Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][S:29][CH2:30][C:31]1[N:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:37][C:34]2[CH:33]=[N:32][C:31]([CH2:30][S:29][CH3:28])=[CH:36][N:35]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: CSCc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSCc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 581.7 mg, 1.758 mmol) in methylene chloride (8.6 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (310 mL, 3.554 mmol) and N,N-dimethylformamide (2 drops). The reaction mixture was stirred at 0° C. for 45 min and then slowly warmed to 25° C. over 6 h. The solution was then concentrated in vacuo. The resulting yellow slurry was dissolved in methylene chloride (7 mL) and then cooled to 0° C. To this solution was added a solution of 5-methylsulfanylmethyl-pyrazin-2-ylamine (267.2 mg, 1.721 mmol) and pyridine (174 μL, 2.151 mmol) in methylene chloride (8.6 mL), followed by a methylene chloride rinse (1.7 mL). The pH of the reaction was roughly 3–4, and a second aliquot of pyridine (50 μL, 0.618 mmol) was added to adjust the pH to roughly 5. The reaction mixture was stirred at 0° C. and slowly warmed to 25° C. overnight. The reaction was then quenched with water (10 mL), stirred at 25° C. for 10 min, and concentrated in vacuo. The reaction slurry was partitioned between ethyl acetate (250 mL) and a 1N aqueous hydrochloric acid solution (250 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (250 mL), a saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL), and a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/2 ethyl acetate/hexanes) afforded the desired chiral 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide (679.0 mg, 84%) as a white foam: mp 75.0–76.7° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O3S2 (M+H)+ 468.1177, found 468.1180.
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:34])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=4[CH:20]=3)=[O:18])=[CH:11][C:10]=2[OH:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C)C.C1COCC1.[BH4-].[Na+]>CC(C)=O>[N:1]1([NH:7][C:8](=[O:34])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([OH:18])[C:19]3[CH:28]=[CH:27][C:26]4[C:25]([CH3:29])([CH3:30])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=4[CH:20]=3)=[CH:11][C:10]=2[OH:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)NN4CCCCC4)c(O)c3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C(O)COc3ccc(C(=O)NN4CCCCC4)c(O)c3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.43 g (7.6 mmol) of N-piperidinyl-2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzamide, 100 ml of isopropanol and 50 ml of THF are introduced into a flask. The mixture is cooled to 0° C. and 144 mg (3.81 mmol) of NaBH4 are added. The mixture is stirred at 0° C. for 1 hour. Acetone is added, the solvents are evaporated, the residue is taken up in water and the mixture is adjusted to pH 6-7 with hydrochloric acid (1N). The mixture is extracted with ethyl acetate, washed with water and dried over sodium sulphate, and the solvents are evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of ethyl acetate and hexane (35:65). After evaporation of the solvents, the oil obtained is crystallised in hexane, filtered and dried, and 4.25 g (86%) of the expected product of melting point 124° C. are collected.
Reaction SMILES: [C:1]1([B:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][Li:21]>[Br-].C[N+](C)(C)C>[CH3:20][B-:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[Li+:21]
Reactant: c1ccc(B(c2ccccc2)c2ccccc2)cc1
Reactant: [Li]C
Agent: C[N+](C)(C)C
Agent: [Br-]
Product: C[B-](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Li+]

