Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].O>O1CCCC1>[O:10]1[C:9]2[CH:13]=[CH:14][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[CH:7][C:8]=2[O:12][CH2:11]1
Reactant: [Li]C
Reactant: CC(=O)c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)OCO2
Temperature: -20 °C
Reaction time: 1 h

Procedure:
About 600 ml of 1.5M methyllithium (solution in ether) was added to 500 ml of tetrahydrofuran. A suspension of 93.45 g of 5-acetyl-1,3-benzodioxole in 900 ml of tetrahydrofuran was added thereto under cooling at -20° C. The mixture was stirred under these conditions for 1 h. Water was added to the reaction mixture. The product was extracted with ethyl acetate, washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 97 g of the intended compound in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Reactant: NCCN1CCCCC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNCCN2CCCCC2)cc1-c1ccccc1C

Procedure:
The desired compound was prepared using the method described in Example 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G, and 1-(2-aminoethyl)piperidine. m/e (ESI) 498 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#N)=[N:6][CH:7]=1.Cl.[CH2:11]([OH:13])[CH3:12].C([OH:16])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:13][CH2:11][CH3:12])=[O:16])=[N:6][CH:7]=1
Reactant: CCO
Reactant: N#Cc1ccc(Cl)cn1
Agent: Cl
Product: CCOC(=O)c1ccc(Cl)cn1
Yield: 97 %

Procedure:
To a solution of the compound (3.16 g) obtained in (2) above in ethanol (5 ml) was added a 2.7N hydrochloric acid-ethanol solution (10 ml) and the mixture was stirred with refluxing for 2 hours. Ethanol was distilled away under reduced pressure, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was distilled away under reduced pressure to give 4.10 g of a pale-brown solid (yield 97%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.N1C=CC=CC=1.[O:24]=[C:25]1[CH2:42][C@@:40]2([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]2[OH:43])[C:35]2[CH2:34][CH2:33][C:32]3[CH:31]=[C:30]([O:44][CH3:45])[CH:29]=[CH:28][C:27]=3[C:26]1=2.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:45][O:44][C:30]1[CH:29]=[CH:28][C:27]2[C:26]3[C:25](=[O:24])[CH2:42][C@@:40]4([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]4[O:43][CH:6]4[CH2:5][CH2:4][CH2:3][CH2:2][O:1]4)[C:35]=3[CH2:34][CH2:33][C:32]=2[CH:31]=1
Reactant: C1=COCCC1
Reactant: COc1ccc2c(c1)CCC1=C2C(=O)C[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CCC1=C2C(=O)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Reaction time: 2 h

Procedure:
47 ml of dihydropyran and 0.96 g of pyridine toluenesufonate were added at room temperature to 15.29 g of 11-keto-3-methoxy-estra-1,3,5(10),8-tetraen-17β-ol (1) in 35 ml of dichloromethane, and it was stirred for 2 hours. Then, the reaction solution was shaken several times with saturated sodium bicarbonate solution, washed with water and dried with magnesium sulfate. The solvent was evaporated in a vacuum, and the residue was purified on silica gel (solvent mixture: cyclohexane/ethyl acetate=8/2). 16.8 g (83%) of light yellowish, viscous oil was thus obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6](=O)[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].CC(O)=O.[CH2:18]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:26]([N:25]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]1[CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]([CH2:1][CH3:2])[CH2:7]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)C1CC(=O)CC1CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Temperature: 0 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
A round-bottom flask was charged with ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol) and DCE (1.8 L). The solution was cooled to about 0° C. and AcOH (45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were added drop-wise, resulting in the formation of a thick suspension. The reaction mixture was warmed to about 10° C. by removing the cooling bath and additional DCE (500 mL) was added. Sodium triacetoxyborohydride (166 g, 781 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for about 20 h. The reaction mixture was slowly poured into saturated aqueous NaHCO3 (1.5 L) with stirring followed by the portion-wise addition of solid NaHCO3 (175 g, 2083 mmol). The mixture was stirred for about 2 h and the organic layer was separated, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The crude yellow oil was purified by flash column chromatography using EtOAc/heptane as eluant (0-20% EtOAc) to yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as a white solid: LC/MS (Table 2, Method a) Rt=3.26 min; MS m/z: 366 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH2:11])[CH2:5][CH2:4]1.Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1.CCN(CC)CC>COCCOC>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N:18]=2)[CH2:5][CH2:4]1
Reactant: COC1CCN(CCN)CC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COC1CCN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Yield: 78.6 %

