Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(OC(=O)C)(=O)C>[C:1]([NH:14][C@@H:15]1[C:21](=[O:22])[O:23][C:18](=[O:20])[CH2:17][CH2:16]1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCC(=O)N[C@H]1CCC(=O)OC1=O
Temperature: 25 °C
Yield: 76.6 %

Procedure:
100 g of Nα-lauroyl-L-glutamic acid was heated with stirring for 5 hours at 60° C. in 200 g of acetic anhydride, and then cooled to room temperature with stirring to allow a crystal to precipitate. This crystal was washed with 1000 mL of hexane and dried to obtain 72.4 g of Nα-lauroyl-L-glutamic anhydride.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>N1C=CC=CC=1>[C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=3)[C:8]2=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Solvent: c1ccncc1
Product: COc1cccc(C(=O)N2C(=O)CN(c3ccccc3)C2=O)c1
Yield: 8.8 %

Procedure:
In a similar manner to Example 8, 580 mg (3.30 mmol) of 1-phenyl-imidazolidin-2,4-dione were reacted with560 mg (3.29 mmol) of 3-methoxybenzoyl chloride. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The resultant residue was purified by column chromatography on silica gel (developing solvent: n-hexane/ethyl acetate) and subjected to crystallization from n-hexane/ethyl acetate to obtain 90 mg (yield: 10.2%) of the title compound.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][O:52]C(C)(OC)C)[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][OH:52])[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1

Procedure:
A solution of 0.812 g of the product of Step A, 4 ml of acetone and 1 ml of N hydrochloric acid was stirred at room temperature for 3 hours and 1 ml of an aqueous solution of 1M sodium bicarbonate, 10 ml of water and 5 ml of ethyl acetate were added thereto to obtain 0.551 g of the syn isomer of tert.-butyl 7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate melting at ≃200° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:33][C:34]2[S:38][C:37]([CH3:39])=[N:36][CH:35]=2)[N:3]=1>CCO.N.CO.C(Cl)Cl.[Pd]>[CH3:32][N:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][O:23][C:21]2[CH:20]=[CH:19][N:18]3[C:14]([C:12]([NH:11][C:9]4[CH:8]=[CH:7][CH:6]=[C:5]5[C:10]=4[CH:2]=[N:3][N:4]5[CH2:33][C:34]4[S:38][C:37]([CH3:39])=[N:36][CH:35]=4)=[O:13])=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH2:31][CH2:30]1
Reactant: Cc1ncc(Cn2nc(I)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: Cc1ncc(Cn2ncc3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Temperature: 25 °C
Reaction time: 7 h
Yield: 19.9 %

Procedure:
A solution of N-(3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (11.5 mg, 0.018 mmol) in absolute EtOH (1 mL) was treated with Pd/C (Degussa, wet, 10% wt, 2 mg), the reaction flask was flushed with hydrogen, and stirring at ambient temperature was continued for seven hours. The reaction was diluted with DCM, the catalyst was removed by filtration, and the filtrate concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with ammonia/MeOH/DCM as eluent to afford 1.9 mg of the desired product. MS (ES+APCI) m/z=531 (M+H) detected.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH2:45][C:46]([NH:48][C:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C:23]([N:25]([CH2:35][C:36]1[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[S:39][CH:40]=1)[C@@H:26]([CH3:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:24]>>[S:39]1[CH:40]=[C:36]([CH2:35][N:25]([C@@H:26]([CH3:34])[CH:27]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])[C:23](=[O:24])[C@@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:20])[CH2:45][C:46](=[O:47])[NH:48][C:49]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]1=2
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 63 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxy-propan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:22](=[O:30])(=[O:29])[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CC(C)=O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:22](=[O:30])(=[O:29])[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=1
Reactant: O=S1(=O)c2ccccc2N(c2ccc(OCc3ccccc3)cc2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=S1(=O)c2ccccc2N(c2ccc(O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.10 g (7.50 mmol) of 10-(4-benzyloxyphenyl)phenothiazine 5,5-dioxide, 2.30 g (35.7 mmol) of 98% ammonium formate and 7.5 g of 10% palladium on activated carbon were heated to boiling under reflux in 225 ml of acetone for 1 hour. After cooling to room temperature, the solution was filtered. The filtrate was concentrated and, after adding 10 ml of methanol, stirred overnight. The solid was filtered off with suction, washed with methanol and dried at 110° C. in a vacuum drying cabinet. 1.47 g (61% of theory) of analytically pure light gray microcrystals having an m.p. of 308-311° C. were obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Product: Fc1ccc(Oc2ccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(4-fluorophenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(4-fluorophenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=O)=O.[Br-:26].[Mg+2].[Br-]>CCOCC>[CH2:6]([Br:26])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCOS(C)(=O)=O
Reactant: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCBr
Reaction time: 48 h

