Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.P(=O)(O)(O)O.[H][H]>CC(O)C.[Pd]>[CH3:4][C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[OH:1]
Reactant: O=Cc1ccc(O)cc1O
Reactant: [H][H]
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CC(C)O
Product: Cc1ccc(O)cc1O
Yield: 98.1 %

Procedure:
2,4-Dihyroxybenzaldehyde (33.97 gm, 0.246 mol) (recrystallized from toluene) was dissolved in spectroscopic grade 2-propanol (3 L) in a round bottom flask fitted with a gas inlet and a bubbler outlet. 10% Palladium on carbon (1.35 gm) was added followed by phosphoric acid (3mL) and the mixture was sparaged with nitrogen. The nitrogen flow was switched to hydrogen and the mixture was rapidly stirred with ice cooling. After 3 hours hydrogen uptake was complete and the catalyst was removed by filtration. The filtrate was stripped down to 200 mL and 200 mL of ethyl acetate was added. The solution was washed with 4×200 mL of water and the combined water extracts back-extracted with ethyl acetate. These organic extracts were water washed and the combined organic layers dried over sodium sulfate and stripped down to afford the product as a colorless crystalline solid (29.95 gm, 98%). M.p.: 106° C. (Lit. 106°-107° C. [J. C. Bell, W. Bridge, and A. Robertson, J. Chem. Soc., 1542-45 (1937)]). NMR (DMSO-d6): δ 1.961 (s, Me), 6.076 (dd, H-6, J[5,6]=8 hz, J[2,6]=2 hz), 6.231 (d, H-2), 6.760 (d, H-5) 8.867 (s, OH), an 9.008 (s, OH).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][OH:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:53][C:54]1[C:59](O)=[CH:58][CH:57]=[CH:56][N:55]=1>C1COCC1>[N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][O:19][C:59]3[C:54]([CH3:53])=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ncccc1O
Reactant: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncccc1OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was synthesised in essentially the same way as compound 18s. Compound 51 (Example 10; 80 mg, 0.30 mmol) and PPh3 (120 mg, 0.46 mmol) were dissolved in dry THF (1.5 ml). Then DIAD (90 μl, 0.46 mmol) and 2-methyl-3-hydroxypyridine (50 mg, 0.46 mmol) were added. The reaction mixture was stirred at RT for 48 hrs. After this time, the solvent was removed and the crude mixture purified by flash column chromatography (silica, DCM/MeOH 1:0 to 94:6) to afford compound 26s (75 mg, 71%). Analyses were performed on the free base. The compound was converted to the HCl salt for testing.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Yield: 92.6 %

Procedure:
To a solution of tert-butyl (3R)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 12 (0.28 g, 0.59 mmol) in methanol (20 mL) was added 5% Pd/C (0.25 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl (3R)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 13 (0.21 g, 91%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH2:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH:11][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[NH:23][CH:24]=[N:25]4)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](N)c1nc2cc(F)ccc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2nc[nH]c12)c1nc2cc(F)ccc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
A mixture of (S)-1-(5-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 29 (379 mg, 1.4 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (340 mg, 1.4 mmol) and DIPEA (1.2 mL, 7.0 mmol) in n-butanol (7 mL) was stirred in a sealed vial for 18 h at 90° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 161 (65 mg, 12%). LCMS: RT 3.34 min [M+H]+ 374.1. 1H NMR (DMSO, 400 MHz): δ 8.19-8.00 (2H, m), 7.92 (1H, s), 7.67-7.41 (6H, m), 7.06 (2H, d, J=7.13 Hz), 5.47 (1H, s), 1.56 (3H, d, J=6.83 Hz)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)/[C:14](=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])/[CH2:13][CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]2
Reactant: CCOC(=O)/C=C1\CCc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To a solution of ethyl (2E)-[5-(benzyloxy)-2,3-dihydro-1H-inden-1-ylidene]acetate (2.10 g, 6.81 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% water wet, 0.5 g), and the mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 24 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-30% ethyl acetate/hexane) to give the title compound (1.45 g, yield 97%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I>CCCCCC.CN(C)C=O>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ccc(O)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To sodium hydride (50% oil dispersion, 43.2 g, 21.6 g of active NaH, 900 mmol), prewashed in dry hexane, in 800 ml of dimethylformamide (DMF) is added 5-hydroxy-2-methylpyridine (98.8 g, 906 mmol) in 700 ml of DMF at 15° and over 0.75 hour. The reaction is allowed to warm to RT and is stirred for 2 hours. It is then cooled to 10°, and methyliodide is added over 0.5 hour. The reaction is again allowed to warm to RT and is stirred overnight. It is then filtered through celite, and the solid is washed with chloroform, filtered and rotoevaporated. The resulting solid is washed with chloroform 3X, and is stirred with chloroform overnight. It is filtered and rotoevaporated, after which ether is added, followed by 10% sodium hydroxide and water. The mixture is extracted with ether (3X). The combined ether extracts are washed with water and with brine, dried over calcium sulfate, filtered and rotoevaporated to give 5-methoxy-2 -methylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:44]=3[N:45]=2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:44]=3[N:45]=2)=[CH:37][CH:36]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1O)C(=O)OC(C)(C)C
Reactant: Cc1ccc2oc(-c3ccc(CCl)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2nc3cc(C)ccc3o2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
5 g (11.35 mmol) of ethyl 5-{(tert-butoxycarbonyl)[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate, 3.51 g (13.62 mmol) of 2-[4-(chloromethyl)phenyl]-5-methyl-1,3-benzoxazole and 3.92 g (28.37 mmol) of potassium carbonate in 50 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→2:1). This gave 6.59 g (9.96 mmol, 87% of theory) of the target compound.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=[S:11].BrBr>C(Cl)(Cl)(Cl)Cl.O>[C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:14]2[C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: Cc1cc(C)c(NC(=S)Nc2ccc(C)c([N+](=O)[O-])c2)c(C)c1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(C)c(Nc2nc3ccc(C)c([N+](=O)[O-])c3s2)c(C)c1
Yield: 45.2 %

