Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[C:17](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][CH:20]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5].C(OCC)(=O)C>[Pd].C(O)C>[CH3:32][C:2]([CH3:1])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][CH:20]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5]
Reactant: CCOC(=O)/C=C/c1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Yield: 81.1 %

Procedure:
A mixed solution of ethyl(2E)-3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate (400 mg, 0.89 mmol) obtained in Example 177 and 10% palladium on carbon (water content: 50%, 40 mg) in ethanol (3 mL)-ethyl acetate (5 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 326 mg (yield: 81%) of the title compound. Melting point: 136-138° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].N1C=CC=CC=1.[S:13](Cl)([CH3:16])(=[O:15])=[O:14]>O1CCCC1>[CH3:16][S:13]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:15])=[O:14]
Reactant: CCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOCCOS(C)(=O)=O

Procedure:
To 30g of 2-ethoxyethanol in 300ml of tetrahydrofuran 27.4ml of pyridine were added and 26.4ml of mesyl chloride added dropwise at room temperature over 15 minutes. The mixture was refluxed overnight, the solid that formed filtered off and the solvent evaporated off from the residue. The residue was distilled under 20m Hg to give 2-ethoxyethyl methanesulphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)[S:5][CH:6]=1.[Br:14]Br>C(Cl)Cl>[Br:14][C:6]1[S:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1cccc(-c2cc(Cl)cs2)n1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cccc(-c2cc(Cl)c(Br)s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 141 %

Procedure:
To a 0° C. solution of 2-(4-chloro-thiophen-2-yl)-6-methyl-pyridine (example Rupp-96) (0.45 g, 1.45 mmol) and CH2Cl2 (10 mL) is added Br2 (0.15 mL, 2.91 mmol). The solution is warmed to ambient temperature and stirred for 1 hour. The solution is washed with sat. NaHCO3 (10 mL), sat. Na2S2O3 (10 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.59 g, 2.04, 95%). 1H NMR (CDCl3), δ 2.55 (s, 3H), 7.05 (d, 7.9 Hz, 1H), 7.29 (s, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.58 (dd, J=7.9, 7.9, 1H). LC/MS (m/z): calcd. for C10H7BrClNS (M+H)+: 288.0; found: 287.9.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10]CC2C=CC=CC=2)=[C:3]1[CH2:18][O:19][CH2:20][CH3:21].[ClH:22].[CH2:23](O)C>[Pd]>[ClH:22].[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([OH:10])=[C:3]1[CH:18]([O:19][CH2:20][CH3:21])[CH3:23]
Reactant: CCO
Reactant: CCOCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd]
Agent: Cl
Product: CCOC(C)c1c(O)c(=O)cc(C)n1C
Yield: 83.3 %

Procedure:
1,6-Dimethyl-2-(1-ethoxymethyl)-3-benzyloxy-pyridin-4(1H)-one (3.65 g, 12 mmol) was dissolved in 40 ml of ethanol and adjusted to pH 1 with concentrated hydrochloric acid prior to hydrogenolysis for 4 hours in the presence of 5% Pd/C catalyst (0.8 g). Filtration followed by rotary evaporation gave the crude product as a white solid. Recrystallization from ethanol/diethyl ether gave the pure title compound (2.48 g, 83.3%) as a white crystalline solid. m.p. 195-199° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C1COCC1>[C:40]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:18](=[O:19])[N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:22][CH2:23]1)(=[O:42])[CH3:41]
Reactant: O=C(NC1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 1 h
Yield: 69 %

Procedure:
The compound obtained in Example 13 (435 mg, 1.00 mmol), triethylamine (0.335 ml) were dissolved in THF (10 ml), and under ice cooling, to the solution was added acetyl chloride (0.142 ml). The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and resulting precipitates were collected by filtration. The filtrate was concentrated under reduced pressure. To the concentrate was added diethyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (331 mg, 0.69 mmol, Yield 69%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]Cl.C(NC1C(Cl)=CC(C(=O)CCCCCl)=C(O)C=1)(=O)C.[C:32]([NH:35][C:36]1[C:41]([Br:42])=[CH:40][C:39]([C:43](=[O:49])[CH2:44][CH2:45][CH2:46][CH2:47][Br:48])=[C:38]([OH:50])[CH:37]=1)(=[O:34])[CH3:33]>>[C:32]([NH:35][C:36]1[C:41]([Br:42])=[CH:40][C:39]([C:43](=[O:49])[CH2:44][CH2:45][CH2:46][CH2:47][Br:48])=[C:38]([O:50][CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=2)[CH:37]=1)(=[O:34])[CH3:33]
Reactant: COc1cc(CCl)cc(OC)c1
Reactant: CC(=O)Nc1cc(O)c(C(=O)CCCCBr)cc1Br
Agent: CC(=O)Nc1cc(O)c(C(=O)CCCCCl)cc1Cl
Product: COc1cc(COc2cc(NC(C)=O)c(Br)cc2C(=O)CCCCBr)cc(OC)c1

