Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:29][O:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])[C:8]([NH:10][CH:11]2[CH2:14][N:13]([C:15]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][N:23]([NH2:26])[C:22]3=[O:27])(=[O:20])=[O:19])=[O:16])[C:12]2=[O:28])=[O:9])[N:6]=1.C[O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49]C)[N:45]=[C:44]1[C:51]([O:53][C:54](=[O:55])[C:43]1=[CH:42]2)=[O:52]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:29][O:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])[C:8]([NH:10][CH:11]2[CH2:14][N:13]([C:15]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][N:23]([NH:26][C:51]([C:44]4[C:43]([C:54]([OH:55])=[O:53])=[CH:42][C:41]5[C:46](=[CH:47][C:48]([OH:49])=[C:39]([OH:38])[CH:40]=5)[N:45]=4)=[O:52])[C:22]3=[O:27])(=[O:19])=[O:20])=[O:16])[C:12]2=[O:28])=[O:9])[N:6]=1
Reactant: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2CCN(N)C2=O)C1=O)c1csc(N)n1)C(=O)O
Reactant: COc1cc2cc3c(nc2cc1OC)C(=O)OC3=O
Solvent: CN(C)C=O
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3nc4cc(O)c(O)cc4cc3C(=O)O)C2=O)C1=O)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a solution of 0.47 g (0.75 mmol) of 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-amino-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt in 10 ml of dimethylformamide was added 0.26 g (0.86 mmol) of 6,7-dimethoxy-2,3-quinoline-dicarboxylic anhydride, and the mixture was stirred overnight at room temperature. After the dimethylformamide was distilled off in vacuo, the residue was dissolved in water and the pH adjusted to 6.5 with 1N potassium hydroxide. Freeze drying yielded 0.76 g of crude product which was purified by column chromatography on XAD resin under mplc conditions with water as eluent to give 0.12 g of 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(3-carboxy-6,7-dihydroxy-2-quinolinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, tripotassium salt, melting point 240°-280° C., dec., and 0.21 g of a mixture of 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[ (3-carboxy-6,7-dihydroxy-2-quinolinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, tripotassium salt and 2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(2-carboxy-6,7-dihydroxy-3-quinolinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, tripotassium salt in a ratio of ca. 2:1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[S:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=N[OH:30])C.[Cl-].[Cl-].[Cl-].[In+3].[OH-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:17])[F:16])[S:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:30]
Reactant: CC=NO
Reactant: N#Cc1ccc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: [Cl-]
Agent: [In+3]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]benzonitrile (50 mg) in toluene (1 mL) were added acetaldehyde oxime (3 eq.) then indium trichloride (0.05 eq.). The mixture was stirred at 120° C. for 2 hours then it was allowed to cool to room temperature. The solution was diluted with ethyl acetate, then treated with ammonium hydroxide (2N). The mixture was washed two times with brine then the organic phase were collected and they were dried over magnesium sulfate, filtered and evaporated under vacuo to give 2-chloro-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]benzamide (50 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1>C(O)=O>[CH:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:37][CH:38]=1)=[O:3]
Reactant: NCCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 0 °C

Procedure:
A mixture of formic acid (0.19 ml) and acetic anhydride (0.4 ml) is stirred with heating at 50°-60° C. for 1.5 hour. Thereto is added 1-{1-[4-(4-aminobutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.6 g) at room temperature and the mixture is stirred at room temperature for 13 hours. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate, water and saline solution and dried with sodium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol=50:1→25:1) to give 1-{1-[4-(4-formylaminobutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.49 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:21]([OH:29])=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=3)=[C:14]([F:30])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31](OCC)(=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:21]4[O:29][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][C:26](=[O:28])[C:22]=4[CH:23]=[CH:24][CH:25]=3)=[C:14]([F:30])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccccc3)cc2F)c1O
Product: CCOC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3F)c2o1

Procedure:
Following the process described in example 1 (point A), starting from 3'-[(E)-2-[4-(4-phenylbutoxy)-2-fluorophenyl]ethen-1-yl]-2'-hydroxy-acetophenone and diethyl oxalate, the title compound was prepared (quantitative yield).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](OCC)=[O:17])=[CH:10][CH:9]=1)=O)C.C(=O)=O.CC(C)=O.[H-].C([NH2+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.C(O)C.O>[CH:16]([CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][CH:4]=[O:3])=[CH:13][CH:12]=1)=[O:17]
Reactant: CCOC(=O)CCc1ccc(CCC(=O)OCC)cc1
Agent: CC(C)C[NH2+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=CCCc1ccc(CCC=O)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 52 %