Procedure:
A mixture of arachidonyl methane sulfonate (1.0 g, 2.7 mmol) and magnesium bromide (2.2 g, 12 mmol) in anhydrous ether (40 mL) was stirred under argon for two days. The resulting suspension was filtered and the solid washed with ether (2×10 mL). The filtrate and wash were combined and solvent evaporated. The resulting residual was treated with hexanes (50 mL). The solid was filtered and solvent evaporated resulting in an oily residual. The crude product was purified by column chromatography on silica gel (230-400 mesh, 30 mL) eluted with hexanes. This gave 1 g of arachidonyl bromide (II) as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:11]=1[NH2:12].C(N(CC)CC)C>CCO>[CH3:14][CH2:13][CH2:11][CH:10]([CH3:16])[CH3:9].[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCC(C)C
Product: Cc1ccc(C)c(Nc2ccnc(Cl)n2)c1

Procedure:
2,4-Dichloropyrimidine (500 mg, 3.36 mmol), 2,5-dimethylaniline (407 mg, 3.36 mmol) and triethylamine (0.51 ml, 3.69 mmol) were dissolved in EtOH (5 ml) with stirring. The reaction mixture was heated at reflux for 12 hours, cooled and evaporated onto silica (5 ml). The residue was purified by column chromatography and eluted with EtOAc (30%): isohexane to give the title product as a waxy solid on evaporation (514 mg, 66%). NMR (300 MHz): 2.1 (s, 3H), 2.27 (s, 3H), 6.42 (d. 1H), 6.99 (d, 1H), 7.08 (s, 1H). 7.18 (d, 1H), 8.03 (d, 1H), 9.45 (s, 1H); m/z: (ES+) 234.3 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[C:21]([O-])(O)=O.[Na+]>CO>[OH:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[C:3]([O:5][CH3:21])=[O:4]
Reactant: O=C(O)C(O)c1ccc2ccccc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 2-hydroxy-2-(naphthalen-2-yl)acetic acid (0.75 g, 1 eq) in dry MeOH was added sulfuric acid (0.1 mL) dropwise and heated to reflux. Stirring was then continued for 2 hours. The reaction mixture was then cooled and poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an oil (0.63 g, 78%) that was not further purified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C(Cl)Cl.[CH3:25][Si:26](OS(C(F)(F)F)(=O)=O)([CH3:28])[CH3:27]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12]([O:21][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(O[Si](C)(C)C)=CC[C@@H]12
Reaction time: 12 h

