Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@H:11](CC([O-])=O)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH:28]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=4)[OH:29])[CH:22]=3)[O:20][C@@:6]1([CH:39]([O:41]C(=O)C)[CH3:40])[CH2:7][O:8]2)(=O)C.C(=O)([O-])[O-:46].[K+].[K+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:9]23[O:20][C@@:6]([CH:39]([OH:41])[CH3:40])([CH2:7][O:8]2)[C@@H:5]([OH:4])[C@H:11]([OH:46])[C@H:10]3[OH:16])=[CH:22][C:23]=1[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=1)[OH:29]
Reactant: CCOc1ccc(C(O)c2cc([C@]34OC[C@](C(C)OC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](CC(=O)[O-])[C@H]4OC(C)=O)ccc2Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOc1ccc(C(O)c2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
To a solution of [(1R,2S,3S,4R,5S)-2,4-diacetoxy-1-(1-acetoxyethyl)-5-[4-chloro-3-[(4-ethoxyphenyl)-hydroxy-methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate 29d (316 mg, 0.5 mmol) in methanol (20 mL) was added potassium carbonate (344 mg, 2.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. Part of the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with water (10 mL×2) and then saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 29 as a white solid (47 mg, 20.0%, HPLC: 99.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.84 (s, 1H), 7.32 (d, 2H), 7.19 (d, 2H), 6.84 (d, 2H), 5.93 (d, 1H), 5.90 (d, 1H), 5.31 (d, 1H), 5.02 (d, 1H), 4.91 (d, 1H), 4.65 (d, 1H), 4.04 (m, 1H), 4.01-3.96 (m, 2H), 3.88-3.82 (m, 1H), 3.79 (d, 1H), 3.61-3.55 (m, 1H), 3.46 (d, 1H), 3.44-3.39 (m, 1H), 1.30 (t, 3H), 1.17 (d, 3H); and MS (ESI, pos. ion) m/z: 5112[M+HCOO]−.
Reaction SMILES: [CH3:1][C@:2]12[C:11](=O)[O:10][C:8](=[O:9])[C@@:7]1([CH3:13])[C@H:6]1[O:14][C@@H:3]2[CH2:4][CH2:5]1.[NH2:15]C1SC2C=C(C(O)=O)C=CC=2N=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[CH3:1][C@:2]12[C:11](=[O:10])[NH:15][C:8](=[O:9])[C@@:7]1([CH3:13])[C@H:6]1[O:14][C@@H:3]2[CH2:4][CH2:5]1
Reactant: C[C@@]12C(=O)OC(=O)[C@]1(C)[C@H]1CC[C@@H]2O1
Reactant: Nc1nc2ccc(C(=O)O)cc2s1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@@]12C(=O)NC(=O)[C@]1(C)[C@H]1CC[C@@H]2O1
Temperature: 180 °C

Procedure:
A mixture of cantharidin (50 mg, 0.26 mmol), 2-amino-6-carboxybenzothiazole (294 mg, 1.27 mmol), and a mixture of dried toluene and dried triethylamine (4 mL; 2:1, v/v) may be sealed in a tube and heated for 3 hours at 180° C. The reaction mixture may be concentrated, followed by flash chromatography (dichloromethane:methanol, 10:1) that may give the product CAN039 (51.9 mg, 55%) of formula (3) as a white solid with the following characterization: mp=180-181° C.; Rf=0.27 (hexane:acetone, 2:1); 1H NMR (CD3OD, 500 MHz): δ 1.34 (6H, s), 1.72-1.74 (2H, m), 1.97-2.00 (2H, m), 4.69-4.70 (2H, m), 8.08 (1H, d, J=8.5 Hz), 8.18 (1H, dd, J=8.5 Hz and 1.5 Hz), 8.70-8.71 (1H, m); 13C NMR (CDCl3): δ 12.1, 23.7, 54.6, 85.0, 85.1, 122.5, 123.9, 127.9, 128.3, 132.7, 151.9, 155.3, 168.0, 178.7; MS (EI) m/z (%): 372 (M+); HRMS calcd. for C18H16N2O5S [M]+ found 358.0776.
Reaction SMILES: C([S@@]([NH:7][C@H:8]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)[CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])=O)(C)(C)C.C(N(CC)CC)C>CO>[F:25][C:20]1[CH:19]=[C:18]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9]2)[CH:23]=[C:22]([F:24])[CH:21]=1
Reactant: COC(=O)C(C)(C)CC[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl (5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate from Step E (300. mg, 0.800 mmol) in MeOH (16 mL) was cooled to 0° C. Hydrogen chloride gas (anhydrous) was bubbled through this cold solution for about 30 seconds, after which time the reaction vessel was sealed and allowed to sit in the ice bath for 15 minutes. Dry nitrogen was then bubbled through the solution for 30 minutes, prior to removal of solvent in vacuo. More MeOH (˜50 mL) was added, and then removed in vacuo. After dissolving in a third volume of MeOH (16 mL), triethylamine (323 mg, 3.2 mmol) was introduced and the mixture was heated to 65° C. for 16 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between diethyl ether (50 mL) and 1 M HCl (50 mL). The organics were washed with additional 1 M HCl (50 mL), water (50 mL) and saturated brine (50 mL). The ethereal solution was dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=240 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@H:10]3[CH2:14][CH2:13][CH2:12][NH:11]3)[CH:5]=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cncc(OC[C@H]3CCCN3)c2)cc1
Yield: 134 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (300 mg, 0.84 mmol) and 4-chlorophenylboronic acid (263 mg, 1.68 mmol, Lancaster Chemical Co.) in toluene (10 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2M solution), and the mixture was heated at reflux for 6 hours. The solvent was removed under vacuum, and the residue was chromatographed on a silica gel column, eluting with 1:5 to 1:2 ethyl acetate/hexane to afford the title compound (325 mg, 100% yield). MS (DCI/NH3) m/z 389 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.47 (s, 9h), 1.90 (m, 2H), 2.05 (br, 1H), 3.40 (br, 2H), 3.92 (br, 1H), 4.19 (br, 2H), 4.25 (br, 1H), 7.44 (m, 2H), 7.52 (m, 3H), 8.31 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10]O.[OH-].[K+].CI>O>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CO
Reactant: Cc1ccc(O)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1ccc(C)c(C)c1
Yield: 81 %