Procedure:
First, 2.78 g of 1,4-bis(2-ethoxycarbonylethyl)benzene was dissolved in 40 ml of absolute toluene, the solution was cooled to -65° C. with dry ice/acetone, and a solution of 1M diisobutylammonium hydride in 24 ml of toluene was added dropwise with stirring over 25 minutes, and the mixture was further stirred at -70° C. for 2 hours. Next, 2.5 ml of ethanol/2.5 ml of toluene, 3 ml of ethanol, and 2.75 ml of water/5.5 ml of ethanol were added dropwise in this order, and after removing cooling bath, the mixture was allowed to warm to a room temperature with stirring. After adding 10 ml of water, the mixture was adjusted to a pH value of not more than 3 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with hexane/ethyl acetate (6:1) to obtain 988 mg of 1,4-bis(2-formylethyl)benzene as a colorless crystal.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]3=[N:13][O:14][N:15]=[C:11]3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[C@@H:29]1[CH2:31][O:30]1>>[N:13]1[O:14][N:15]=[C:11]2[CH:10]=[C:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][N:4]([CH2:31][C@@H:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:24](=[O:28])[O:25][CH2:26][C:27]=5[C:19]=4[CH3:18])[OH:30])[CH2:3][CH2:2]3)[CH:17]=[CH:16][C:12]=12
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: c1cc2nonc2cc1CCN1CCNCC1
Product: Cc1c([C@@H](O)CN2CCN(CCc3ccc4nonc4c3)CC2)ccc2c1COC2=O

Procedure:
5-[(1R)-2-{4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion as to the synthesis described in EXAMPLE 12 starting from 5-[2-(piperazin-1-yl)ethyl]-2,1,3-benzoxadiazole and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one. LC/MS: [(M+1)]+=423.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[F:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][NH:22]2)=[CH:18][CH:17]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16]([F:15])[CH:24]=2)[CH2:20][CH2:21]1)=[O:14]
Reactant: Fc1ccc2c(c1)NCC2
Reactant: O=C(O)CSc1nc2ccccc2s1
Product: O=C(CSc1nc2ccccc2s1)N1CCc2ccc(F)cc21
Yield: 70 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 6-fluoroindoline to yield 43 as a white solid (70%): MS m/z: 345 (M+H)+. Anal. Calcd. For, C17H13N2FOS2: C, 59.28; H, 3.80; N, 8.13; S, 18.62; F, 5.52. Found: C, 59.51; H, 3.85; N, 8.13; S, 18.73; F, 5.37.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:38])[CH:6]([O:18][P:19]([CH:23]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH:24]([CH3:26])[CH3:25])([O:21]C)=[O:20])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(#N)C>[CH2:31]([O:30][C:28]([NH:27][CH:23]([P:19]([OH:21])([O:18][CH:6]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C:5]([OH:38])=[O:4])=[O:20])[CH:24]([CH3:25])[CH3:26])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)C(CCCNC(=O)OC(C)(C)C)OP(=O)(OC)C(NC(=O)OCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)C(NC(=O)OCc1ccccc1)P(=O)(O)OC(CCCNC(=O)OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 102.3 %

Procedure:
1 M LiOH (5 mL) was added to a solution of 2-[(1-benzyloxycarbonylamino-2-methylpropyl)-methoxy-phosphinoyloxy]-5-tert-butoxycarbonylamino-pentanoic acid methyl ester (187 mg, 0.35 mmol) in acetonitrile (5 mL). The mixture was stirred at 50° C. over night and concentrated under reduced pressure. The crude product was purified using chromathography (iPrOH/conc. aq. NH3/H2O, 4:2:1) to yield 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphinoyloxy]-5-tert-butoxycarbonylamino-pentanoic acid (180 mg, 100%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[S:22][C:21](C4CCN(C(OC(C)(C)C)=O)CC4=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C@H:11]([CH3:37])[CH2:10]2)=[C:5]([C:38]([F:41])([F:40])[F:39])[CH:4]=1.BrC1SC(S(N2CCN(C3C=CC(F)=CC=3C(F)(F)F)C[C@H]2C)(=O)=O)=CC=1.[O:69]=[C:70]1[NH:75][CH2:74][CH2:73][N:72](C(OC(C)(C)C)=O)[CH2:71]1>CCOC(C)=O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[S:22][C:21]([N:75]4[CH2:74][CH2:73][NH:72][CH2:71][C:70]4=[O:69])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[C@H:11]([CH3:37])[CH2:10]2)=[C:5]([C:38]([F:41])([F:40])[F:39])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2=O)s1
Agent: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(Br)s1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCNCC2=O)s1