Procedure:
10 g of 3-methoxy-estra-1,3,5(10)-trien-17-one (35.2 mmol) is mixed with exclusion of moisture under inert gas with 30 ml of methylene chloride distilled on P2O5 and 10.5 g of trifluoromethanesulfonic acid trimethylsilyl ester (47.2 mmol, D=1.15). Then, about 7 ml of triethylamine (KOH dried, M=101.2; D=0.726) is added in portions with stirring and gentle cooling, and the solution reacts clearly in an alkaline way. Then, it is allowed to stand for 12 hours at room temperature, and after the reaction has been completed, the solvent is removed in a vacuum. The remaining viscous residue is extracted three times with about 20 ml of absolute ether under inert gas. The ether solution, in which the steroid is present, is used directly in the next step.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].ON1C2C=CC=CC=2N=N1.[C:44]([NH:51][CH2:52][CH2:53][C:54](O)=[O:55])([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].Cl.CN(C)CCCN=C=NCC>CC#N>[C:47]([O:46][C:44]([NH:51][CH2:52][CH2:53][C:54]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:55])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.62 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 1-hydroxybenzotriazole (0.3 g, 2.22 mmol), N-BOC-b-alanine (0.42 g, 2.22 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride 0.53 g, 2.78 mmol) were added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N citric acid (30 ml), H2O (2×30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 100:2) to give 3-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide (0.57 g, 67%) as a white solid: mp 96-98° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.50 (t, J=5.8 Hz, 1H), 7.82-7.67 (m, 3H), 6.81 (t, J=5.1 Hz, 1H), 5.19-5.11 (dd, J=5.4 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 3.21-3.13 (dd, J=6.8 and 13.1 Hz, 2H), 2.92-2.85 (m, 1H), 2.64-2.33 (m, 4H), 2.08-2.04 (m, 1H), 1.37 (s, 9H); 13C NMR (DMSO-d6) δ d 172.71, 170.87, 169.77, 167.46, 166.93, 155.45, 139.27, 134.67, 133.17, 131.47, 127.03, 121.80, 77.57, 48.84, 37.63, 36.69, 35.62, 30.91, 28.21, 21.96; Anal. Calcd. For C22H26N4O7+0.28H2O: C, 57.01; H, 5.78; N, 12.09. Found: C, 56.99; H, 5.89; N, 11.79.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6](/[CH:8]=[C:9](\[CH3:12])/[CH:10]=O)[CH:7]=1.CC1C=CC(S([NH:24][NH2:25])(=O)=O)=CC=1.[OH-].[Na+].[O:28]1[CH2:33][CH2:32][N:31]([S:34]([C:37]2[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=2)[C:40](Cl)=[O:41])(=[O:36])=[O:35])[CH2:30][CH2:29]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]([C:8]2[C:9]([CH3:12])=[CH:10][N:25]([C:40]([C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([S:34]([N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)(=[O:36])=[O:35])[CH:38]=3)=[O:41])[N:24]=2)[CH:7]=1
Reactant: C/C(C=O)=C\c1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)N2CCOCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cn(C(=O)c2cccc(S(=O)(=O)N3CCOCC3)c2)nc1-c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A mixture of (E)-3-(5-chloro-2-hydroxyphenyl)-2-methylacrylaldehyde (40 mg, 0.203 mmol) and 4-methylbenzenesulfonohydrazide (41.7 mg, 0.224 mmol) in Acetonitrile (3 mL) were stirred at room temperature for 3 h and then acetonitrile (2 mL), Sodiumhydroxide (8.95 mg, 0.224 mmol) were added and the mixture was heated at reflux for 16 h, then Sodiumhydroxide (12.21 mg, 0.305 mmol) and 3-(morpholinosulfonyl)benzoyl chloride (88 mg, 0.305 mmol) (made from 3-(morpholinosufonyl)benzoic acid) were subsequently added and the mixture was stirred at room temperature for 2 h. Reaction was monitored by TLC. After completion of the reaction, the product was extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and solvent was removed by vacuum. The resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the desired product (3-(5-chloro-2-hydroxyphenyl)-4-methyl-1H-pyrazol-1-yl)(3-(morpholinosulfonyl)phenyl)methanone (30 mg, 0.064 mmol, 31.3% yield) as a solid. 1HNMR (400 MHz, CDCl3): δ 8.28 (m, 2H), 8.20 (d, 1H, J=8.0 Hz), 7.95 (d, 1H, J=8.4 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.18 (dd, 1H, J=2.8 & 8.8 Hz), 6.87 (d, 1H, J=8.4 Hz), 3.68 (m, 4H), 3.02 (m, 4H), 2.40 (s, 3H). ESI-MS: 462.0 [M+H]+
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6]2[C:8]([CH3:22])=[C:9]([O:14]CC3C=CC=CC=3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)[CH3:2].[K+].[Br-]>>[CH2:1]([CH:3]1[CH2:7][C:6]2[C:8]([CH3:22])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)[CH3:2]
Reactant: CCC1Cc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: [Br-]
Agent: [K+]
Product: CCC1Cc2c(C)c(O)c(C)c(C)c2O1

