Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][OH:17])[C:9]=2[F:18])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH3:29][O:28][C:26](=[O:27])[O:17][CH2:16][C:10]1[C:9]([F:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(CO)c(F)c1-c1cccc(Cl)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)OCc1ccc(OC)c(-c2cccc(Cl)c2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32, 3.00 g, 11.3 mmol) in pyridine (2.31 g, 29.3 mmol) and tetrahydrofuran (40 mL) was cooled to 0° C. in an ice water bath. The reaction vessel was purged with nitrogen and methyl chloroformate (2.34 g, 24.8 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature overnight. The white suspension was adjusted to pH 2 by addition of 1 N aqueous hydrochloric acid (˜25 mL) and the yellow biphasic solution was diluted with dichloromethane (200 mL) and water (150 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The dichloromethane extracts were combined, washed with water (2×200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and the solvent removed under vacuum to give I-145 (3.84 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.Br[CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:10][C:11]([C:15]#[N:16])=[C:12]([O:14][CH2:25][CH2:26][N:27]2[C:28](=[O:37])[C:29]3[C:30](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:32])[N:13]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCCN1C(=O)c2ccccc2C1=O

Procedure:
Using the procedure described in Example 25, 6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile from Step C of Example 129 was reacted with N-(2-bromoethyl)phthalimide to afford the title compound. MS (electrospray) m/e 513.9 MH+ (Rt=4.2 min LC/MS).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH2:45][CH3:46])[C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH2:45][CH3:46])[C:35]([NH:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(CCC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner in Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-n-propylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH2:7]Br)[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH2:7][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)/C=C/CBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)/C=C/CN1CCCCC1
Yield: 79.6 %

Procedure:
A mixture of ethyl-4-bromocrotonate (193 mg), piperidine (94 mg) and potassium carbonate (276 mg) in acetonitrile (10 ml) was stirred and heated at reflux for 3 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was partitioned between water (2×15 ml) and ethyl acetate (20 ml). The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange oil (157 mg).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1>CCO.C(O)(=O)C>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([N:12]=[C:4]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:1][C:2]3=[O:3])[CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Nc1ccc2cn[nH]c2c1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a mixture of isatin (147 mg, 1 mmol) and 6-aminoindazole (133 mg, 1 mmol) in EtOH (5 mL) was added 2 drops of acetic acid. The resulting mixture was capped and microwaved 60 min at 120° C. After cooling to rt, the precipitate was collected by suction filtration to give 135 mg (48%) of title compound as yellow solid. 1H NMR indicated a 85:15 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H, NH), 11.00 (s, 1H, NH), 8.09 (s, 1H), 8.36 (d, J=8.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.89 (t, J=8.0 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 6.66 (t, J=7.6 Hz, 1H), 6.32 (d, J=7.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.1.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ncccn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ncccn4)c23)C1
Temperature: 160 °C
Reaction time: 48 h
Yield: 39.9 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2-carboxamide (110 mg, 0.328 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (197 mg, 0.982 mmol) and stirred at 160° C. for 48 hours in a sealed tube. The mixture was concentrated in vacuo, and the residue was diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-85% CH3CN/water gradient; 25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(pyrimidine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (67.6 mg, 40% yield) as a solid. LCMS (APCI+) m/z 416, 418 (M+H)+, Retention time=3.40 minutes (Method 2).
Reaction SMILES: [OH:1][C:2]1[C:3](=O)[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[Na+].Cl.[CH3:17][O:18][NH2:19]>C(O)C>[CH3:17][O:18][N:19]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:12])[CH:11]=[C:2]1[OH:1]
Reactant: CON
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C1C(O)=CC(=O)c2ccccc21
Yield: 94.4 %

Procedure:
2-Hydroxy-1,4-naphthoquinone (3 g, 17 mmol) was dissolved in ethanol (30 mL) and aqueous sodium hydroxide (1N, 51 mL, 51 mmol) and treated with methoxyamine hydrochloride (2.86 g, 34 mmol) at 80° C. for 5 h. The mixture was cooled, the solvents were evaporated, and the crude mixture was acidified using 10% HCl (20 mL). The solids were filtered, rinsed with water, and dried in the vacuum to give the title compound (3.26 g, 93%).
Reaction SMILES: [CH:1]1([Si:6](OC)([O:9][CH3:10])[O:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14].CC(C)([O-])C.[K+].[Cl-].[NH4+]>>[C:13]([O:17][Si:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O:9][CH3:10])[O:7][CH3:8])([CH3:16])([CH3:15])[CH3:14]
Reactant: CO[Si](OC)(OC)C1CCCC1
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CO[Si](OC)(OC(C)(C)C)C1CCCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 21 %