Procedure:
Prepared by acid treatment (1N HCl in EtOAc) of tert-butyl 4-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)-3-oxopiperidine-1-carboxylate, as a white solid [tert-butyl 4-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)-3-oxopiperidine-1-carboxylate was prepared according to procedures similar to those described in Example 29FH from (R)-1-(5-bromothiophen-2-ylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazine (292 mg, 0.6 mmol), and tert-butyl 3-oxopiperazine-1-carboxylate (181 mg, 0.9 mmol) as a white solid (major product, 89.4 mg, 86%)]. HRMS: calcd for C20H22F4N4O3S2+H+, 507.11422. found (ESI-FTMS, [M+H]1+), 507.11461.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:34])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:68]([O:75][C:76]([N:78]1[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]1)=[O:77])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:68]([O:75][C:76]([N:78]1[CH2:83][CH2:82][N:81]([C:31](=[O:32])[CH2:30][NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:34])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:80][CH2:79]1)=[O:77])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)OCc2ccccc2)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
To a solution of 3.34 g ({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetic acid in 100 ml DMF were added 1.9 ml DIPEA, 2.7 g HATU and 1.4 ml 1-benzyloxycarbonylpiperazine. After stirring for 1 h it was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/methanol gradient.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.N12CCN(CC1)CC2.[NH2:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][C:17]=1I>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:27]([O:26][C:25]([NH:24][CH2:23][C:19]1[CH:18]=[C:17]2[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[NH:15][C:16]2=[N:21][C:20]=1[CH3:22])=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(=O)C(=O)O
Reactant: Cc1nc(N)c(I)cc1CNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1nc2[nH]c(C(=O)O)cc2cc1CNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 92158 %

Procedure:
Under argon, pyruvic acid (6.90 ml, 100.1 mmol) and 1,4-diazabicyclo[2.2.2]octane (843 g, 7.51 mmol) were added to a solution of tert-butyl [(6-amino-5-iodo-2-methylpyridin-3-yl)methyl]carbamate (840 mg, 2.31 mmol) in N,N-dimethylformamide (0.5 ml), and the flask was evacuated and flushed with argon. Then argon was passed through the solution for 5 min and then palladium(II) acetate (25.9 mg, 0.11 mmol) was added and the mixture was heated to 100° C. for 2 h. The cooled solution was filtered through Celite and the dimethylformamide was distilled off. The residue was then taken up in water and acidified with hydrochloric acid, giving a 5-{[(tert-butoxycarbonyl)amino]methyl}-6-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (650 g, 88% of theory). HPLC-MS: log P=0.58; mass (m/z): 306.1 (M+H)+; 1H-NMR (DMSO) 1.37 (s, 9H), 2.33 (s, 3H), 4.17 (d, 2H), 6.57 (s, 1H), 7.68 (s, 1H).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30](O)([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2c(Cl)cccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2c(Cl)cccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with ethyl [4-chloro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (75%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.33-7.27 (m, 2H), 7.12 (d, 1H), 6.71 (d, 1H), 6.50-6.48 (m, 1H), 5.10 (s, 1H), 4.54-4.42 (m, 4H), 4.19 (q, 2H), 3.11-2.90 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 388.8 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl.[CH2:12](O)[CH3:13]>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][CH3:13])=[O:7])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-iodobenzoic acid, 25 ml ethyl alcohol and 20 ml solution of dry HCl in ethyl alcohol was refluxed for 2 hours. The solid was dissolved after 1 hour of boiling. The reaction solution was cooled to room temperature and evaporated under vacuum to a volume of 10 ml. A lower organic layer formed with the chemical conversion of the acid to the ester. The resulting mixture was cooled in an ice bath. To this mixture 80 ml of diethyl ether, dry sodium hydrogen carbonate (1 gram) and 50 grams of ice were added. This solution was stirred, washed by dissolution of a saturated solution of sodium bicarbonate in 50 ml water and water, dried over sodium sulfate, and evaporated under vacuum, yielding ethyl 4-iodobenzoate as a liquid oil product (5.43 gram, 96.1% yield) [1H-NMR (CDCl3): d7.8 (s, 1H), d7.79 (s, 1H), 7.6 (s, 1H), d4.4 (d, 2H, J=7.1 Hz), d1.4 (s, 3H)].
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]Br>CN(C=O)C.C(OCC)C.O>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[N:9]1
Reactant: COC(CBr)OC
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(Cn1ncc2ccc([N+](=O)[O-])cc21)OC
Temperature: 25 °C