Procedure:
To a mixture of 1-mesityl-3-(4-methyl-3-nitrophenyl)thiourea (500 mg, 1.52 mmol) in carbon tetrachloride (25 ml) was added dropwise bromine (0.097 ml, 1.90 mmol) in carbon tetrachloride (10 ml) over 1 h. The mixture was refluxed for 18 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and concentrated under vacuum. The residue was triturated with ether. The resulting solid was collected by filtration to afford 225 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[C:12]([CH3:26])[C:11]3[C:10]([OH:27])=[CH:9][CH:8]=[C:7]([F:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:40][O:41][C:42](=[O:46])[C@H:43](Cl)[CH3:44]>O>[CH3:40][O:41][C:42](=[O:46])[C@@H:43]([O:27][C:10]1[CH:9]=[CH:8][C:7]([F:28])=[C:6]2[C:11]=1[C:12]([CH3:26])=[C:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=1)[C:4]([CH:1]1[CH2:2][CH2:3]1)=[N:5]2)[CH3:44]
Reactant: COC(=O)[C@@H](C)Cl
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](C)Oc1ccc(F)c2nc(C3CC3)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 40 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
A mixture of 2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.064 g), N,N-dimethylformamide (0.86 mL), potassium carbonate (0.071 g) and (R)-2-chloropropionic acid methyl ester (0.032 g) was stirred at 40° C. for 3 days. The mixture was cooled to 0° C., diluted with water (40 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (0:1 to 4:6 by volume) gave title compound as a colourless oil (0.033 g).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:16][N:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4]1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH:3]3[CH2:16][N:6]4[C:7](=[O:15])[NH:8][C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:5]4=[N:4]3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccccc2C2=NC(CBr)CN12
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC#N
Product: O=C1Nc2ccccc2C2=NC(CN3CCN(c4ccccc4)CC3)CN12
Yield: 76.2 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one (0.5 g, 1.78 mmol), N-phenylpiperazine (0.28 mL, 3.56 mmol) in acetonitrile (25 mL) was refluxed for 13 hours. The hot mixture was filtered and washed with acetonitrile (10 mL) to give 2-(4-phenyl-1-piperazinyl)methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one (490 mg, 76%). An analytical sample was prepared from a mixture of acetonitrile and methanol (1:1), mp 257°-258° C. ms: m/z 361 (M+). 1H NMR (300 MHz, DMSO-d6): δ2.43-2.73 (m, 7H, CH2), 3.11 (t, 3H, CH2), 3.65 (q, 1H, CH), 3.91 (t, 1H, CH), 4.41 (m, 1H, CH), 6.75 (t, 1H, Ar--H), 6.91 (d, 2H, Ar--H), 7.06 (q, 2 H, Ar--H), 7.17 (q, 2H, Ar--H), 7.48 (p, 1H, Ar--H), 7.78 (d, 1H, Ar--H), 10.53 (s, 1H, NH). Anal. Calcd for C21H23N5O: C, 69.78; H, 6.41; N, 19.38. Found: C, 69.79; H, 6.45; N, 19.37.
Reaction SMILES: C1(S)C=CC=CC=1.[CH2:8]([NH2:11])[CH2:9][NH2:10].[CH3:12][CH2:13][CH:14]([CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C@@H:30]1[C:61](=[O:62])[NH:60][C@@H:59]([C@H:63]([OH:65])[CH3:64])[C:57](=[O:58])[N:56]2[C@@H:52]([CH2:53][C@@H:54]([OH:66])[CH2:55]2)[C:50](=[O:51])[NH:49][C@@H:48]([C@H:67]([OH:77])[C@@H:68]([OH:76])[C:69]2[CH:74]=[CH:73][C:72]([OH:75])=[CH:71][CH:70]=2)[C:46](=[O:47])[NH:45][C@@H:44]([C@H:78]([OH:83])[CH2:79][C:80]([NH2:82])=O)[C:42](=[O:43])[N:41]2[C@@H:37]([C@@H:38]([OH:84])[CH2:39][CH2:40]2)[C:35](=[O:36])[NH:34][C@H:33](O)[C@H:32]([OH:86])[CH2:31]1)=[O:28])[CH3:18])[CH3:15]>>[CH3:12][CH2:13][CH:14]([CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C@@H:30]1[C:61](=[O:62])[NH:60][C@@H:59]([C@H:63]([OH:65])[CH3:64])[C:57](=[O:58])[N:56]2[C@@H:52]([CH2:53][C@@H:54]([OH:66])[CH2:55]2)[C:50](=[O:51])[NH:49][C@@H:48]([C@H:67]([OH:77])[C@@H:68]([OH:76])[C:69]2[CH:74]=[CH:73][C:72]([OH:75])=[CH:71][CH:70]=2)[C:46](=[O:47])[NH:45][C@@H:44]([C@H:78]([OH:83])[CH2:79][CH2:80][NH2:82])[C:42](=[O:43])[N:41]2[C@@H:37]([C@@H:38]([OH:84])[CH2:39][CH2:40]2)[C:35](=[O:36])[NH:34][C@H:33]([NH:10][CH2:9][CH2:8][NH2:11])[C@H:32]([OH:86])[CH2:31]1)=[O:28])[CH3:18])[CH3:15]
Reactant: NCCN
Reactant: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O
Agent: Sc1ccccc1
Product: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](NCCN)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CCN)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O