Procedure:
Proceeding as in Example 4, Step (b), but replacing iodomethane with 3,5-dimethoxybenzylchloride and 1-(4-acetylamino-5-chloro-2-hydroxyphenyl)-5-chloropentan-1-one with 1-(4-acetylamino-5-bromo-2-hydroxyphenyl)-5-bromo-pentan-1-one, gave 1-[4-acetylamino-5-bromo-2-(3,5-dimethoxybenzyloxy)phenyl]-5-bromopentan-1-one.
Reaction SMILES: O=[C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[N:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=[N+:15]=[N-:16].[O-]CC.[Na+].O>C(O)C>[CH2:24]([NH:23][C:21]([C:20]1[CH:26]=[CH:27][C:17]([N:14]2[C:2]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[C:3]([C:4]([OH:6])=[O:5])[N:16]=[N:15]2)=[CH:18][CH:19]=1)=[O:22])[CH3:25]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)c1cccs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2cccs2)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 89.3 %

Procedure:
Ethyl 3-oxo-3-(2-thienyl)propanoate (500 mg, 2.50 mmol) and 4-azido-N-ethylbenzamide (500 mg, 2.50 mmol, 1.0 eq.) obtained in Example 43a) were dissolved in ethanol (20 ml), a solution of sodium ethoxide in ethanol (20%, 1.3 g, 3.82 mmol, 1.5 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 7 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1). The organic layer was extracted with 2% aqueous sodium carbonate solution. The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (764 mg, 89%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:14][C:15]([OH:17])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:18]C(N)=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[C:9](=[O:10])[NH:18][C:15](=[O:17])[CH2:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)O)c(CC(=O)O)c1
Reactant: NC(N)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc2c(c1)CC(=O)NC2=O
Temperature: 25 °C
Yield: 42 %

Procedure:
An amount of 1.5 g (6.35 mmol) of 4-tert-butyl-2-(carboxymethyl)benzoic acid and urea (763 mg, 12.7 mmol) were heated neat at 145-148° C. for 1.5 hours. The mixture is cooled to room temperature and 200 mL of chloroform is added and washed 3× with water, dried over sodium sulfate and evaporated. The crude product is purified by column chromatography 4% methanol methylene chloride to give 580 mg (41% yield) of the product as a brown solid. MS (ESI) m/z 218.2 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:1][C@H:2]2[CH2:3][CH2:4][C@@H:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of trans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (359 mg, 1.46 mmol) in tetrahydrofuran (15 ml) were added p-nitrobenzoic acid (245 mg, 1.46 mmol), triphenylphosphine (422 mg, 1.61 mmol) and a 40%-diethyl azodicarboxylate/toluene solution (0.73 ml, 1.61 mmol) at 0° C., and stirred at 0° C. for 30 minutes and then at room temperature for 3 hours. The reaction solution was concentrated and the resulting residue was dissolve in a mixed solution of ethanol (10 ml) and diisopropyl ether (10 ml) at 60° C. Then, the resulting solution was allowed to cool and the crystals formed were filtered under reduced pressure to obtain cis-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl 4-nitrobenzoate (427 mg, 74%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[CH2:18]([O:20][C:21](=[O:50])[C@@H:22]([NH:26][C:27](=[O:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]1)[CH:23]([CH3:25])[CH3:24])[CH3:19]>>[CH3:25][CH:23]([CH3:24])[C@H:22]([NH:26][C:27](=[O:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:37][CH2:38][N:39]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:40][CH2:41]1)[C:21]([O:20][CH2:18][CH3:19])=[O:50]
Reactant: CCOC(=O)[C@@H](NC(=O)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)C(C)C
Reactant: O=C1CCc2ccc(OCCCCBr)cc2N1
Product: CCOC(=O)[C@@H](NC(=O)COc1ccccc1N1CCN(CCCCOc2ccc3c(c2)NC(=O)CC3)CC1)C(C)C