Procedure:
Crude 2-(4-methoxy-1-piperidinyl)ethylamine (288) (3.8 g, 23.9 mmol) was added to a stirred solution of chloride 21 (1.77 g, 8.0 mmol) and Et3N (2.2 mL, 16.0 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 42 (2.16 g, 79%) as a yellow solid: mp (MeOH/EtOAc) 131-133° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.82 (br s, 1H, NH), 3.50-3.56 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.21-3.26 (m, 1H, CHO), 2.97-3.03 (m, 4H, H-6, H-8), 2.72-2.82 (m, 2H, CH2N), 2.60 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.20-2.26 (m, 2H, CH2N), 2.15 (br p, J=7.4 Hz, 2H, H-7), 1.84-1.92 (m, 2H, CH2), 1.57-1.65 (m, 2H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 76.2, 56.3, 55.5, 50.7 (2), 38.2, 33.1, 32.3, 30.8 (2), 25.7. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 63.0; H, 7.4; N, 20.4%.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:7]([NH:9][C@H:10]([C:13](C(OCC)=O)=[O:14])[CH2:11][CH3:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:30]([NH2:32])[CH3:31]>C(Cl)(Cl)Cl.CO>[NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:2]([C:7]([NH:9][C@H:10]([C:13]([NH:32][CH2:30][CH3:31])=[O:14])[CH2:11][CH3:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CCN
Reactant: CCOC(=O)C(=O)[C@H](CC)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCNC(=O)[C@H](CC)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Yield: 64 %

Procedure:
This compound was synthesized from protected α-ketoester derived from Z-Leu-Abu-CO2Et and ethylamine in 64% yield by the procedure described in Example PKC47. Single spot on TLC, Rf =0.36 (CHCl3 /CH3OH 50;1); mp 130°-132° C. Anal. calcd. for C21H31N3O5 : 405.45; C, 62.20; H, 7.71; N, 10.36. Found: C, 61.92; H, 7.62; N, 10.31. NMR (CDCl3) ok. MS (FAB) m/e=406 (M+1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[C:21]#[C:22][CH3:23])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[CH2:17][C@@H:16]2[C:21]#[C:22][CH3:23])=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC#CC1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#C[C@H]1CN(S(=O)(=O)c2ccccc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,1,1,3,3,3-hexafluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol (155 mg, 0.423 mmol, Example 241, Step 3) and triethylamine (302 μL, 2.17 mmol, Sigma-Aldrich, St. Louis, Mo.) in DCM (3.2 mL) was added benzenesulfonyl chloride (63.5 μL, 0.504 mmol, Sigma-Aldrich, St. Louis, Mo.) drop-wise at 0° C. The solution was stirred for 30 min and then diluted with DCM and washed with water followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-4-(phenylsulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol as a mixture of enantiomers.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]CC3C=CC=CC=3)[CH:15]=2)[CH:10]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:10]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc(C3CCN(Cc4ccccc4)CC3OCc3ccc4ccccc4c3)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Oc1cccc(C2CCN(Cc3ccccc3)CC2OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
A solution of 250 mg (0.487 mmol) of (3RS,4RS)-1-benzyl-4-(3-benzyloxyphenyl)-3-(naphthalen-2-ylmethoxy)-piperidine in 1.1 ml of methylene chloride was treated at room temperature with 247 μl (236 mg, 1.946 mmol, 4 eq.) of N,N-dimethylaniline and 195 mg (1.46 mmol, 3.0 eq.) of aluminium trichloride and stirred at room temperature for 2.5 hours. Subsequently, the mixture was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 4:1 mixture of methylene chloride and hexane as the eluent. There were obtained 65 mg (32% of theory) of (3RS,4RS)-1-benzyl-4-(3-hydroxyphenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a beige coloured solid; MS: 423 (M)+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[OH-].[Na+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[O:16][CH3:17]>C(O)C.O>[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:1][C:2](=[O:3])[CH3:4])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C=CC(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.1 %

Procedure:
To a solution of acetone (15.30 g, 263.76 mmol) in a mixture of ethanol (35 mL) and water (15 mL) were added sodium hydroxide (2.90 g, 72.54 mmol) and 4-hydroxy-3-methoxybenzaldehyde (5.01 g, 32.97 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction was cooled to 0° C. and quenched with 2.0 N hydrochloric acid until the solution became slightly acidic. The solution was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water (50 mL) and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated at reduced pressure to afford 4-(4-hydroxy-3-methoxy-phenyl)but-3-ene-2-one (5.52 g, 87% yield) as a yellow solid: MS (EI) for C11H12O3: 193 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:13][OH:14])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccccc1C=NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-nitrobenzaldehyde (115 g) and hydroxylamine hydrochloride (6.6 g) in ethanol (110 ml) and water (4 ml) was added sodium acetate (13.6 g) and the mixture was stirred at room temperature for 4 hours. The mixture was poured into water (500 ml) and the mixture filtered to give the title product.
Reaction SMILES: [F:1][CH:2]([F:32])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:31]=[CH:30][C:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][C:23]=4[CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[F:32][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:31]=[CH:30][C:24]4[CH2:25][CH2:26][N:27]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:28][CH2:29][C:23]=4[CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C(=O)CCl
Reactant: FC(F)COc1ccccc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5ccccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-Difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.100 g, 0.230 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.035 mL, 0.344 mmol) in a manner analogous to Example 313 to give product (0.045 g, 38%). MP=213-215° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.49 (s, 1H), 8.77 (d, 1H), 7.65 (m, 2H), 7.40 (m, 2H), 7.35 (s, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.22 (br m, 1H), 4.35 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 2.75 (m, 7H), 2.55 (m, 4H). MS=521 (MH)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[N:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.COCCOC.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>[Br:7][C:5]1[CH:6]=[C:2]([C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: OB(O)c1ccncc1
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: CCO
Solvent: COCCOC
Product: Brc1csc(-c2ccncc2)c1
Yield: 51.5 %