Procedure:
According to WO96/24613 and U.S. Pat. No. 5,552,521, primary amide group in Pneumocandin B0 is reduced to amine group (47% of yield), and then the resulting product reacts with thiophenol and ethylenediamine in turn to obtain caspofungin.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:45][N:44]=[N:43][N:42]=4)[C:37]([CH3:40])([CH3:39])[S:38][C@H:34]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[C:50]1([CH2:56][C:57](Cl)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O.CC(C)=O>[C:50]1([CH2:56][C:57]([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:42][N:43]=[N:44][N:45]=4)[C:37]([CH3:39])([CH3:40])[S:38][C@H:34]23)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (788 mg., 4.14 mmoles), acetone (35 ml.) and 6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazoly)penam (2.0g., 4.14 mmole) is stirred for twenty minutes at room temperature and is then diluted with water (100 ml.) and ispropylether (100 ml.). The biphasic mixture is stirred vigorously and adjusted to pH 7 with 2N sodium hydroxide. Phenylacetyl chloride (700 mg., 4.55 mmole freshly distilled) is added and the reaction mixture maintained at pH 5.5-6.5 by addition of 2N sodium hydroxide as necessary. Reaction is continued until the pH levels off at 6.5. The two phases are separated and the aqueous phase is washed with ether (2 × 50 ml.). Chloroform (100 ml.) is added and the pH is adjusted to 2 by addition of 6N HCl. The mixture is stirred, the phases separated and the aqueous phase extracted with chloroform (2 × 50 ml.). The chloroform phases are combined, dried (Na2SO 4), and then concentrated under reduced pressure to about 50 ml. volume. A 1:1 solution of ether-hexane is added dropwise with vigorous stirring until precipitation of the product is complete. The white precipitate is filtered and air-dried. The yield is 850 mg. (57.4%), m.p. 168°-170°. NMR (DMSO-d6): 7.30 (s, 5H), 5.80-5.42 (m, 2H), 5.28 (s, 1H), 3.60 (s, 2H), 1.68 (s, 3H) and 1.10 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]O.N1C=CC=CC=1.P(Br)(Br)[Br:21]>C(OCC)C>[CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][Br:21]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCc1cccc(CO)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)=CCc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
130 mg of the resulting alcohol compound was dissolved in 20 ml of ethyl ether, and 2 ml of pyridine and 270 mg of phosphorus tribromide were added. The mixture was stirred for 1 hour under ice cooling. The reaction mixture was poured into ice water, and ethyl ether was added. The mixture was worked up in a customary manner to give 109 mg (yield 62%) of the captioned compound as a pale yellow oil.
Reaction SMILES: C(O[C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12]Br)C.[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:16].NC1C=CC=CC=1>>[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:12][C:6]3[C:5](=[CH:10][C:9]([F:11])=[CH:8][CH:7]=3)[C:4]2=[O:14])=[CH:26][CH:27]=1)[CH3:16]
Reactant: CCOC(=O)CCCc1ccc(N)cc1
Reactant: CCOC(=O)c1cc(F)ccc1CBr
Solvent: Nc1ccccc1
Product: CCOC(=O)CCCc1ccc(N2Cc3ccc(F)cc3C2=O)cc1