Procedure:
(S)-Ethyl 3-methyl-2-(2-(2-(4-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl)piperazin-1-yl)phenoxy)acetamido)butanoate (14b) (Scheme 2) was synthesized from the compounds 3 and 13b by following the protocol described for the compound 14a (Example 15). Colorless oil, 0.27 g (58%). 1H NMR (400 MHz, CDCl3): δ 0.83 (d, J=7.0 Hz, 3H); 0.90 (d, J=7.0 Hz, 3H); 1.24 (t, J=7.2 Hz, 3H); 1.60-1.69 (m, 2H); 1.74-1.79 (m, 2H); 2.13 (quintet, J=6.4 Hz, 1H); 2.43 (t, J=7.2 Hz, 2H); 2.55 (t, J=7.2 Hz, 2H); 2.65 (broad s, 4H); 2.82 (t, J=7.2 Hz, 2H); 3.01-3.13 (m, 4H); 3.90 (t, J=6.0 Hz, 2H); 4.05 (q, J=7.2 Hz, 2H); 4.53-4.56 (m, 1H); 4.60 (two s, 2H); 6.39 (d, J=2.4 Hz, 1H); 6.45-6.47 (m, 1H); 6.84-6.87 (m, 1H); 6.92-6.95 (m, 3H); 7.56 (d, J=9.2 Hz, 1H); 9.46 (broad s, 2H). MS (ESI): m/z=581.30 (M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]1([CH2:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>O.ClCCl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([NH:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To solution of 8.5 parts of intermediate 18, namely 5-benzoyl-2-nitrobenzoic acid, in 66.5 parts of dichloromethane were added 5.3 parts of 1,1'-carbonylbis[1H-imidazole]. After stirring for 1 hour at room temperature, there were added 9.8 parts of benzenemethanamine. Stirring at room temperature was continued for 8 hours. The reaction mixture was diluted with 100 parts of water and acidified with HCl. The organic layer was separated, dried, filtered and evaporated. The residue was purified twice by column chromatography (silica gel; CHCl3 /CH3OH 98:2; CH3COOC2H5 /C6H5CH3 10:90). The eluent of the desired fractions was evaporated and the residue was crystallized from methylbenzene, yielding 8.1 parts (72.5%) of 5-benzoyl-2-nitro-N-(phenylmethyl)benzamide; mp. 167.4° C. (interm. 19).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=O)=O.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)C.N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][C:12]1[C:7]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(Oc1ncccc1Cc1cccs1)C(F)(F)F
Reactant: C#CC1(O)CN2CCC1CC2
Agent: [Pd]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2ncccc2Cc2cccs2)CN2CCC1CC2
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
A mixture of 89 mg of 3-(2-thienylmethyl)-2-pyridyl trifluoromethanesulfonate, 50 mg of 3-ethynyl-3-quinuclidinol, 64 mg of tetrakis (triphenylphosphine) palladium(0), 11 mg of cuprous iodide, 105 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring at 70° C. for 1.5 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, followed by extracting with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed, and the residue was subjected to NH-silica gel (Fuji silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 88 mg of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C:8](O)=[O:9])[CH3:3].C1C=CC2N(O)N=[N:29][C:27]=2C=1.C(N(CC)CC)C.CN>C(Cl)Cl>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C:8]([NH:29][CH3:27])=[O:9])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CSc1ccc(Oc2ccc(C(=O)O)cc2CN(C)C)cc1
Agent: CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(Oc2ccc(SC)cc2)c(CN(C)C)c1
Reaction time: 0.5 h

Procedure:
The product from example 158 (480 mg, 1.51 mmol) WSCDI (377 mg, 2 mmol), HOBt.H2) (255 mg, 1.66 mmol) and triethylamine (0.53 mL, 3.78 mmol) were dissolved in DCM (0.03 M). After stirring for 30 min, MeNH2 (condensed, 2 mL) was added and the mixture stirred for a further 12 h. The mixture was then evaporated and the residue partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (3 times). The combined organic layers were dried (MgSO4) and evaporated to a yellow oil, which was purified by flash chromatography [SiO2; DCM/ MeOH/ 880 NH3 (93:7:1)]. The desired title amide was isolated as its hydrochloride salt (285 mg, 63%); Free base: δH(CDCI3, 400 MHz) 2.12 (6 H, s), 2.41 (3 H, s), 2.92 (3 H, d), 3.46 (3 H, s), 6.78 (1 H, brd), 6.84 (2 H, d), 7.20 (2 H, d), 7.63 (1 H, dd), 7.82 (1 H, d); MS m/z (ES+) 331 (MH+)
Reaction SMILES: [NH3:1].Cl[C:3]([CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]>C(Cl)Cl>[NH2:1][C:3]([CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: N
Reactant: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A saturated solution of gaseous ammonia in 25 ml of methylene chloride is added drop by drop at -10° C. to a solution of 5.6 (17 mmol) of ethyl 2-(chlorocarbonyl)-7-(4-chlorophenyl)heptanoate in 50 ml of methylene chloride. The mixture is stirred for 30 minutes at room temperature, suction filtered from the ammonium chloride, the filtrate is washed with water, and dried and concentrated. The concentrate is chromatographed on silica gel with a mixture of toluene and dioxane (5:1). 3.6 g (68% of theory) is obtained of ethyl 2-(aminocarbonyl)-7-(4-chlorophenyl)heptanoate, M.P. 110°-111° C.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[H-].[Na+].[CH2:10]([O:17][C:18](=[O:21])[CH2:19]Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18](=[O:21])[CH2:19][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Product: CC(=O)C(CC(=O)OCc1ccccc1)C(C)=O
Yield: 51 %