Procedure:
More specifically, in the case of the tetramethylammonium methyltriphenylborate, phenyl bromide is reacted with metallic magnesium in diethyl ether to prepare a Grignard reagent, the reagent is added dropwise to a solution containing boron trifluoride diethyl etherate dissolved in diethyl ether, the mixed solution is stirred for several hours to obtain triphenylborane, the triphenylborane obtained is added to methyllithium without passing through isolation to form lithium methyltriphenylborate, and tetramethylammonium bromide is added thereto to effect ion exchanging, as a result, tetramethylammonium methyltriphenylborate is obtained.
Reaction SMILES: CS(C)(=O)=C.[CH3:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])=[O:8].[CH3:19]COCC>CS(C)=O.O>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[C:7]1([CH3:19])[O:8][CH2:6]1
Reactant: CCOCC
Reactant: COc1ccc(OC)c(C(C)=O)c1
Agent: C=S(C)(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(OC)c(C2(C)CO2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of dimethylsulfoxonium methylide (69.4 mM) in dimethyl sulfoxide (65 ml.) at room temperature is added solid 2,5-dimethoxyacetophenone (10 g., 55.5 mM). The reaction mixture is stirred for one hour at 25° C., for one-half hour at 50° C. and is then cooled. The mixture is diluted with water (50 ml.) and added to a mixture of ice water (200 ml.)--ether (250 ml.)--low boiling petroleum ether (25 ml.). The organic extract is washed twice with water (250 ml.), dried (MgSO4) and evaporated to an oil. Fractional distillation of the oil yields 2,5-dimethoxy-α-methylstyrene oxide.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:6]23[O:10][C@:9](O)([CH2:11][C:12](=[CH2:13])[C@@H:5]2[CH2:4][CH2:3]1)[C@H:8]([CH:15]([CH3:17])[CH3:16])[CH2:7]3.[Mn]([O-])(=O)(=O)=[O:19].[K+]>C(O)(=O)C>[CH3:16][C:15]1[C:8]2[C:7]([CH:6]=[C:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:12]([CH3:13])[CH2:11][C:9]=2[O:10][CH:17]=1)=[O:19]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=C1C[C@@]2(O)O[C@@]3(C[C@H]2C(C)C)[C@@H](C)CC[C@@H]13
Agent: C/C1=C/C(=O)c2c(C)coc2C/C(C)=C\CC1
Agent: [K+]
Solvent: CC(=O)O
Product: CC1=CC(=O)c2c(C)coc2CC(C)=CCC1

Procedure:
2.45 g (0.01 mol, 96%) of curcumol was dissolved in 40 mL of acetic acid, and to it was added an aqueous solution dissolved with 4 g potassium permanganate. The mixture was heated under reflux for several hours followed by removal of the organic solvent under vacuum. The mixture was extracted with 100 mL of 50% ethyl acetate and water. The ethyl acetate was washed with water several times and dried over anhydrous sodium sulfate. The solvent wad removed under vacuum to afford a dark solid. After separated by silica gel column, 1.45 g of white curzerenone derivative was obtained, yield: 61%, HPLC: 98%, Melting point: 138-140° C., i.e. Compound No. 31 of formula (III) wherein Z is O.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:36])[C:12]([CH:14]([C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:43]([OH:46])(=[S:45])[CH3:44]>>[CH2:8]([O:10][C:11](=[O:36])[CH:12]([CH2:13][S:45][C:43](=[O:46])[CH3:44])[CH:14]([C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:9]
Reactant: C=C(C(=O)OCC)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: CC(O)=S
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 45 °C
Yield: 65 %

Procedure:
Triethylamine (0.096 g, 0.95 mmol) was added to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-phenyl-ethyl]-acrylic acid ethyl ester (0.34 g, 0.86 mmol) in thioacetic acid (3.5 mL) at 0° C. under argon. The mixture was heated at 45° C. for 24 h. Ethyl acetate was added and the organic phase was washed with aqueous saturated sodium bicarbonate and brine and dried. After filtration and evaporation in vacuo the crude product was purified by flash chromatography (CH2Cl2/ethyl acetate, 1:0→100:5) to give 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-4-phenyl-butyric acid ethyl ester (0.264 g, 65%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[OH:27][N:3]1[C:4]([CH3:17])([CH3:16])[CH2:5][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:7][C:2]1([CH3:18])[CH3:1]
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1O
Temperature: 25 °C