Procedure:
To 3,4-dimethylphenol(19.3 g, 0.16 mol), methanol(150 ml) and KOH(9.65 g, 0.25 mol) were added and then refluxed for 2 hrs. Methyl iodide(36.5 g, 0.25 mol) was added thereto, refluxed for 3 hours and then followed by addition of water(150 ml). The resulting mixture was extracted with ethylacetate and purified by column chromatography to obtain the titled compound.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[CH2:18]1[O:20][CH:19]1[CH2:21][OH:22]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]([CH2:21][OH:22])[CH2:18][O:20][C:16]2=[O:17])=[CH:11][CH:10]=1
Reactant: OCC1CO1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCC(CO)N1c1ccc(Cl)cc1
Reaction time: 20 h
Yield: 143 %

Procedure:
A 8.5 ml quantity of triethylamine was added dropwise to a dichloromethane (25 ml) solution of 2.5 g of 4-chlorophenyl isocyanate and 2.5 g of glycidol at 40° C., and the mixture was stirred at the same temperature for 20 hours. The reaction mixture was washed with 5% hydrochloric acid, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by dichloromethane-ethanol gradient elution to give 5.30 g of the title compound as an oil (yield 69%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[O:20][CH:17]1[CH2:16][CH2:15][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl

Procedure:
The product of Step 2 (10.15 g, 23.6 mmol) was dissolved in dichloromethane (150 ml) and trifluoroacetic acid (40 ml, 519 mmol) added and the resultant solution stirred. After 90 minutes the dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The resultant oil was partitioned between ethyl acetate (100 ml) and 2M aq NaOH (100 ml). The layers were separated and the organics extracted with 10% aq citric acid (100 ml). The layers were separated and the aqueous basified with 2M aq NaOH and extracted with ethyl acetate (200 ml). The organics were dried (MgSO4), filtered and the solvent removed to give the sub-titled product as a pale oil which solidified on standing (4.62 g, 59%; MS: (M+H) 329).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8]>CCO>[NH2:18][C:16]1[CH:15]=[CH:14][C:4]([O:5][CH2:6][C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[C:3]([O:2][CH3:1])[CH:17]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(=O)N1CCCC1
Solvent: CCO
Product: COc1cc(N)ccc1OCC(=O)N1CCCC1
Reaction time: 5 h
Yield: 85 %

