Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12]C)=[O:11])=[C:2]1[C:14]([O:16]C)=[O:15].[H-].[Na+].[CH3:20]I.[OH-].[K+]>CN(C)C=O.CCO.CCOC(C)=O>[CH3:20][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[C:2]1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Reactant: CI
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1c(C(=O)O)c(C(=O)O)c2ccccc21
Temperature: 75 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
An ice cold solution of dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol) in N,N-dimethylformamide (DMF) (31.5 ml) was treated with NaH (0.617 g, 15.44 mmol) and methyl iodide (0.881 ml, 14.15 mmol) and warmed to 75° C. After 8 h, the reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl. The combined organics were washed with water (3×), brine, dried (MgSO4), filtered and concentrated. The residue was treated with a solution of KOH (8.66 g, 154 mmol) in EtOH (200 mL) and heated to reflux (95° C. bath temp). After 8 h, the reaction mixture was cooled to ambient temperature, diluted with EtOAc and the layers partitioned. The aqueous layer was extracted with EtOAc (2×) and acidified with 1 M HCl to pH 3. The aqueous layer was then extracted with EtOAc and the organics were washed with brine, dried (MgSO4), filtered and concentrated to afford 1-methyl-1H-indole-2,3-dicarboxylic acid (2.82 g, 12.87 mmol, 100% yield) as a white solid. The acid was suspended in DCM (30 mL) and treated dropwise with TFAA (4.39 ml, 32.2 mmol). After 2 h, the reaction mixture was concentrated in vacuo to afford 4-methyl-1H-furo[3,4-b]indole-1,3(4H)-dione as a purple solid. The anhydride was suspended in MeOH (100 mL) and stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo to afford 3-(methoxycarbonyl)-1-methyl-1H-indole-2-carboxylic acid (2.95 g, 12.65 mmol, 98% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ=8.00 (s, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 7.40-7.33 (m, 1 H), 7.28 (s, 1 H), 3.82 (d, J=5.7 Hz, 6 H); LCMS (m/z) ES+=234 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:39][NH:40][S:41]([CH3:44])(=[O:43])=[O:42]>CC(C)=O.O.C(OCCCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:40]([CH3:39])[S:41]([CH3:44])(=[O:43])=[O:42])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 60 °C
Yield: 82.5 %

Procedure:
In a 200 L-volume glass-lined reaction vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 17.9 kg (62.0 mol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine prepared as above, 107.7 kg of butyl acetate, 11.1 kg (80.3 mol.) of potassium carbonate (available from Asahi Glass Works, Co., Ltd., Lot No. 1111632, particle size distribution: 75-250 μm: 14%, 75 μm pass: 86%), and 12.9 kg (67.7 mol.) of p-toluenesulfonyl chloride. The mixture was heated at 60° C. for 2 hours, to carry out reaction. Subsequently, the reaction mixture was cooled to room temperature. To the cooled mixture were added 8.8 kg (80.6 mol.) of N-methylmethanesulfonamide and 12.9 kg (93.3 mol.) of potassium carbonate, and the resulting mixture was heated at 122-125° C. for 3 hours, for carrying reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture were added acetone and water, and the organic liquid portion was separated. The organic liquid portion was then washed successively with aqueous sodium hydroxide solution (3 wt. %) and a saturated aqueous sodium chloride solution. The washed organic liquid portion was concentrated under reduced pressure. Isopropyl alcohol and water were added to the residue, resulting in precipitation of a crystalline product. The crystalline product was filtered on a filter paper and washed with isopropyl alcohol. The washed crystalline product and 85.7 kg of acetone were placed in a 200 L-volume glass lined reaction vessel equipped with a stirrer, a thermometer and a reflux condenser. The mixture was stirred at 50-55° C., to dissolve the crystalline product in acetone. The insoluble was removed with a line filter. Subsequently, 58.3 kg of water was added to the solution, to precipitate a crystalline product. The crystalline product was collected on a filter paper and washed with an acetone/water mixture, to give 19.5 kg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine.