Procedure:
10 grams acetylacetone were reacted with 5 grams of a 50% suspension of sodium hydride in paraffin oil and with 25 grams bromoacetic acid-benzylester in accordance with a procedure analogous to that set out in Example (2b). 3,3-diacetyl-propionic acid-benzylester having a Kp0.005 of 126°-128° C. was obtained. This substance was further reacted with phenylhydrazine by a procedure analogous to that set out in Example (2c). 3,5-dimethyl-1-phenyl-pyrazol-4-acetic acid-benzylester, having a Kp0.001 of 205°-209° C., was obtained in a yield of 51%.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[N:27]([CH2:38][C:39]#[CH:40])[C:26]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.CCOC(C)=O>[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[N:27]([CH2:38][C:39]#[CH:40])[C:26]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH2:47][OH:48])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C#CCn1c(-c2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Tetrabutylammonium fluoride (1.3 eq., 1M solution in THF) was added dropwise to an ice cooled solution of methyl 3-cyclohexyl-1-prop-2-yn-1-yl-2-(2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate in THF (0.036M). The mixture was stirred at 0° C. for 1 h then diluted with EtOAc, washed with saturated aq. NH4Cl, water and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 3:1). After evaporation of the solvents the product was obtained as white solid (63%). MS (ES+): 402.6 (M+H+).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:17](Cl)[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C.C1(C)C=CC=CC=1>[CH2:17]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCCCC1
Reactant: ClCOCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: -78 °C

Procedure:
The carboxylic esters (621A; 3.75 g) were dissolved in anhydrous diethyl ether (50 ml) and cooled to −78° C., under an atmosphere of nitrogen. KHMDS (69 ml of a 0.5M solution in toluene) was added dropwise and the resulting mixture was stirred for a further 15 min., before the addition of BOMCl (1.7 eq.) and the reaction flask was removed from the cooling vessel and allowed to warm slowly to room temperature. Water (approx. 10 ml) was added and the mixture was partitioned between EtOAc and 10% aq. HCl. The organic phase was separated, washed with sat. aq. sodium bicarbonate, water, dried (MgSO4), and the volatiles removed under reduced pressure. The residue was purified by silica gel column chromatography using EtOAc:Hexanes (1:20) as eluent, providing the intermediate benzyl ether (3.01 g), a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][C:12](=[N:14][OH:15])[NH2:13].C(NC(C)C)(C)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][C:12](=[N:14][O:15][C:38]([CH:35]1[CH2:37][CH2:36]1)=[O:39])[NH2:13]
Reactant: O=C(Cl)C1CC1
Reactant: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)cccc21)=NO
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)cccc21)=NOC(=O)C1CC1
Yield: 54.8 %

Procedure:
A stirred solution of 2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-hydroxyacetimidamide (0.40 g, 1.0 mmol), diisopropylamine (0.16 g, 1.6 mmol) and cyclopropane carbonyl chloride (0.16 g, 1.6 mmol) in dichloromethane (20 mL) was stirred for 16 h at ambient temperature. The colorless solid that precipitated from the solution was filtered, washed with water (5 mL) and diethyl ether (5 mL) to afford 2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-[(cyclopropylcarbonyl)oxy]ethanimidamide as a colorless solid (0.25 g, 53%): 1H NMR (300 MHz, DMSO-d6) δ7.31 (dd, J=8.0, 8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.64 (br s, 2H), 6.54 (s, 1H), 6.47 (s, 1H), 5.88 (s, 2H), 4.77 (ABq, 2H), 4.43 (ABq, 2H), 1.75-1.67 (m, 1H), 0.86-0.73 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.9, 171.9, 156.5, 153.6, 148.9, 144.8, 141.9, 130.8, 130.0, 128.6, 117.4, 108.8, 104.4, 101.8, 104.5, 101.8, 104.4, 101.8, 93.0, 77.5, 58.4, 11.7, 8.45, 8.42; MS (ES+) m/z 456.1 (M+1), 478.1 (M+23).