Procedure:
A suspension of 2-(2-methoxy-4-nitrophenoxy)-1-(pyrrolidin-1-yl)ethanone (2.03 g; 7.24 mmol) and 10% Pd(C) (1.54 g; 1.45 mmol) in EtOH (20 mL) was hydrogenated at 55 psi of H2 for 5 h. After filtration through fiberglass filter paper, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 100:0 to 19:1 gradient) to afford the title compound (1.54 g; 85%) as an orange gum. 1H NMR (CDCl3) δ 1.81-1.86 (m, 2H), 1.91-1.96 (m, 2H), 3.49-3.56 (m, 6H), 3.81 (s, 3H), 4.58 (s, 2H), 6.19 (dd, J=8.80 Hz, 2.20 Hz, 1H), 6.30 (d, J=2.75 Hz, 1H), 6.81 (d, J=8.80 Hz, 1H); 13C NMR (CDCl3) δ 23.78, 26.22, 45.90, 46.10, 55.73, 70.47, 100.70, 106.54, 117.06, 140.41, 142.01, 150.69, 167.13; HPLC a) column: Phenomenex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.2% H3PO4 to 90% MeOH/10% H2O/0.2% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 0.19, 0.66 min retention time, (98%); HPLC b) column: Phenomenex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 0.99 min retention time; MS (ES): m/z 251 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([OH:19])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:30][N:31]1CCOC[CH2:32]1.CNC.C1COCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:30][N:31]([CH3:32])[C:17]([C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])=[O:19]
Reactant: CN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 87 %

Procedure:
(2S)-1-{[(Phenylmethyl)oxy]carbonyl}-2-piperidinecarboxylic acid (2.0 g, 7.595 mmol) and HOBt (1.231 g, 9.114 mmol) were dissolved in CH2Cl2 (40 mL), and 4-methylmorpholine (2.5 mL, 22.78 mmol), 2.0 M solution of dimethyl amine in THF (4.55 mL, 9.114 mmol), and EDCI (1.750 g, 9.114 mmol) were added. This solution was stirred overnight, and was then washed with 1 N HCl (25 mL) and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-100% ethyl acetate/hexanes) to provide phenylmethyl (2S)-2-[(dimethylamino)carbonyl]-1-piperidinecarboxylate (1.919 g, 87%). LCMS: (M+H)+: 291.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20]Br>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc(Br)c(CBr)c1
Product: COc1ccc(Br)c(CCc2ccc(C(=O)O)cc2)c1

Procedure:
The title compound was prepared from 4-methylbenzoic acid and 1-bromo-2-(bromomethyl)-4-methoxybenzene using the procedure described for the preparation of INTERMEDIATE 10. 1H NMR (400 MHz, CD3OD): δ 7.90 (d, J=8.3 Hz, 2H); 7.40 (d, J=8.7 Hz, 1H); 7.27 (d, J=8.2 Hz, 2H); 6.72-6.66 (m, 2H); 3.68 (s, 3H); 3.01-2.91 (m, 4H). LCMS1 3.68 min. (M-OH)=317
Reaction SMILES: O.NN.[CH3:4][C:5]1[N:6]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]([C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=O)[N:9]=1.[OH-].[K+].O>C(O)CO>[CH3:4][C:5]1[N:6]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:7]=[C:8]([CH2:10][C:12]2([C:15]([F:16])([F:17])[F:18])[CH2:13][CH2:14]2)[N:9]=1
Reactant: Cc1nc(C(=O)C2(C(F)(F)F)CC2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1nc(CC2(C(F)(F)F)CC2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
Hydrazine hydrate (30 mL) was added to a solution of (2-methyl-1-trityl-1H-imidazol-4-yl)[1-(trifluoromethyl)cyclopropyl]methanone (15.78 g, 34.2 mmol) and powdered potassium hydroxide (9.6 g, 171 mmol) in ethylene glycol (200 mL). After stirring at 120° C. for 20 min, the reaction mixture was heated at 180° C. for 2 h. After cooling to ambient temperature, water was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1C=O.CC(C)=[O:22]>>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:22])[CH2:3][CH:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)=O
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Product: O=C1CC(c2ccccc2)Oc2ccccc21

Procedure:
Analogously, (-)-4H-2-carboxamido-4-phenyl-thieno[3,2-c][1]benzopyran, [α]43625 =-110° (c=0.5, acetone) is prepared starting from the pure enantiomeric 4-chloro-3-formyl-flav-3-ene which is obtained by chloroformylation of (-)-flavanone [(-) at 436 nm].
Reaction SMILES: [CH3:1][P:2]([O-:9])[O:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:10][C:11]([O:13][CH:14]([C:17]#[N:18])[CH:15]=[CH2:16])=[O:12]>>[C:11]([O:13][CH:14]([C:17]#[N:18])[CH2:15][CH2:16][P:2]([CH3:1])(=[O:9])[O:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:12])[CH3:10]
Reactant: CC(C)CCOP(C)[O-]
Reactant: C=CC(C#N)OC(C)=O
Product: CC(=O)OC(C#N)CCP(C)(=O)OCCC(C)C
Temperature: 72 °C
Reaction time: 2.75 h
Yield: 102.3 %

