Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][S:7]([NH:10][CH2:11][C:12]([NH2:14])=[O:13])(=[O:9])=[O:8].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C)C=O.O>[CH2:24]([N:10]([CH2:11][C:12]([NH2:14])=[O:13])[S:7]([CH2:6][C:5]1[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=1)(=[O:9])=[O:8])[CH:23]=[CH2:22]
Reactant: NC(=O)CNS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(CC(N)=O)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.96 g of 3-trifluoromethylbenzylsulfonamidoacetamide was dissolved in 10 ml of dry dimethylformamide. To this ice-cooled solution was added 0.24 g of sodium hydride. The reaction mixture was stirred for 15 minutes at room temperature and then 0.95 ml of allyl bromide dissolved in 5 ml of dimethylformamide was added dropwise. Reaction was essentially instantaneous. After about 30 minutes, the reaction mixture was diluted with 150 ml of water and extracted twice with 75 ml portions of diethyl ether. Petroleum ether was added to the combined ether phases until cloudiness occurred, and this solution was washed with 100 ml of water. The organic phase was dried over magnesium sulfate and stripped to a white solid. Trituration with carbon tetrachloride afforded 2.8 g of the title compound, m.p. 91° to 92° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[C:20](=[O:29])[N:19]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.I[CH3:38]>C1COCC1>[CH2:11]([C:18]1([CH3:38])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[C:20](=[O:29])[N:19]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CI
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)N(C(=O)OC(C)(C)C)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(Cc1ccccc1)N(C(=O)OC(C)(C)C)C2=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Lithium bis(trimethysilyl)amide (5.04 mL, 5.04 mmol, 1 M in THF) was added to a solution of the tert-butyl 3-benzyl-5-methoxy-1-oxoisoindoline-2-carboxylate (example 1.3, 890 mg, 2.52 mmol) in THF (8 mL) at −78° C. After stirring the solution at −78° C. for 1 hr, iodomethane (465 mg, 3.27 mmol) was added, this was stirred at −78° C. for 1.5 hours. LC/MS showed complete conversion. Quenched the reaction mixture with saturated NaCl solution, then extracted with ethyl acetate, the combined organic layer was washed 1× with saturated NaCl solution. The organic phase was dried on Na2SO4 and the solvent was evaporated. The residue was purified by flash-chromatography on silica gel with 25-40% ethyl acetate in hexane, 750 mg (2.04 mmol, 81%) of the product was obtained.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].C(N(CC)C(C)C)(C)C.Cl[C:17]([O:19][CH:20]([Cl:22])[CH3:21])=[O:18]>O1CCCC1>[Cl:22][CH:20]([O:19][C:17]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:18])[CH3:21]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COC(=O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)COC(=O)OC(C)Cl
Reaction time: 3 h

Procedure:
To an ice-water bath cooled solution of methyl glycolate (13.5 mL) and N,N-diisopropylethylamine (30.46 mL) in tetrahydrofuran (180 mL) was added dropwise with stirring 25.0 g of 1-chloroethyl chloroformate. The 0° C. bath was removed, and the mixture stirred for an additional 3 hr. After filtration to remove insoluble amine hydrochloride, the THF solution was evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, dried over anh. sodium sulfate, and evaporated under reduced pressure to give 31.1 g of reddish oil. NMR.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[S:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[N:5]=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Nc1nc2ccccc2s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2ccccc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (1200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Aminobenzothiazole (100.0 l grams; 0.67 mole) is then added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the reaction mixture is evaporated to dryness to yield the desired product benzothiazol-2-yl isocyanate dimer as a yellow solid having a melting point of 250° to 252° C.
Reaction SMILES: C(OC(=O)[NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[N:10]=1)=S)C.Cl.NO.CC[N:26](C(C)C)C(C)C>CO.CCO>[S:17]1[CH:18]=[CH:19][C:15]([C:11]2[N:10]3[N:26]=[C:6]([NH2:5])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=2)=[CH:16]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cccc(-c2ccsc2)n1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2cccc(-c3ccsc3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A suspension of ethyl({[6-(3-thienyl)pyridin-2-yl]amino}carbonothioyl)carbamate (4.0 g; 13.01 mmol; 1.0 eq.), hydroxylamine hydrochloride (4.52 g; 65.1 mmol; 5.0 eq.) and DIEA (6.55 mL) in MeOH/EtOH (1:1, 120 mL) was stirred at rt for 2 hours and then at 70° C. for 3 hours. Solvents were removed under reduced pressure, the residue was taken up in dioxane/water (1:1) and filtered to give the title compound as a white powder (2.3 g; 82%). HPLC, Rt: 1.75 min. (purity 94.8%). LC/MS, M+(ESI): 217.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19]([CH3:27])([CH3:26])[C:20]#[C:21]/[CH:22]=[CH:23]/[CH2:24]Br.C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[CH2:24]/[CH:23]=[CH:22]/[C:21]#[C:20][C:19]([O:18][CH3:17])([CH3:27])[CH3:26])[CH3:2]
Reactant: COC(C)(C)C#C/C=C/CBr
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C/C=C/C#CC(C)(C)OC)P(=O)(OCC)OCC
Reaction time: 5 h
Yield: 55.8 %