Procedure:
To a solution of 25.4 g (0.1 mole) of the lactam compound prepared in Example 1 in 200 ml of chloroform is added portionwise 38 g (0.22 mole) of m-chloroperbenzoic acid over a one-hour period. The reaction mixture is stirred for an eighteen-hour period at ambient temperature. The mixture is then filtered to remove the m-chlorobenzoic acid formed. The filtrate is washed successively with 1N sulfuric acid, with water and with 10% aqueous sodium bicarbonate and then dried. The solvent is removed in vacuo and the residue recrystallized from tolueneheptane to give the above-named compound as an orange solid melting at 158°-164° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[CH2:17][N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:18]1([CH2:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:7]=2[N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(F)(F)F)cc2N2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CN2CCNCC2)c(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-(morpholin-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate (1.30 g, 3.03 mmol, 1.00 equiv), dichloromethane (20 mL). The mixture was cooled to 0° C. Trifluoroacetic acid (3 mL) was added dropwise. The resulting solution was stirred overnight at room temperature and concentrated under pressure to yield 0.800 g (crude) of 4-[2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl]morpholine as a light yellow solid. LCMS (ESI, m/z): 330 [M+H]+.
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.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:14][CH:13]=3)=[O:17])[CH2:23][C:22]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A suspension of the carboxylic acid of Step B (1.0 g, 4.38 mmol) in thionyl chloride (6 mL) was heated at reflux for 1 hour. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a light brown solid. The acid chloride was then dissolved in dichloromethane (10 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine (1.2 g, 6.52 mmol) and N,N-diisopropylethyl amine (1.7 mL, 9.76 mmol) in dichloromethane (25 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification of the residue by flash chromatography using a solvent gradient from 15% to 50% of ethyl acetate in hexane provided the title compound (1.5 g, 86.8%) as a white solid, m.p. 187-189° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4]1.[Cl:24][C:25]1[C:34]([CH:35]=O)=[N:33][C:32]2[NH:31][C:30](=[O:37])[CH2:29][O:28][C:27]=2[CH:26]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[Cl:24][C:25]1[C:34]([CH2:35][NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:4]2)=[N:33][C:32]2[NH:31][C:30](=[O:37])[CH2:29][O:28][C:27]=2[CH:26]=1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CN)C3)c2c1
Reactant: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CNCc4nc5c(cc4Cl)OCC(=O)N5)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of 1-{2-[(3S)-3-(Aminomethyl)-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (0.149 g, 0.472 mmol) in 1:1 (MeOH/CH2Cl2) (25 mL) were added 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003064421, Example 15(c)) (0.100 g, 0.472 mmol) and sodium sulphate (0.100 g) and the resulting solution stirred for 18 hours at ambient temperature. Na(OAc)3BH (0.300 g, 1.42 mmol) was added and the solution stirred an additional 2 h. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil and then further purified by HPLC(CH3CN/H2O) to yield the title compound as a white powder (0.041 g, 17%).
Reaction SMILES: FC(F)(F)S(O)(=O)=[O:4].N[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:14][CH:15]=1.ClCCl.N([O:27][C:28]([CH3:31])(C)C)=O>COCCOC.CCCCC>[C:28]([O:27][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:14][CH:15]=1)(=[O:4])[CH3:31]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)COc1ccc(N)cn1
Solvent: COCCOC
Solvent: CCCCC
Solvent: ClCCl
Product: COC(=O)COc1ccc(OC(C)=O)cn1
Reaction time: 0.17 h