Procedure:
2,4-Dibromothiophene (2.97 g, 12.28 mmol), pyridine-4-boronic acid (1.50 g, 12.28 mmol), potassium carbonate (5.52 g, 39.91 mmol) and tetrakis(triphenylphosphine)palladium (0) (426 mg, 0.38 mmol) were refluxed in ethanol/1,2-dimethoxyethane (1:4 v/v; 100 mL) at 100° C. for 7 hours. The solution was allowed to cool, and then filtered and evaporated. The residue was purified by flash chromatography using a gradient of ethyl acetate in hexane to give a yellow solid as the sub-title compound (1.52 g), m/z 240, 242 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17](C#N)=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[Mg+].[Br-].Cl.CCO[C:29]([CH3:31])=[O:30]>C1COCC1.CCOCC>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17]([C:29](=[O:30])[CH3:31])=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NCC2(c3ncccc3F)CCC2)nn1
Reactant: CCOC(C)=O
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carbonitrile (500 mg, 1.8 mmol, 1.0 equiv) was dissolved in THF (4.5 mL) and transferred to a 20 dram vial. The mixture was cooled to 0° C. and MeMgBr (1.8 mL, 5.3 mmol of a 3M solution in Et2O, 2.9 equiv) was added. The reaction was stirred at this temperature for 15 min. The reaction mixture was poured into ice water, acidified to pH of 2 with 2N aqueous hydrochloric acid, and then extracted EtOAc (30 mL). The organic layer was then separated, dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (50% EtOAc/hexanes) to give 104 mg (18%) of 1-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)ethanone as a white powder. m/z=301.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>ClCCl>[C:1]([O:5][C:6]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:20](=[O:23])[CH:21]=[CH2:22])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 100.3 %

Procedure:
To a stirred solution of 5.0 g (29.2 mmol) D-Proline tert-butyl ester and 4.5 ml (32.1 mmol) triethylamine in 180 ml dichloromethane at 0° C. was added dropwise 3.6 ml (43.8 mmol) acryloyl chloride and stirring continued for 48 h at room temperature. The reaction mixture was then washed sequentially with water, saturated ammonium chloride solution, once more with water and then with saturated brine, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford 6.6 g (100%) of the title compound as a yellow oil. MS m/e (%): 243 (M+NH4+, 33), 226 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][PH:28]([CH:30]([NH:34][C:35](=[O:44])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:31]([CH3:33])[CH3:32])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:46].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:30]([NH:34][C:35](=[O:44])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:31]([CH3:33])[CH3:32])([OH:46])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)CCc1ccccc1)[PH](=O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
The benzyl (S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)phosphinoyloxy)hexanoate (117 mg) obtained in the above step (b) was dissolved in a mixed solvent of dioxane (4.5 ml) and water (1.5 ml) and added with sodium periodate (40.4 mg), and then the mixture was stirred at room temperature for 15 hours. The organic substances were extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium thiosulfate and saturated brine, successively, and dried over anhydrous magnesium sulfate. Then the solvent was evaporated to obtain benzyl (S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoate (100.8 mg, 84%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1.Cl.[CH3:27][O:28][NH2:29]>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:29][O:28][CH3:27])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1
Reactant: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Reactant: CON
Agent: Cl
Product: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)NOC)cc12

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluoro-benzyl)-3-ethoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ; 8.75 (s, 1H), 8.37 (s, 1H), 7.61 (s, 1H), 7.21–7.28 (m, 1H), 6.88–7.00 (m, 2H), 5.54 (s, 2H), 4.70 (s, 2H), 3.82 (s, 3H), 3.59 (q, 2H, J=7.0 Hz), 1.20 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 376.1. HRMS calcd for C19H20F2N3O3 (M+H) 376.1473. found 376.1485. HPLC: 99.24% purity.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:12][C:11]=2[C:23]([NH2:25])=[O:24])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[C:33]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])=[N:12][C:11]=2[C:23]([NH2:25])=[O:24])=[CH:8][CH:9]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(CNC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a suspension of 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide hydrochloride (0.030 g, 0.08 mmol) in DCM (2 mL) was added triethylamine (25 uL) followed by benzoyl chloride (11 uL) and the resulting mixture stirred at room temperature for 2 hours The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 5-(4-(benzamidomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.0128 g, 0.03 mmol, 36%). 1H NMR (DMSO) δ 4.54 (2H, d), 7.40 (2H, t), 7.49 (4H, m), 7.55 (1H, m), 7.74 (3H, m), 7.92 (2H, m), 8.18 (2H, d), 9.15 (1H, t). LCMS (2) Rt: 2.82 min; m/z (ES+) 434.