Procedure:
In a 100 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 25.0 g (0.131 mole) of cyclopentyl trimethoxysilane, 9.74 g (0.131 mole) of tert.-butyl alcohol and 20 mg (0.18 m mole) of potassium tert.-butoxide, which were then reacted with each other by heating under stirring in an oil both of 80° C. for 10 hours. After cooled, ammonium chloride was added to neutralize the alkali. Then, tert.-butoxy cyclopentyl dimethoxysilane of 6.25 g (0.0269 mole) was obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 21%.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])[CH:20]=[C:19]([C:29]([O:31][CH3:32])=[O:30])[CH:18]=[CH:17]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:1]1[C:5]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])[CH:20]=[C:19]([C:29]([O:31][CH3:32])=[O:30])[CH:18]=[CH:17]3)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)c1ccc2cc(Cl)c(N(C)C(C)C)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2cc(-c3cc4ccccc4s3)c(N(C)C(C)C)cc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a solution of benzo[b]thiophen-2-ylboronic acid (180 mg, 1.01 mmol) in dioxane (6 mL) was added methyl 6-chloro-7-(isopropyl(methyl)amino)-2-naphthoate (120 mg, 0.41 mmol), K3PO4 (259 mg, 1.23 mmol), Pd(PPh3)4 (24.0 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 1% to 4% ethyl acetate in petroleum ether to afford methyl 6-(benzo[b]thiophen-2-yl)-7-(isopropyl(methyl)amino)-2-naphthoate as a light yellow solid (140 mg, 87.5%).
Reaction SMILES: [F:1][C@:2]1([CH3:17])[C@H:6]([OH:7])[C:5](=[CH2:8])[O:4][C@H:3]1[N:9]1[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]1=[O:16].[C:18](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C1COCC1>[O:16]=[C:10]1[NH:11][C:12](=[O:15])[CH:13]=[CH:14][N:9]1[C@@H:3]1[O:4][C:5](=[CH2:8])[C@@H:6]([O:7][C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@:2]1([F:1])[CH3:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a mixture of chiral 1-((2R,3R,4R)-3-fluoro-4-hydroxy-3-methyl-5-methylene-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (18.3 g, 75.6 mmol) and DMAP (27.7 g, 227 mmol) in anhydrous THF (900 mL) at 0° C. was added BzCl (15.9 g, 113.4 mmol) dropwise. The reaction mixture was stirred at 0° C. for 0.5 h, then sat. NaHCO3 was added to quench the reaction. The mixture was extracted with EA (300 mL×3). The combined organic extract was washed with H2O, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography column (DCM:MeOH=160:1 to 120:1) to give the title compound as a white solid (17 g, 65%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C@:15]3([CH3:20])[C:17]([CH3:19])([CH3:18])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:10](=[O:21])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C@:15]3([CH3:20])[C:17]([CH3:18])([CH3:19])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:10](=[O:21])[N:9]1[CH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)[nH]n1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c(=O)c3c(n2Cc2ccccc2)[C@@]2(C)CC[C@@H]3C2(C)C)cs1
Temperature: 110 °C
Yield: 61.5 %

