.06 mol) with 4 M HCl (3 drops). The mixture was subjected microwaves at 130° C. for 10 minutes. Trace starting materials were present so the reaction mixture was resubjected to the same microwave conditions. The resulting solid was collected by filtration and washed with cold methylene chloride and dried in a vacuum oven at 50° C. overnight to give 38 mg (50%) of an off-white solid 2-[5-Chloro-2-(7-oxo-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. MP: 262-269° C.; 1HNMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.50 (s, 1H), 8.78 (d, 1H, J=5.3 Hz), 8.69 (d, 1H, J=8.08 Hz), 8.24 (s, 1H), 7.76 (d, 1H, J=7.58), 7.59 (s, 1H), 7.48 (t, 1H, J=7.58 Hz), 7.42 (d, 1H, J=7.58), 7.17 (t, 1H, J=8 Hz), 2.77-2.85 (m, 8H), 2.5 (d, 3H); MS (m/e) 436 (M+1).
Reaction SMILES: C([Mg]Br)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH:14]([F:16])[F:15].CN(C)[CH:19]=[O:20].O>C1COCC1>[F:15][CH:14]([F:16])[C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)c(C(F)F)c1
Agent: CC(C)[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(F)cc1C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Isopropyl magnesium bromide (30 mL, 1M in THF, 30 mmol) was added dropwise to an ice-cooled solution of 1-bromo-2-(difluoromethyl)-4-fluorobenzene (44; 6 g, 26.7 mmol) in THF (100 mL). The reaction mixture was then allowed to warm to room temperature and stirred for 3 hr. Dimethylformamide (3.5 ml, 45.2 mmol) was added and the reaction stirred for 3 hr. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 2-(difluoromethyl)-4-fluorobenzaldehyde 45 (3.2 g, 68.5%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>O>[Cl:21][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([F:16])[CH:13]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2[nH]c1=O
Solvent: O
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Temperature: 70 °C

Procedure:
50 g of 3-ethoxycarbonyl-6,7-difluorocarbostyril are added in the course of 10 minutes with stirring at 20° C. to 200 cm3 of phosphoryl chloride. The suspension is heated to a temperature in the region of 70° C. and maintained at this temperature for 3 hours. After cooling to approximately 10° C., the solution obtained is poured with stirring into a mixture of 1,000 cm3 of water and 1,000 g of crushed ice. The temperature is allowed to rise to approximately 20° C. and the mixture is extracted with twice 500 cm3 of dichloromethane. The combined organic extracts are washed with 1,000 cm3 of water, and 1,000 cm3 of water to which sodium bicarbonate has been added to pH 7, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at approximately 40° C. 45.6 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline are obtained in the form of a beige solid, melting point 108° C. which is used without further purification for the subsequent steps.
Reaction SMILES: [Li][C:2](C)(C)[CH3:3].[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(I)C>C1COCC1>[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:2][CH3:3])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [Li]C(C)(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Cl)ccc21
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
t-BuLi (3.7 mL of 1.7 M solution in pentane) was added dropwise to a solution of N-(benzensulfonyl)-5-chloroindole (1) (J. Org. Chem. 1981, 46, 3859) (1.5 g, 5.14 mmol) in THF (35 mL) at −70° C., under a nitrogen atmosphere. The mixture was stirred for 15 min, allowed to warm to room temperature over 20 min, cooled to −70° C., and treated with a solution of ethyl iodide (0.84 mL, 10.5 mmol) in dry THF (5 mL). The mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, stirred for 2 h, poured into ice (15 g), and a saturated aqueous NH4Cl solution and then extracted with ether (3×20 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to give a residue which was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 8:2) and crystallization from ethylacetate/cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][C:13]=2[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].[CH3:30]O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][C:13]=2[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2C)nc1Cl
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)c(C)o3)cc2C)nc1Cl
Yield: 80 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methylphenyl)-1,3-oxazole-4-carboxylate obtained in Example (109f) (0.13 g, 0.33 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (5 mL), to obtain 0.10 g of the title compound as a colorless solid (80%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].OO.O.O.O.O.O.S([O-])([O-])(=[O:33])=S.[Na+].[Na+].O>C(O)(=O)C>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)=[O:33])=[CH:18][CH:17]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1ccc(Sc2ccc(OCCCC)cc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1ccc(S(=O)c2ccc(OCCCC)cc2)cc1
Reaction time: 12 h
Yield: 90 %

Procedure:
In 200 g of acetic acid was dissolved 30 g of bis(4-butoxyphenyl) sulfide obtained in Synthesis Example 1-17. While the solution was maintained at an internal temperature of 30° C., 8.8 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 12 hours, after which under ice cooling, a mixture of 0.9 g sodium thiosulfate pentahydrate and 30 g water was added dropwise to quench the reaction. The solution was combined with 200 g of methylene chloride and 50 g of water for extraction. The organic layer was separated, washed with water, and concentrated in vacuum. On subsequent purification by silica gel chromatography, 28 g of the target compound, bis(4-butoxyphenyl) sulfoxide was obtained as amorphous solid. Yield 90%.