Reaction SMILES: O([C@:9]([C@@H:21]([CH:23]([O:25][Si](C(C)(C)C)(C)C)O)[OH:22])([OH:20])[C:10]([F:19])([F:18])[C:11]([O:13]S(C)(=O)=O)=O)[Si](C(C)(C)C)(C)C.[CH3:33][C:34]1[C:35]([O:45][Si](C)(C)C)=[N:36][C:37]([O:40][Si](C)(C)C)=[N:38][CH:39]=1.ClCCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CO>[CH3:33][C:34]1[C:35](=[O:45])[NH:36][C:37](=[O:40])[N:38]([C:11]([C:10]([F:18])([F:19])[C@@H:9]([C@@H:21]([CH2:23][OH:25])[OH:22])[OH:20])=[O:13])[CH:39]=1
Reactant: Cc1cnc(O[Si](C)(C)C)nc1O[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)OS(C)(=O)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CO
Solvent: ClCCCl
Product: Cc1cn(C(=O)C(F)(F)[C@H](O)[C@H](O)CO)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.59 g. of 3,5-bis(t-butyldimethylsiloxy)-1-methanesulfonyloxy-2-desoxy-2,2-difluororibose was added 1.60 g. of 5-methyl-2,4-bis(trimethylsilyloxy)pyrimidine and 45 ml. of dry 1,2-dichloroethane. To this mixture was added 1.45 g. of trifluoromethanesulfonyloxytrimethylsilane, and the clear solution was stirred under nitrogen at reflux for about 2-3 hours. The reaction was then cooled to ambient temperature and 1.35 ml. of methanol were added and the suspension was stirred for 30 minutes. The precipitate was filtered and the filtrate was reduced to one-half its volume under vacuum and then diluted with an equal volume of dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solution was filtered and the filtrate was saturated with anhydrous hydrogen bromide. The reaction mixture was stirred for 30 minutes and was then concentrated under vacuum. The residue was dissolved in methanol and the solution was evaporated to dryness under vacuum. The residue was dissolved in water and the solution was extracted twice with diethyl ether. The water layer was then evaporated to dryness. The residue was taken up in ethanol and evaporated repeatedly to azeotrope off all water. One g. of crude product was obtained, and was chromatographed on 30 g. of Woelm silica gel (70-150 mesh), eluting with ethyl acetate to yield 0.76 g. of desired product. It was further purified by recrystallization from ethyl acetate to obtain 0.37 g. of white crystalline product. nmr (CD3OD, 90 MHz) δ1.93 (s, 3H); 3.5-4.67 (series of m, 4H); 4.83 (bs, 3H); 6.3 (t, J=9Hz, 1H); 7.47 (m, 1H); mass spec. m/e=278=Parent.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O.[N+]([O-])(O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: Clc1ccn(-c2cccnc2)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a 100 mL, round bottom flask was charged 3-(3-chloro-1H-pyrazol-1-yl)pyridine (2.00 g, 11.1 mmol) and concentrated sulfuric acid (4 mL). This suspension was cooled to 5° C. and 2:1 concentrated nitric acid/sulfuric acid (3 mL, prepared by adding the concentrated sulfuric acid to a stifling and cooling solution of the nitric acid) was added dropwise at a rate such that the internal temperature was maintained <15° C. The reaction was allowed to warm to 20° C. and stirred for 18 hours. A sample of the reaction mixture was carefully diluted into water, basified with sodium hydroxide (50 wt % in water) and extracted with ethyl acetate. Analysis of the organic layer indicated that the reaction was essentially complete. The reaction mixture was carefully added to ice cold water (100 mL) at <20° C. It was basified with sodium hydroxide (50 wt % in water) at <20° C. The resulting light yellow suspension was stirred for 2 hours and filtered. The filter cake was rinsed with water (3×20 mL) and dried to afford an off-white solid (2.5 g, quantitative): mp 141-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.23-9.06 (m, 1H), 8.75-8.60 (m, 1H), 8.33 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.64 (ddd, J=8.5, 4.7, 0.7 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 149.49, 140.75, 136.02, 134.43, 132.14, 131.76, 127.22, 124.31; EIMS m/z 224 ([M]+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH:10]=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][C:15]([CH3:17])=[O:16]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][CH:10]([OH:11])[CH2:14][C:15](=[O:16])[CH3:17])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(=O)CC(O)C=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 168 h
Yield: 67 %

Procedure:
To a solution of 4-nitrocinnamaldehyde 8 (110 mg, 0.61 mmol; alternatively other aldehyde acceptors are shown in the Figures and can be obtained commercially or as described herein) in 15 mL of DMF and 31 mL of acetone (alternatively other ketone donors are shown in the Figures and can be obtained commercially or as described herein), PBS buffer (571 mL, degassed and kept under argon) was added slowly to avoid precipitation. Antibody 38C2 (8.0 mL of a 120 mM solution) was added. The final concentrations of 4-nitrocinnamaldehyde and Ab38C2 were 1.0 mM and 1.9 mM, respectively in a total volume of 625 mL containing 5% (v/v) of acetone. The reaction mixture was kept in a dark place at room temperature for seven days under Argon. The reaction mixture was saturated with sodium chloride and extracted with 3×150 mL of ethyl acetate. The extracts were dried over MgSO4 and evaporated to yield 140 mg of crude product. Purification by FC (1:2, ethyl acetate/hexane) gave 96 mg (67%) of pure aldol product (30) with an ee of 91%.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[CH3:12])C.[OH:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22]CC(N(OC)C)=O)[CH2:18]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH:12]=[C:14]([CH2:15][CH2:22][N:19]1[CH2:20][CH2:21][C@@H:17]([OH:16])[CH2:18]1)[NH:3][C:4]2=[O:13]
