Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.N1C=CC=CC=1.C(Cl)Cl>O>[CH3:2][C:1]([O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:3]
Reactant: CC(=O)Cl
Reactant: Oc1cnc2ccccc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.35 ml of acetyl chloride are added dropwise to a mixture of 2.5g of 3-hydroxyquinoline (prepared by the method described by Mills and Watson in J.Chem. Soc., 97, 753 (1910)), 8.6 ml of pyridine and 50 ml of methylene chloride, while cooling with ice. After the reaction mixture has been stirred at room temperature for 10 minutes, 50 ml of water are added. Customary working up and purification of the crude product by FC over 50 g of silica gel (mobile phase C) gives 3-methylcarbonyloxyquinoline: Rf (A)=0.55; IR (CH2Cl2): 1770(s) cm-1.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)C.CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:18](=[O:20])[NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A reaction mixture of BOC-L-4-iodophenylalanine (10 g, 25.6 mmol), tert-butylamine (2.19 g, 30 mmol), DMF (25 mL), HBTU (9.7 g, 25.6 mmol), and diisopropylethylamine (6.6 g, 51 mmol) was stirred for 2 hours. The mixture was diluted with 40 mL of diethylether, washed with 1N HCl (2×25 mL), saturated NaHCO3 (2×25 mL), and saturated solution of brine (2×25 mL). The organic layer was separated, dried with Na2SO4, and evaporated to dryness. The crude was purified by column chromatography (silica gel, 25% EtOAc/hexanes) to yield the title compound (10.2 g).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(OC(=O)C)(=O)C.[N:23]([O-])=O.[Na+]>>[C:1]([NH:23][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])(=[O:4])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=N[O-]
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(NC(C)=O)C(=O)OCC
Temperature: 40 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
0.67 mol of acetic acid is fed into a mixture made from 0.38 mol of diethyl malonate, 1.14 mol of acetic anhydride and 0.5 mol of sodium nitrite, with stirring, at a temperature of 40° C., in such a way as to prevent the reaction temperature from exceeding 50° C. (metering time: about 3 hours). Stirring is continued for 4 hours at 50° C., followed by cooling to room temperature. Salts derived from the reaction are filtered off, and the salt is then washed with about 100 ml of methyl tert-butyl ether. The sodium acetate from the post precipitation is filtered off, and the mother liquor is mixed with 5 g of platinum/carbon (5%). The mixture is hydrogenated at a hydrogen pressure of 5 bar and a temperature of from 45 to 50° C.Hydrogen uptake ceases after about 4 hours. The mixture is cooled and the pressure released, and some of the solvent is removed by distillation in vacuo. After crystallization of the product the solid is isolated by filtration. This gives a yield of 85% of diethyl acetylaminomalonate.
Reaction SMILES: C([NH+](CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]([N:21]2[CH2:24][C@H:23]([NH2:25])[C:22]2=[O:26])=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C(#N)C>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]([N:21]2[CH2:24][C@H:23]([NH:25][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:22]2=[O:26])=[O:20])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)N2C[C@H](N)C2=O)cc1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)N2C[C@H](NC(=O)Cc3ccccc3)C2=O)cc1

Procedure:
(S)-1-[[[(4-Methylphenyl)sulfonyl]amino]-carbonyl]-2oxo-3-aminoazetidine, triethylammonium salt (626 mg, see example 2) was dissolved in dry acetonitrile (25 ml) and stirred under nitrogen in an ice bath. Triethylamine (0.57 ml) was added, followed by phenylacetyl chloride (0.324 ml). After 3 hours an equal volume of water was added, the pH was adjusted to 7.5, and the acetonitrile was removed in vacuo. The aqueous residue was extracted twice with ethyl acetate to remove neutral material. The aqueous layer was then acidified to pH 2.0 and extracted three times with ethyl acetate. The acidic extract was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo, yielding 544 mg. This crude product, and an additional 481 mg of crude product from two other runs were combined and purified by chromatography on a column of SilicAR CC-4 (100 g), using dichloromethane and dichloromethane:methanol, 99:1 as eluants. The amorphous product was crystallized from acetonitrile to give 154 mg of crystalline material, melting point 170°-172° C.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][N:10]1[C:23]2[CH:22]=[C:21]([S:24][CH3:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2.[Cl:26][C:27]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:28]=1[C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30].C(=O)(O)[O-].[Na+]>O>[Cl:26][C:27]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:28]=1[C:29]([CH:31]1[CH2:32][CH2:33][N:34]([CH2:7][CH2:8][CH2:9][N:10]2[C:23]3[CH:22]=[C:21]([S:24][CH3:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:35][CH2:36]1)=[O:30]
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CCNCC1
Reactant: CSc1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc2c(c1)N(CCCN1CCC(C(=O)c3ccc(Cl)cc3Cl)CC1)c1ccccc1S2
Reaction time: 5 h
Yield: 79.9 %