Procedure:
3.36 g of diethylphosphonoacetic acid ethyl ester is dissolved in 40 ml of ethanol, 0.60 g of 60% oily sodium hydride is added under ice cooling and stirring, 1.09 g of (E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide is added dropwise, and the mixture is stirred under ice cooling for 1 hour and then at room temperature for 5 hours. 15 ml of acetic acid is added to the reaction solution, the solvent is distilled off under reduced pressure, and the residue is extracted with a system of water and ethyl acetate. The organic layer is post-treated in a conventional manner, and the product is purified by silica gel column chromatography [Wako gel C-200, 100 g; hexane/ethyl acetate=1/2] and medium pressure liquid chromatography [Lobar column, size B, Lichroprep Si 60F (produced by Merck Co.); hexane/ethyl acetate=1/1→1/2] to obtain 1.01 g of (E)-diethylphosphono(6-methoxy-6-methyl-2-hepten-4-ynyl)acetic acid ethyl ester as colorless oil.
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18]2)=[C:11]([N+:23]([O-:25])=[O:24])[CH:10]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2([C:21]#[N:22])[CH2:18][CH2:19][CH2:20]2)=[C:11]([N+:23]([O-:25])=[O:24])[CH:10]=1
Reactant: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1O
Temperature: 70 °C
Yield: 98 %

Procedure:
A solution of 1-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (2.78 g, 8.22 mmol), from Step 2, in EtOH (30 mL) was treated with 10% Pd/C (0.87 g, 0.822 mmol), fitted with hydrogen filled balloon and heated to 70° C. for 3 hours under hydrogen atmosphere. The catalyst was filtered off and washed with EtOH. Solvent was concentrated to provide 1-(4-(hydroxyl)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (2 g, 99%). MS (ESI) m/z 249 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c12
Product: Cc1csc2nc(-n3ccnc3C)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:78])([F:77])[C:49]1[CH:50]=[C:51]([C:59]([CH3:76])([CH3:75])[C:60]([N:62]([CH3:74])[C@H:63]2[C@H:67]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:66][NH:65][CH2:64]2)=[O:61])[CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1>C1COCC1>[F:77][C:48]([F:47])([F:78])[C:49]1[CH:50]=[C:51]([C:59]([CH3:75])([CH3:76])[C:60]([N:62]([C@H:63]2[C@H:67]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:66][N:65]([C:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:3][O:2][CH3:1])[CH2:9][CH2:8]3)=[O:12])[CH2:64]2)[CH3:74])=[O:61])[CH:52]=[C:53]([C:55]([F:56])([F:57])[F:58])[CH:54]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Reactant: COCC1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC1CCC(C(=O)N2C[C@@H](N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)CC1
Reaction time: 48 h
Yield: 48.2 %

Procedure:
To a stirred solution of 4-methoxymethyl-cyclohexanecarboxylic acid (described in JP60258141) (7.4 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 12.7 mg (48%) of the title compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[CH:33]=[C:32]([CH3:34])[NH:31][C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:45](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[CH:33]=[C:32]([CH3:34])[N:31]([CH3:45])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5[nH]c(C)cc5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)cc(C)n5C)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-4-yl)benzo[d]thiazol-6-yl)acetate (100 mg, 0.16 mmol) in DMF (5 mL) was added cesium carbonate (68 mg, 0.208 mmol). The reaction solution was stirred at room temperature for 5 minutes, iodomethane (30 mg, 0.208 mmol) was added. The reaction solution was stirred for 30 minutes and quenched with water. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C36H35ClN4O3S: 639.2 (M+H+); Found: 639.3 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=1>>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:18][CH2:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=1
Reactant: BrCCCCCCBr
Reactant: OCCc1cccc(Cl)c1
Product: Clc1cccc(CCOCCCCCCBr)c1