Procedure:
To a mixture of 6-nitroindazole (10.0 g, 61 mmol) and K2CO3 (9.31 g, 67.5 mmol) in DMF (60 mL) at room temperature was added 2-bromoacetaldehyde dimethylacetal (7.98 mL, 67.5 mmol), after which the mixture was heated to 50 C for 18 hours. The mixture was cooled to room temperature, diluted with diethyl ether (60 mL) and H2O (50 mL) and extracted with diethyl ether (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to an orange oil. The residue was purified by MPLC (SiO2, 9:1 Hexane:ethyl acetate to 4:1 Hexane:ethyl acetate) to provide 1-(2,2-dimethoxyethyl)-6-nitro-1H-indazole as an orange oil. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.27 (s, 6 H), 4.71 (d, J=4.75 Hz, 2 H), 4.79 (m, 1 H), 7.97 (m, 2 H), 8.34 (s, 1 H), and 8.76 (s, 1 H); MS (ESI) 252 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1cccc(F)c1
Product: N#Cc1cc(-c2cccc(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light grey solid (67 mg, 88%), MS (ISN) m/z=306.5 [(M+H)+], mp 248.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[CH:18][C:17]([CH:22]=O)=[CH:16]3.CC(O)=O.Cl.Cl.[NH2:31][CH2:32][CH:33]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:34][NH:35][C:36]1([C:41]([O:43][CH3:44])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[CH:18][C:17]([CH2:22][NH:31][CH2:32][CH:33]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:34][NH:35][C:36]1([C:41]([O:43][CH3:44])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1)=[CH:16]3
Reactant: O=Cc1cnc2cc3c(cc2c1)C[C@@]1(C3)C(=O)Nc2ncccc21
Reactant: COC(=O)C1(NCC(CN)c2ccccc2)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(NCC(CNCc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2′-oxo-1′,2′, 6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-3-carbaldehyde (80.0 mg, 0.254 mmol, Intermediate 1) and HOAc (31 μL, 0.533 mmol) in dry chloroform (3 mL) was added a solution of methyl 1-[(3-amino-2-phenylpropyl)amino]cyclopentanecarboxylate dihydrochloride from Step D (106 mg, 0.304 mmol) and Hunig's base (106 μL, 0.609 mmol) in dry chloroform (2 mL). After 15 minutes, sodium triacetoxyborohydride (108 mg, 0.507 mmol) was added. After 4 hours of stirring, the mixture was diluted with DCM and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted once with DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a residue. The residue was then was applied to a silica gel column for purification, eluting with a gradient of DCM:MeOH (with 10% NH4OH)—99:1 to 86:14 to give the title compound. MS: m/z=576 (M+1).
Reaction SMILES: O.NN.O[N:5]1C2C=CC=CC=2N=[N:6]1.Cl.C(N=C=NCCCN(C)C)C.[CH2:26]([O:33][C:34]([NH:36][C@H:37]1[CH2:45][O:44][C@H:40]([C:41](O)=[O:42])[CH2:39][CH2:38]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[NH:5]([C:41]([C@H:40]1[O:44][CH2:45][C@H:37]([NH:36][C:34](=[O:35])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:38][CH2:39]1)=[O:42])[NH2:6]
Reactant: On1nnc2ccccc21
Reactant: O=C(N[C@@H]1CC[C@@H](C(=O)O)OC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)[C@@H]1CC[C@@H](NC(=O)OCc2ccccc2)CO1
Reaction time: 18 h
Yield: 86.1 %

Procedure:
Hydrazine monohydrate (0.23 ml, 3.86 mmol), 1-hydroxybenzotriazole (434 mg, 3.21 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (740 mg, 3.86 mmol) were added to an N,N-dimethylformamide (16 ml) solution of the compound (898 mg, 3.21 mmol) obtained in Step 3 above at room temperature and the resulting mixture was stirred for 18 hours. The reaction mixture was subjected to extraction with chloroform:methanol [10:1 (v/v)] and the organic layer was washed with saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography [dichloromethane:methanol=49:1→13:1 (v/v)] to give 811 mg (86%) of the title compound as a colorless solid.