Reactant: CON(C)C(=O)CCN1CC[C@@H](O)C1
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1C
Product: O=c1[nH]c(CCN2CC[C@@H](O)C2)cc2c(Cl)cccc12
Yield: 2.3 %

Procedure:
In the same manner as in Example 16b and using N,N-diethyl-3-chloro-2-methylbenzamide (3.43 g) and (R)-3-(3-hydroxypyrrolidin-1-yl)-N-methoxy-N-methylpropanamide (3.08 g), (R)-5-chloro-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one (102 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]([NH:23][CH:24]([C:30](=O)[CH3:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:22])[NH:13]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.O1CCOCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:30]([CH3:31])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][C:21]=1[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)[C@H](CCCOCc1ccccc1)NC(=O)OC(C)(C)C)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(O)c(CCCOCc2ccccc2)nc1C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-{[5-(benzyloxy)-N-(tert-butoxycarbonyl)-L-norvalyl]amino}-3-oxobutanoate (5.31 g, 11.8 mmol) in ethanol (20 mL) was added 4N hydrochloric acid in 1,4-dioxane (20 mL) at room temperature. After being stirred for 16 h at same temperature, the reaction mixture was concentrated in vacuo. A solution of the residue in pyridine (40 mL) was heated at 60° C. for 23 h. After being cooled to ambient temperature, the mixture was concentrated in vacuo. The residue was poured into water, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. To a solution of the residue in dichloromethane (20 mL) was added manganes dioxide (1.03 g) at room temperature. After being stirred for 1.5 h at same temperature, the reaction mixture was filtrated through celite with chloroform. The filtrate was combined and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:methanol=19:1) to give ethyl 5-[3-(benzyloxy)propyl]-6-hydroxy-3-methylpyrazine-2-carboxylate. MS (APCI): m/z 331 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C:3]([O:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=[O:4].C(Cl)Cl.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>CN(C1C=CN=CC=1)C.O>[CH3:17][C:2]([CH3:1])([C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])[C:3]([O:5][CH2:6][C:7]([CH3:10])([CH3:11])[CH2:8][O:9][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])=[O:4]
Reactant: CC(C)C(=O)C(C)(C)C(=O)OCC(C)(C)CO
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(C)(C)COC(=O)C(C)(C)C(=O)C(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a 1-L flask was charged 2,2,4,4-tetramethyl-1,3-cyclobutanedione (140.2 g, 1.0 moles), neopentyl glycol (208.3 g, 2 moles), potassium carbonate (138 g, 1.0 moles) and methylene chloride (500 g). The batch was refluxed for three hours then clarified to remove salts. The methylene chloride was removed with a rotary evaporator. Toluene (250 g) was added to the residue and the organic layer washed six times with 150 mL demineralized water. The organic layer was dried with sodium sulfate and the solvent removed with a rotary evaporator at 75° C./3 mmHg to provide 3-hydroxy-2,2-dimethylpropyl 2,2,4-trimethyl-3-oxopentanoate (244 g, 96.3% GC assay). To a 2-L flask was charged 3-hydroxy-2,2-dimethylpropyl 2,2,4-trimethyl-3-oxopentanoate (97.6 g, 0.4 moles), methylene chloride (600 g), DMAP (0.04 g) and triethylamine (50.4 g, 0.504 moles) and the resulting mixture cooled to 0-5° C. Added dropwise over an hour was methacryloyl chloride (50 g, 0.48 moles). After the addition was complete, the reaction was held at <10° C. for 30 minutes then heated to reflux and held for six hours. GC analysis indicated starting material remained so additional methacryloyl chloride (6 g) and triethylamine (6 g) were added. After one hour at reflux, the reaction was cooled and 600 mL demineralized water added. Lower product layer decanted and upper water layer discarded. Water wash was repeated four times. Organic layer dried with sodium sulfate and then removed with a rotary evaporator to provide 123 g crude product (93.7% GC assay). Material distilled in a Kugelrohr apparatus to provide the desired product in 96% GC assay and 94.9% NMR assay.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]([NH:9][C:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:21][CH2:22][S:23]([CH3:25])=[O:24])[C:13]1=[O:26])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].ClC1C=CC=C(C(OO)=[O:35])C=1.C([O-])(O)=O.[Na+]>ClCCl>[NH2:1][C:2]([C@@H:4]([NH:9][C:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:21][CH2:22][S:23]([CH3:25])(=[O:35])=[O:24])[C:13]1=[O:26])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)CCn1c(=O)n(C(=O)N[C@H](C(N)=O)C(C)(C)C)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)n1c(=O)n(CCS(C)(=O)=O)c2ccccc21)C(N)=O
Reaction time: 8 h

Procedure:
A mixture of N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(methylsulfinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (Example 33, 150 mg), m-chloroperbenzoic acid (70%, 170 mg) and NaHCO3 (150 mg) in dichloromethane (5 mL) was stirred overnight and quenched with sat. Na2S2O3 aq. (25 mL) The whole was extracted with ethyl acetate (25 mL×2). The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated in vacuo. The residue was purified by preparative TLC to yield the titled compound. (100 mg)
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[C:13]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([NH:22][CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:36])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCCCc1ccccc1)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 72 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 3-phenylpropan-1-amine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-(3-phenylpropyl)-isonicotinamide was obtained as a colorless solid in 72% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.82-8.78 (m, 1H), 8.56-8.50 (m, 2H), 8.05-8.03 (m, 2H), 7.64-7.50 (m, 4H), 7.32-7.16 (m, 5H), 3.31-3.27 (m, 2H), 2.67-2.62 (m, 2H), 1.90-1.80 (m, 2H); MS (ES+) m/z 360.5 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1.I[CH3:12]>CN(C=O)C>[Br:3][C:4]1[N:9]=[C:8]([NH:10][CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
NaH (150 mg, 3.80 mmol, 60%) was added to a solution of 6-bromo-pyridin-2-ylamine (300 mg, 1.73 mmol) in DMF at 0° C. followed by iodomethane (3.47 mL, 6.94 mmol). The reaction mixture was stirred for 1 hour at room temperature and was quenched with water. The aqueous phase was extracted with Et2O. The organic phase was washed with water, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 90 mg (0.48 mmol, 28%) of (6-bromo-pyridin-2-yl)-methyl-amine.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C:3]1=[O:10].[BH4-].[Na+]>CO>[Cl:1][C:2]1([Cl:11])[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C@H:3]1[OH:10]
Reactant: O=C1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.0 g of (1S,6R)-8,8-dichlorobicyclo [4.2.0]oct-2-en-7-one, the compound of formula (4), is dissolved in 120 ml of methanol and treated at 0° C. with 1.2 g of sodium borohydride, and the mixture is stirred at 25° C. for 1 hour. The solvent is removed under reduced pressure and the residue partitioned between methylene chloride and water. The extract is dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue is recrystallized from hexane to give (1S,6R,7R)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-ol, [α]D =+214.4° (CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1n[nH]c2cc(Cl)c(C#Cc3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1n[nH]c2cc(Cl)c(C#Cc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
A solution of methyl 6-chloro-5-(phenylethynyl)-1H-indazole-3-carboxylate (20 mg, 0.064 mmol) in methanol (1 mL) was treated with 10 N aqueous sodium hydroxide (2 drops) and stirred at room temperature for 16 hours. The reaction mixture was then treated with additional 10 N aqueous sodium hydroxide (2 drops) and heated to 70° C. for two hours. The cooled reaction mixture was evaporated in vacuo, and treated with 1 N citric acid. The resulting solids were collected by filtration, dried and purified using prep-HPLC to afford the title compound (1 mg). MS (ES+) 374.9 (M+DMSO)+. Retention time: 1.8 min; Xbridge C18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow: 2.0 mL/min.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:35]=[CH:34][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>ClCCCl>[C:14]([C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
98 mg (0.55 mol) of 6-fluoro-1H-indol-7-carboxylic acid, 168 mg (0.50 mmol) of (4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine and 105 mg (0.55 mmol) of EDC.HCl were dissolved in 5 ml 1,2-dichloro-ethane. The reaction mixture was stirred at rt over night and heated to 80° C. for 3 h. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 108 mg (43%) product as a colorless viscous oil. MS (ISP) 497.2 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH:8]([CH2:12][N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])[CH2:7]2)[O:5][CH2:4][CH2:3]1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:28]([O:27][C:25]([N:9]1[CH2:10][CH2:11][C:6]2([O:5][CH2:4][CH2:3][O:2]2)[CH2:7][CH:8]1[CH2:12][N:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]1=[O:22])=[O:26])[CH3:29]
Reactant: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a suspension of the above 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.1 mmol) and ethyl chloroformate (0.24 ml, 2.5 mmol) in dry tetrahydrofuran (14 ml) cooled in an ice bath under nitrogen was added diisopropylethylamine (0.95 ml, 5.4 mmol) and the reaction mixture was stirred at ambient temperature for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between dichloromethane (25 ml) and 1N hydrochloric acid (25 ml). The layers were separated, and the aqueous layer extracted with dichloromethane (20 ml). The combined organic extracts were washed with a saturated sodium bicarbonate solution (50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was triturated with n-butylchloride, filtered and dried with nitrogen which afforded 0.47 g (61%) of 7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid ethyl ester.