Procedure:
The de-benzylization of the 2-(RS)-ethyl-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane is done by following the procedure given in example 15. A white solid is obtained. m.p. 73°-75° C.; IR (KBr): 3378 cm-1 (νOH); 1H-NMR (CDCl3): δ4.9-4.5 (1H,m), 4.2 (1H,s), 3.3-2.7 (2H,m), 2.1 (6H,s), 2.0 (3H,s), 1.8- 1.5 (2H,m), 1.1 (3H,t).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[N:5]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH2:16][OH:17]>O1CCOCC1>[CH3:14][O:13][C:6]1[N:5]=[C:4]([O:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)COc1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride is added to a mixture of 2-chloro-6-methoxy-3-nitropyridine, methyl glycolate and 1,4-dioxane at 10° C. The mixture is stirred at room temperature for 2 hours, then, poured into ice water, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 6-methoxy-2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[OH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>CC(C)=O>[OH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:2][CH2:3][CH3:4])[CH2:8][CH2:7]1
Reactant: OC1CCNCC1
Reactant: CCCI
Solvent: CC(C)=O
Product: CCCN1CCC(O)CC1

Procedure:
1-Iodopropane (22 ml) was added dropwise during 15 minutes to a stirred suspension of 4-hydroxypiperidine (20 g) in acetone (250 ml) and the resultant mixture was stirred at ambient temperature for 20 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and 2N aqueous sodium hydroxide solution. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to give 4-hydroxy-N-propylpiperidine as an oil (19.6 g); NMR Spectrum: (DMSOd6) 0.82 (t, 3H), 1.16 (m, 4H), 1.66 (m, 2H), 1.91 (m, 2H), 2.06 (t, 2H), 2.64 (m, 2H), 3.38 (m, 1H), 4.45 (d, 1H); Mass Spectrum: M+H+ 144.
Reaction SMILES: [NH2:1][C:2]12[CH2:8][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([N:24]1[CH2:28][C@@H:27]([F:29])[CH2:26][C@H:25]1[C:30]#[N:31])=[O:23]>CN(C)C=O>[CH2:12]([O:11][C:9]([C:5]12[CH2:8][C:2]([NH:1][CH2:21][C:22]([N:24]3[CH2:28][C@@H:27]([F:29])[CH2:26][C@H:25]3[C:30]#[N:31])=[O:23])([CH2:3][CH2:4]1)[CH2:7][CH2:6]2)=[O:10])[CH3:13]
Reactant: CCOC(=O)C12CCC(N)(CC1)C2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)C2
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ethyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate (50.0 mg) was dissolved in N,N-dimethylformamide (2 mL) and potassium-carbonate (40.0 mg) was added to the solution. (2S,4S)-1-(2-Bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (64.2 mg) in N,N-dimethylformamide (1 mL) was then added dropwise at room temperature and the mixture was stirred for 1 hour. The insoluble materials were filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (NH silica, eluant: ethyl acetate) to give (2S,4S)-1-[[N-(4-ethoxycarbonylbicyclo[2.2.1]hept-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (89.0 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:30][CH:29]([OH:31])[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[C:21]([O:39][CH3:40])=[CH:20][CH:19]=1>>[CH3:40][O:39][C:21]1[C:22]([N:24]2[CH2:30][CH:29]([OH:31])[CH2:28][NH:27][CH2:26][CH2:25]2)=[N:23][C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)=[CH:19][CH:20]=1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: COc1ccc(Br)nc1N1CCN(C(=O)OC(C)(C)C)CC(O)C1
Product: COc1ccc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCNCC(O)C1
Yield: 4.5 %

Procedure:
Following the procedures as described in EXAMPLE 86 and starting with 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine and tert-butyl 4-(6-bromo-3-methoxy-2-pyridyl)-6-hydroxy-1,4-diazepane-1-carboxylate, 207 was obtained as an off-white solid (4.4 mg, 4.5%) over 2 steps. MS (ESI) m/z: 433.1 [M+H]+