Procedure:
(4.12 g), T.l.c. (ER- HX 1:79) Rf 0.16, from 1,6-dibromohexane (11.71 g) and 3-chlorobenzeneethanol (2.5 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[Cl:18][C:19]1[S:23][C:22]([S:24](Cl)(=[O:26])=[O:25])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[S:23][C:22]([S:24]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[CH2:9][OH:10])(=[O:26])=[O:25])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: N[C@@H]1CCCC[C@H]1CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a suspension of trans-2-aminocyclohexylmethanol hydrochloride (214 mg, 1.30 mmol) and triethylamine (0.538 mL, 3.9 mmol) in 5 mL dichloromethane at 0° C. was added a solution of 5-chlorothiophene-2-sulfonyl chloride (0.267 mL, 1.23 mmol) in 1 mL dichloromethane. The reaction was stirred at 0° C. for 30 min and at room temperature for 30 min. The crude reaction mixture was purified by flash chromatography on silica gel using a gradient of 0 to 100% ethyl acetate in hexane to give 5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (330 mg, 84%). 1H NMR (400 MHz, CDCl3) δ ppm 7.40 (d, J=4.03 Hz, 1H), 6.91 (d, J=4.03 Hz, 1H), 5.24 (d, J=7.30 Hz, 1H), 3.86 (d, J=11.33 Hz, 1H), 3.32-3.48 (m, 1H), 3.05 (d, J=6.55 Hz, 1H), 2.32 (br. s., 1H), 1.72-1.83 (m, 1H), 1.58-1.73 (m, 3H), 1.11-1.36 (m, 5H). MS [M+H]+=310; [M+Na]+=332.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)([O-])=O.O>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: O
Product: N#CC=Cc1ccc(N)cc1
Yield: 76 %

Procedure:
A mixture of 120 parts of acrylonitrile and 1000 parts of acetone is introduced into the solution of the diazo derivative obtained from 276 parts of p-nitroaniline. Then, 40 parts of cupric chloride crystallised with 2 molecules of water are added and the mixture is stirred vigorously. The evolution of nitrogen is exothermic and the temperature should be kept at 30°-32° C. by means of a cooling bath. When the diazonium chloride has disappeared (6 hours), yellow leaflets melting at 108° C. are filtered off. After recrystallisation from methanol, one obtains 330 parts of 2-chloro-3-(4-nitrophenyl) propionitrile which melts at 112° C. This product is then dehydrohalogenated by means of 200 parts of crystallised sodium acetate in a mixture of 340 parts of water and 800 parts of ethyl alcohol. The mixture is refluxed for 12 hours and 225 parts of 4-nitrocinnamonitrile are isolated in the cold. Melting point: 202° C. The 4-nitro-cinnamonitrile thus obtained is then reduced by the Bechamp method in 2000 parts of water and 800 parts of ethyl alcohol. The 4-aminocinnamonitrile is obtained which melts at 109°-110° C. Yield: 76%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]1[C:44]2[CH:45]=[C:46]([S:49]([NH:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)(=[O:51])=[O:50])[CH:47]=[CH:48][C:43]=2[S:42][N:41]=1>C(Cl)Cl.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]3[C:44]4[CH:45]=[C:46]([S:49](=[O:50])(=[O:51])[NH:52][CH2:53][C:54]5[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=5)[CH:47]=[CH:48][C:43]=4[S:42][N:41]=3)=[O:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc3snc(NCCCN)c3c2)cc1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CNS(=O)(=O)c2ccc3snc(NCCCNC(=O)c4ccc(-c5ccc(OC)cc5)cc4)c3c2)cc1
Reaction time: 0.25 h
Yield: 21.1 %