Procedure:
A solution of (4R,7S)-1-benzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 49; 109 mg, 0.38 mmol), tetrabutylammonium iodide (147 mg, 0.39 mmol) and 4-(chloromethyl)-2-methylthiazole (Maybridge plc, Tintagel, Cornwall, UK; 60 mg, 0.40 mmol) in dimethylformamide (3.9 mL) was heated at 100° C. for 24 h. A second portion of 4-(chloromethyl)-2-methylthiazole (120 mg, 0.81 mmol) was added and the mixture was heated at 110° C. overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with saturated aqueous sodium thiosulfate (150 mL), saturated aqueous sodium hydrogen carbonate (150 mL) and brine (150 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage 40S system, eluting with 2% methanol/dichloromethane, to give (4R,7S)-1-benzyl-7,8,8-trimethyl-2-(2-methyl-thiazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (92 mg, 61%) as a reddish-brown semi-solid. APCI(+)-MS (M+H) 394.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][CH:18]1[C:49](=[O:50])[NH:48][CH:47]([CH:51]([OH:53])[CH3:52])[C:45](=[O:46])[N:44]2[CH:40]([CH2:41][CH:42]([OH:54])[CH2:43]2)[C:38](=[O:39])[NH:37][CH:36]([CH:55]([OH:65])[CH:56](O)[C:57]2[CH:62]=[CH:61][C:60]([OH:63])=[CH:59][CH:58]=2)[C:34](=[O:35])[NH:33][CH:32]([CH2:66][OH:67])[C:30](=[O:31])[N:29]2[CH:25]([CH:26]([OH:69])[CH:27]([CH3:68])[CH2:28]2)[C:23](=[O:24])[NH:22][CH:21]([OH:70])[CH:20]([OH:71])[CH2:19]1)=[O:16])[CH3:4]>C(O)C.[Ni]>[CH3:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][CH:18]1[C:49](=[O:50])[NH:48][CH:47]([CH:51]([OH:53])[CH3:52])[C:45](=[O:46])[N:44]2[CH:40]([CH2:41][CH:42]([OH:54])[CH2:43]2)[C:38](=[O:39])[NH:37][CH:36]([CH:55]([OH:65])[CH2:56][C:57]2[CH:62]=[CH:61][C:60]([OH:63])=[CH:59][CH:58]=2)[C:34](=[O:35])[NH:33][CH:32]([CH2:66][OH:67])[C:30](=[O:31])[N:29]2[CH:25]([CH:26]([OH:69])[CH:27]([CH3:68])[CH2:28]2)[C:23](=[O:24])[NH:22][CH:21]([OH:70])[CH:20]([OH:71])[CH2:19]1)=[O:16])[CH3:4]
Reactant: CCC(C)CCCCCCCCCCC(=O)NC1CC(O)C(O)NC(=O)C2C(O)C(C)CN2C(=O)C(CO)NC(=O)C(C(O)C(O)c2ccc(O)cc2)NC(=O)C2CC(O)CN2C(=O)C(C(C)O)NC1=O
Agent: [Ni]
Solvent: CCO
Product: CCC(C)CCCCCCCCCCC(=O)NC1CC(O)C(O)NC(=O)C2C(O)C(C)CN2C(=O)C(CO)NC(=O)C(C(O)Cc2ccc(O)cc2)NC(=O)C2CC(O)CN2C(=O)C(C(C)O)NC1=O
Reaction time: 0.25 h
Yield: 73.9 %