Procedure:
By using 2-bromomethyl-5-fluorobenzoic acid ethyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(6-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester as an orange oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:36][CH3:37])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:19]>C(O)C.N1CCCCC1>[CH2:36]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3 carboxylic acid (3-diethylamino-propyl)-amide as a yellow solid (74.4 mg, 61%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[C:6]([OH:8])=O.[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[N:30]=[C:31]([NH2:35])[S:32][C:33]=1[Cl:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>C(Cl)Cl>[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[N:30]=[C:31]([NH:35][C:6](=[O:8])[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:2]=2[F:1])([C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:14][CH:15]=2)[CH3:9])[S:32][C:33]=1[Cl:34]
Reactant: COC(=O)Cc1nc(N)sc1Cl
Reactant: CC(Oc1ccc(F)cc1F)(C(=O)O)c1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)Cc1nc(NC(=O)C(C)(Oc2ccc(F)cc2F)c2ccc(S(C)(=O)=O)cc2)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 250.2 %

Procedure:
To a mixture of 2-(2,4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid (0.110 g, 0.22 mmol), (2-Amino-5-chloro-thiazol-4-yl)-acetic acid methyl ester (0.071 g, 0.32 mmol), HOBt (0.052 g, 0.38 mmol), and EDCI (0.074 g, 0.38 mmol) in methylene dichloride (10 ml) was added N-methylmorpholine (0.039 g, 0.38 mmol). The resulting mixture was stirred at room temperature for overnight followed by dilution with 10 ml methylene dichloride. The reaction mixture was poured onto water (20 ml), and organic layer separated, washed with water (2×20 ml), brine (20 ml), dried over sodium sulfate and solvent evaporated to get residue which was purified by preparative TLC using 50% ethyl acetate in hexane as mobile. To give desired compound (0.30 g). 1H NMR (400 MHz, CDCl3): δ 1.45 (t, J=7.2 Hz, 3H), 1.93 (s, 3H), 3.14 (s, 3H), 3.77 (d, J=2.8 Hz, 1H), 4.26 (q, J=7.2 Hz, 1H), 6.69-6.77 (m, 2H), 6.96-7.02 (m, 1H), 7.89 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H); MS (D) m/z: 559.00 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])([CH3:28])[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)OC(=O)C(F)(F)F)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:38])[C:5]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])([CH3:28])[CH2:6][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccccc1OC)C(OC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Reaction time: 48 h
Yield: 25 %

Procedure:
3-(4-Benzyloxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-3-(2,2,2-trifluoro-acetoxy)-propionic acid ethyl ester was dissolved in ethyl acetate (350 mL), treated with 5% palladium on carbon (8.77 g), and stirred under an atmosphere of hydrogen for 48 h. The suspension was filtered through celite and concentrated in vacuo. The residue was purified by flash column chromatography (25% ethyl acetate in hexanes) to provide the title compound as a light yellow oil (1.73 g, 25%). 1H NMR (400 MHz, CDCl3): δ 7.12 (d, 2H, J=6.65 Hz), 6.98–6.93 (m, 5H), 4.24–4.15 (m, 2H), 3.75 (s, 3H), 3.23 (d; 1H, J=13.69 Hz), 3.13 (d, 1H, J=13.69 Hz), 1.30 (s, 3H), 1.22 (t, 3H, J=7.43 Hz). MS [EI+] 331 (M+H)+, [EI−] 329 (M−H)+. Rf=0.14 in 25% ethyl acetate in hexanes.