Procedure:
To a solution of 4′-methoxybiphenyl-4-carboxylic acid (34 mg, 0.1 mmol) in methylene chloride (1 mL), diethyl cyanophosphonate (23 μL, 0.2 mmol) and 4-methylmorpholine (34 μL, 0.3 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-(4-methoxybenzyl)benzo[d]isothiazole-5-sulfonamide (57 mg, 0.1 mmol) in methylene chloride (1 mL) was then added and the resulting reaction mixture was allowed to stir for 7 h. Upon diluting the reaction mixture with methylene chloride (20 mL) and 10% HCl aqueous solution, a precipitate was observed, filtered and air-dried to provide 4′-methoxy-N-(3-(5-(N-(4-methoxybenzyl)sulfamoyl)-benzo[d]isothiazol-3-ylamino)propyl)biphenyl-4-carboxamide (13 mg). 1H NMR (300 MHz, DMSO-d6): 9.01 (br s, 1H), 8.58 (t, 1H), 8.47 (d, 1H), 7.88-7.91 (m, 3H), 7.70 (d, 2H), 7.66 (d, 2H), 7.50 (dd, 1H), 7.34 (d, 1H), 7.13 (d, 2H), 7.03 (d, 2H), 6.78 (d, 2H), 3.88 (d, 2H), 3.80 (s, 3H), 3.67 (s, 3H), 3.42-3.48 (m, 2H), 3.31 (m, 2H), 2.00-2.09 ppm (m, 2H). MW=616 confirmed by LC-MS, tr=13.65 min (Method Y) MH+=617.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[N:29]1([C:35]([C:37]2[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C.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>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:41]3[CH:42]=[C:37]([C:35]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:36])[CH:38]=[CH:39][CH:40]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
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: CN(C)C=O
Product: CC(On1ccc2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
To a solution of 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine (75 mg, 0.195 mmol, 1.0 eq) in DMF (1.2 mL), was added Pd(PPh3)4 (15 mg), 2.0 M K2CO3 (1.0 mL), and [3-(morpholin-4-ylcarbonyl)phenyl]boronic acid (1.8 eq, 0.351 mmol). The reaction mixture was microwaved at 90° C. for 30 minutes. The upper layer was removed with a pipette, filtered, and purified with preparation HPLC to give the product.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[Br:19]Br>>[Br:19][C:8]1[N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[C:6]2=[N:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)n2ccnc12
Reactant: BrBr
Product: O=C(c1ccccc1)c1ccc(Cl)n2c(Br)cnc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.4 %

Procedure:
100 mg (0.39 mmol) of (5-Chloroimidazo[1,2-a]pyridin-8-yl)(phenyl)methanone (example L, step 3) are dissolved in 5 ml glacial acid. 30 mg (0.19 mmol) of bromine are added dropwise to the solution. The mixture is stirred for 20 h at rt. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP 18-Column, eluent: acetonitrile-water-gradient) to yield 64 mg (49.0% of th.) (3-Bromo-5-chloroimidazo[1,2-a]pyridin-8-yl)(phenyl)methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:18])([CH3:17])[CH:15]=[CH:16][C:6]3=[CH:5][C:4]=2[N:3]=1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:30])=S.[Na+].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:18])([CH3:17])[C@H:15]4[O:30][C@H:16]4[C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)C=C3
Reactant: O=S([O-])([O-])=S
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H]1O[C@@H]31
Yield: 94 %

Procedure:
To a solution of 7-chloro-2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (200 mg, 0.77 mmol) in ethyl acetate (3.0 mL), N-methyl imidazole (0.012 mL, 0.154 mmol) and ent-Ph,Ph salen manganese complex (8.0 mg, 0.0077 mmol) were added at room temperature and sodium hypochlorite aqueous solution (1.0 g, 1.513 mol/kg, 1.54 mmol) was added dropwise in water bath, and the resulting mixture was stirred in water bath for 40 minutes. In water bath, sodium hypochlorite aqueous solution (1.0 g, 1.513 mol/kg, 1.54 mmol) was added dropwise, and the resulting mixture was further stirred in water bath for 30 minutes. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, the resulting solution was filtered through celite and extracted. The organic phase was washed with sodium hydrogencarbonate aqueous solution and then with sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=10/1) to obtain (3S*,4S*)-7-chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (yield: 94%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C@@H:33]([CH3:35])[OH:34].[C:40]1([C:46]2[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[C:40]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:45]=[CH:44][C:43]([O:34][C@@H:33]([CH3:35])[C:32]([O:37][CH2:38][CH3:39])=[O:36])=[CH:42][CH:41]=1
Reactant: CCOC(=O)[C@@H](C)O
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Oc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 1a) from diethylazodicarboxylate (6.74 ml), triphenylphosphine (13.11 g), (R)-(+)-ethyl lactate (5.67 ml) and 4-phenylphenol (8.51 g) in dry tetrahydrofuran (125 ml). The residue obtained after work-up was purified by column chromatography over silica eluting with isohexane:dichloromethane (2:3) to give the sub-title compound as an oil (11.3 g).