Procedure:
1.46 ml of trifluoromethanesulfonic acid was added to a mixture of 3.0 g of 5-amino-2-(methoxycarbonyl)methoxypyridine, 9 ml of 1,2-dimethoxyethane and 3 ml of dichloromethane dropwise at −10° C. The mixture was stirred for 10 minutes at the same temperature, then, to the reaction solution was added a solution of 2.35 ml of t-butyl nitrite in 1 ml of 1,2-dimethoxyethane dropwise at −10° C. or lower. 1,2-dimethoxyethane was added to the mixture, and it was stirred for 20 minutes at the same temperature, then, into the mixture was poured n-pentane. The precipitated solid was washed with n-pentane, then it was dissolved in 18 ml of acetic anhydride, and the mixture was stirred for 2 hour at 80° C. The mixture was poured into ice-water, and extracted with t-butyl methyl ether. The organic layer was concentrated, then diluted with t-butyl methyl ether. The dilute was washed with saturated aqueous sodium bicarbonate solution, then saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 1.4 g of 5-acetoxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:13]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[F:18])=[O:11])=[N:31][CH:30]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 441 [M+1]+.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH2:20][N:21]3[C:26]4([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:25][CH2:24][CH2:23][C:22]3=[O:32])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[C:40]1[O:41][C:42]2[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=2[N:44]=1>CN(C=O)C>[O:41]1[C:42]2[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=2[N:44]=[C:40]1[N:29]1[CH2:30][CH2:31][C:26]2([N:21]([CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH:13]=[CH:12][N:11]4[S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[C:22](=[O:32])[CH2:23][CH2:24][CH2:25]2)[CH2:27][CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCNCC5)cccc32)cc1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(c4nc6ccccc6o4)CC5)cccc32)cc1
Temperature: 80 °C
Yield: 79.9 %

Procedure:
To the stirred solution of 1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undecan-2-one (TFA salt) (300 mg, 0.55 mmol) in DMF (6 mL) were added K2CO3 (380 mg, 2.75 mmol) and 2-chloro benzoxazole (101 mg, 0.66 mmol). The mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude mixture water was added and extracted with ethyl acetate. The organic layer was dried over anhydride sodium sulfate, filtered and concentrated to obtain a solid which was purified by flash column chromatography (eluent: 3% methanol in chloroform) to yield the title compound (250 mg, 80%). [LCMS RtE=1.75 min, [M+H]+=569.1].
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH3:18])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[O:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[N+:15]([C:14]1[C:9]([O:8][CH3:7])=[C:10]([C:29]2[O:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=2)[CH:11]=[C:12]([CH3:18])[CH:13]=1)([O-:17])=[O:16]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cc(C)cc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Br)o1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccc(C(=O)O)o2)cc(C)cc1[N+](=O)[O-]
Yield: 27.7 %

Procedure:
To a solution of the solvent mixture of 30 mL of 1,4-dioxane and 15 mL of water was added 2-(2-methoxy-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 24a (3.1 g, 7.5 mmol) followed by 5-bromofuran-2-carboxylic acid (1.3 g, 6.8 mmol), tetrakis(triphenylphosphine)palladium (0.43 g, 0.4 mmol) and sodium carbonate (1.6 g, 15.1 mmol). The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled and filtered. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The resulting residue was diluted with 50 mL of water and adjusted to pH 3 with concentrated hydrochloric acid and filtered. The filter cake was washed with ethyl acetate and dried to obtain the title compound 5-(3-nitro-2-methoxy-5-methyl-phenyl)-furan-2-carboxylic acid 46a (522 mg, 29%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]3[C:18]([C:19]=2I)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:28].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]3[C:18]([C:19]=2[C:32]#[C:31][CH2:30][CH2:29][OH:33])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:28]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)c(I)c2ccccc21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)c(C#CCCO)c2ccccc21
Yield: 86.9 %

Procedure:
In a similar manner to Step 2 of Example 161, 4-chloro-7-[1-(tert-butoxycarbonyl)-3-iodoindol-2-yl]isoindolinone (148 mg, 0.291 mmol) was dissolved in diethylamine (7.4 mL), and the Solution was treated with bis(triphenylphosphine)dichloropalladium (16.3 mg, 0.0233 mmol), copper iodide (11.1 mg, 0.0582 mmol) and 3-butyn-1-ol (0.220 mL, 2.91 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-3-(4-hydroxy-1-butynyl)indol-2-yl]isoindolinone (114 mg, yield 87%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:37]N)=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([N:37]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1
Reactant: NNc1ccnc2cc(Cl)ccc12
Reactant: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4cc(Cl)ccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-31) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=499.1 (M+H)+