Procedure:
235.0 g of isopentyl methanephosphonite are heated to 72° C. under nitrogen. 0.5 g of tert.-amyl perpivalate is added to the solution, and 63.9 g of acrolein cyanohydrin acetate, in which 3.6 g of tert.-butyl pereodecanoate are dissolved, are added dropwise, with vigorous stirring at 72° C., within 2.75 hours. After reaction is complete, the mixture is stirred at 72° C. for 5 min, and 154.8 g of isopentyl methanephosphonite are distilled out. (Recovery: 94.8%). 143.8 g of 93.6% pure isopentyl (3-acetoxy-3-cyanopropyl)methylphosphinate (yield=97.9%) are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=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>[Cl:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:26]([NH:25][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)[CH:3]=1)=[O:34]
Reactant: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3NC(=O)c3cccc(Cl)c3)CC2)CC1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(-c4cccnc4)cc3NC(=O)c3cccc(Cl)c3)CC2)CC1
Temperature: 80 °C
Yield: 14.1 %

Procedure:
To a solution of 0.050 g (0.091 mmol) of N-{5′-bromo-4-[2-(4-methyl-[1,4]diazepan-1-yl)-2-oxo-ethyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-3-chloro-benzamide in N,N-dimethylformamide (3 mL) is added 0.011 g (0.091 mmol) of 3-pyridyl boronic acid followed by 0.100 g (0.725 mmol) of potassium carbonate and 0.010 g (0.009 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture is flushed with argon for 2 minutes and heated at 80° C. for 18 hours. The mixture is filtered and purified by preparative reverse phase HPLC to provide 0.007 g (14%) of the title compound (125) as a white solid. [M+H]+=547.8.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[C:10]([F:29])=[C:11]([C:16](=O)[C:17](=[C:24]2[S:27]CS2)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:38][NH2:39]>C(O)C>[CH2:30]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[C:10]([F:29])=[C:11]([C:16]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:24]([SH:27])[NH:38][N:39]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NN
Reactant: O=C(C(=C1SCS1)c1ccncc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Solvent: CCO
Solvent: O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]c(S)c1-c1ccncc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-(3-Dibenzylamino-2,6-difluoro-phenyl)-2-[1,3]dithietan-2-ylidene-2-pyridin-4-yl-ethanone (1.26 g, 2.44 mmol) was suspended in absolute ethanol (10 mL). Hydrazine monohydrate (0.473 mL, 9.755 mmol, 4 eq) was added dropwise and the mixture was stirred at 60° C. for 2 hours. The suspension was concentrated under reduced pressure, taken up with toluene (2×20 mL) and evaporated to dryness. The crude product (1.35 g) was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([C:17]3[CH:18]=[CH:13][N:14]=[C:15]([NH:19][CH:20]4[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)[N:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: Fc1ccc2cc[nH]c2c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(F)c(F)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 6,7-difluoro-1H-indole and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM-protecting group with TBAF. Yield: 100 mg (27%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([NH:16]C(=O)C(C)(C)C)=[C:11]([CH3:23])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.O>C(O)(=O)C>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH3:23])[C:12](=[CH:13][C:14]=2[CH3:15])[NH2:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C)cc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C)cc1N
Temperature: 100 °C
Reaction time: 72 h

Procedure:
The product from stage b) (10.4 g) in glacial acetic acid (36 ml) was treated with hydrochloric acid (24.5 ml of 15% solution) at 70° C. The mixture was stirred for 3 days at 100° C. On cooling, water was added and the mixture extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution, dried (MgSO4) and concentrated to give the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[OH:28])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH:31]1(Br)[CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[O:28][CH:31]2[CH2:34][CH2:33][CH2:32]2)=[O:17])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc3ccccc3c2O)Cc2ccccc2C1
Reactant: BrC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2ccc3ccccc3c2OC2CCC2)Cc2ccccc2C1
Reaction time: 0.17 h

Procedure:
A solution of 2-[(1-hydroxynaphthalene-2-carbonyl)amino]indan-2-carboxylic acid ethyl ester (289) (560 mg, 1.5 mmol) in dry DMF is treated with NaH oil dispersion (60%, 100 mg, 2.25 mmol, 1.5 eq) and stirred for 10 min. The cyclobutyl bromide (405 mg, 3 mmol, 2 eq) is added and the reaction heated and stirred in the microwave at 150° C. for 3 hours. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (75 mL) and washed with water (2×30 mL) and brine (30 mL). The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (200 g silica gel, 10% EtOAc in heptane) to give white solid. (290 mg, 45%)
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@H:23]([C:36]([N:38]([C@@H:50]([CH3:58])[CH:51]([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>>[CH2:56]([O:55][CH:51]([O:52][CH2:53][CH3:54])[C@@H:50]([N:38]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)[C:36](=[O:37])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH3:58])[CH3:57]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 83 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.