Procedure:
Mulundocandin (220 mg, 2.2 mM) in ethanol (8 ml)) was stirred with 15 ml of W-2 Raney nickel (pH 7) in ethanol (30 ml) for 3 hours at room temperature. After standing for 15 minutes the supernatent solution was decanted and Raney nickel washed with 3×30 ml. ethanol with stirring and filtered. Combined ethanolic solutions were concentrated by distillation under a reduced pressure of 60-70 mm/Hg at 35° C. to obtain 160 mg (75%) of crude deoxymulundocandin as a slightly green solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
4-Hydroxybenzoic acid (1.1 g, 7.96 mmoL) and aniline (742 mg, 7.23 mmol) were dissolved in 20 mL of dry DMF. To the above solution EDCI (1.53 g, 7.23 mmol) was added in one portion and the resulting mixture was stirred at rt overnight under nitrogen. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated, washed consecutively with 1 N HCl, water, saturated sodium bicarbonate solution, water, and brine, and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography using 10% EtOAc in hexane to give 450 mg (29% yield) of 4-Hydroxy-N-phenyl-benzamide. MS (ES) m/z: 214.08 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[N:49]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:36]>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH2:55][N:49]([C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:50][CH2:51]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)([OH:3])=[O:2].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>O1CCCC1.O>[CH2:16]([O:15][C:13]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[C:1]([OH:3])=[O:2])=[O:14])[CH:17]=[CH2:18]
Reactant: O=C(O)C1CCCCN1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCCCC1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-carboxypiperidine (50 g) in tetrahydrofuran (200 ml) and water (200 ml) was adjusted to around pH 9.5 with 20% aqueous sodium hydroxide. To the solution was added dropwise allyl chloroformate (45 ml) at 5° C., while adjusting pH to around 9.5 with 20% aqueous sodium hydroxide. After stirring for 30 minutes at 0° C., the mixture was washed with ethyl acetate. After addition of ethyl acetate (200 ml), the mixture was adjusted to around pH 2.0 with concentrated hydrochloric acid (30 ml) and 1N hydrochloric acid. The mixture was extracted with ethyl acetate (200 ml), washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil of 1-allyloxycarbonyl-2-carboxypiperidine (88.7 g), which was dissolved in methanol (440 ml). To this solution was added dropwise, sulfuric acid (6.9 ml) and the mixture was refluxed for 2 hours. To the mixture was added dropwise triethylamine (29.5 ml) at 20° C. Evaporation of the solvent gave a residue which was taken up into a mixture of ethyl acetate (400 ml) and water (100 ml). The organic layer was separated, washed with water, 1N aqueous hydrochloric acid, brine, 5% aqueous sodium hydrogen carbonate and brine successively, and dried over magnesium sulfate. Evaporation of the solvent gave 1-allyloxycarbonyl-2-methoxycarbonylpiperidine (92.5 g).
Reaction SMILES: [Br-].C[N+:3]1[CH:4]=[CH:5][N:6]2[C:11]3[CH2:12][C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[NH:9][C:8](=[O:20])[C:7]=12.C>N1C=CN=C1.CN(C)C=O.O>[CH3:19][C:16]1[CH:15]=[CH:14][C:13]2[CH2:12][C:11]3[N:6]4[CH:5]=[CH:4][N:3]=[C:7]4[C:8](=[O:20])[NH:9][C:10]=3[C:18]=2[CH:17]=1
Reactant: Cc1ccc2c(c1)-c1[nH]c(=O)c3n(cc[n+]3C)c1C2
Agent: [Br-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)-c1[nH]c(=O)c3nccn3c1C2
Temperature: 100 °C
Reaction time: 16 h
Yield: 18.3 %

Procedure:
A solution of 2.3 g of 3,7-dimethyl-4-oxo-5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazinium bromide in 15 g of imidazole is stirred under a nitrogen atmosphere for 20 hours at 160° C., cooled to 100° C. and then poured over 60 g of a mixture of distilled water and ice. The insoluble matter is separated by filtration, washed twice with a total of 10 ml of distilled water and with 5 ml of ethyl ether and then air dried. The product (1.7 g) is chromatographed on 100 g of neutral silica gel (0.020-0.045 mm) contained in a column 3.2 cm in diameter, eluting under pressure with a dichloromethane-methanol mixture (97-7 by volume) and collecting 10-ml fractions. The fractions 35 to 182 are pooled and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 40° C. The product obtained (0.6 g) is dissolved in a boiling mixture of 64 ml of dimethylformamide and 16 ml of distilled water and the solution, supplemented with decolorizing charcoal, is filtered hot, cooled and kept for 16 hours at 5° C. The crystals are separated by filtration, washed with 3 ml of distilled water and with 3 ml of ethanol and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 60° C. 0.3 g of 7-methyl-5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained which decomposes without melting above 300° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): 2.40 (s, 3H: Ar--CH3); 3.98 (s, 2H: --CH2-- in position 10); 7.15 (broad d, J=8 Hz 1H: --H8); 7.49 (d, J=8 Hz, 1H: --H9); 7.60 and 7.99 (2s broad, 1H each: --H of imidazole); 7.72 (broad s, 1H: --H6); 12.35 (unresolved complex, 1H: --CONH--)].
Reaction SMILES: CON(C)[C:4]([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27]>C1COCC1>[C:11]1([C:8]2[O:7][C:6]([C:4]([C:22]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=3)=[O:5])=[CH:10][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)o1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccc(-c3ccccc3)o2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of 38d (0.231 g, 1 mmol.) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 4.0 mL, 2 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with water, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1d as white crystals (35.5%). 1H NMR (CDCl3) δ 7.85-7.82 (m, 1H), 7.48-7.36 (m, 4H), 7.35 (s, 2H), 7.25 (d, 1H, J=4.0 Hz), 6.86 (d, 1H, J=4.2 Hz), 3.96 (s, 3H), 3.95 (s; 6H); MS (ESI) m/z 339.1 (M+H)+.