Procedure:
To 75 ml of dry dimethylformamide was added 2.0 g of 10-(3-chloropropyl)-2-methylthiophenothiazine, 1.7 g of 4-(2,4-dichlorobenzoyl)piperidine, and 5.0 g of sodium bicarbonate. The reaction mixture was stirred at 90° for five hours, poured into 200 ml of water, and extracted with ethyl acetate. This extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. This oil was purified by high pressure liquid chromatography on a silica gel column, utilizing ethyl acetate/dichloromethane (1:2 by volume) as the eluent. Concentration of the appropriate fractions yielded 2.7 g of 4-(2,4-dichlorobenzoyl)-1-[3-(2-methylthio-10H-phenothiazin-10-yl)propyl]piperidine as an oil.
Reaction SMILES: C1C=[CH:5][NH+:4]=[CH:3]C=1.Br[Br-]Br.[CH2:10]([O:12][C:13]([C:15]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:27]=[O:28])[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:18](C)[NH:17][C:16]=1[CH3:35])=[O:14])[CH3:11].N1C=CC=C[CH:37]=1.CNC>ClCCl>[CH2:32]([O:31][C:29]([C:19]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:27]=[O:28])[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])=[C:16]([CH3:35])[N:17]([CH3:37])[C:18]=1[N:4]([CH3:5])[CH3:3])=[O:30])[CH3:33]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C=O
Reactant: c1cc[nH+]cc1
Reactant: c1ccncc1
Agent: CNC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N(C)C(N(C)C)=C(C(=O)OCC)C1c1ccccc1C=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Pyridine hydrobromide perbromide (3.2 g) was added to a solution of 4-(2-formylphenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethylester (3.15 g) and pyridine (1.3 ml) in dicloromethane (100 ml) at 0° C. and stirred for 0.5 hours. The mixture was then cooled to -10° C., treated with dimethylamine (10.6 ml) and stirred at -10° C. for 1 hour. The solvent was evaporated and the residue taken up with ethyl acetate. The solid was filtered off and the solution evaporated to dryness to obtain a red oil, which was eluted on a silica gel column (Ethyl acetate/Petrol ether/Methanol, 7:3:1) to yield the title compound as a yellow solid (from petrol ether) (2.3 g), m.p. 115°-120° C. T.l.c. (CH2Cl2 /Methanol, 95:5) Rf. 0.38.
Reaction SMILES: S([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(OCCC#C)(=O)=O.N1C=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1CC[NH:25][CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+].C[N:34](C)C=O>>[N:34]1[CH:11]=[CH:10][CH:9]=[CH:15][C:14]=1[CH:12]1[CH2:13][NH:25][CH2:24][CH2:23][N:22]1[CH2:17][CH2:18][C:19]#[CH:20]
Reactant: CN(C)C=O
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: C#CCCN1CCNCC1c1ccccn1

Procedure:
A solution of 3-butynyl tosylate (25.0 g, 0.11 mol), 1-(2-pyridinyl)piperazine (12.1 g, 0.074 mol), and sodium bicarbonate (6.9 g, 0.082 mol) in 200 mL of dimethylformamide is heated at 80° C. for 18 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 200 mL of dichloromethane and 200 mL of water. The aqueous layer is extracted with 100 mL of dichloromethane and the combined organic layers are dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 25% ethyl acetate/75% hexane) to give the title compound as a white solid; mp 57°-58° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:7][NH2:8].[C:9]([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)(N1C=CN=C1)=[O:10].[CH3:21]N(C)CCN>ClCCl>[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][NH:8][C:9]([NH:16][CH2:20][CH2:19][N:18]([CH3:17])[CH3:21])=[O:10]
Reactant: CN(C)CCN
Reactant: NCC1CCC=CO1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN(C)CCNC(=O)NC[C@H]1CCC=CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
C-(3,4-Dihydro-2H-pyran-2-yl)-methylamine (free base) (13.3 g, 118 mmol) and 1,1′-carbonyl diimidazole (28.6 g, 176 mmol) were dissolved in dichloromethane (900 mL) and stirred for 2 h at room temperature. Under an Argon atmosphere N,N-Dimethyl ethylene diamine [51.2 mL, 470 mmol; dissolved in dichloromethane (250 mL)] was added and the reaction mixture stirred for 65 h at room temperature. The reaction mixture was concentrated to about one third volume under reduced pressure and extracted three times with water (100 mL). The organic layer was dried with sodium sulphate and the remaining solvent removed under reduced pressure to yield 1-[(R)-1-(3,4-Dihydro-2H-pyran-2-yl)methyl]-3-(2-dimethylamino-ethyl)urea (24.2 g, 91%) as pale yellow liquid. Analytical data 1-[(R)-1-(3,4-Dihydro-2H-pyran-2-yl)methyl]-3-(2-dimethylamino-ethyl)-urea: HPLC-MS: (M+H)+=228.2 at rt=1.155 min., column: Chromolith SpeedROD RP-18e 50-4, 6 mm; solvent A: water+0.1% TFA, solvent B: acetonitrile+0.1% TFA, gradient: 4% B at 0.0 min, 100% B at 2.6 min., 100% B at 3.3 min, flow: 2.4 mL/min., UV: 220 nm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][S:16]([O-:18])=[O:17].[Na+]>CN(C=O)C>[CH3:15][S:16]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])(=[O:18])=[O:17]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 120 °C
Yield: 63.5 %

Procedure:
A mixture of 2-fluoro-5-nitro-benzotrifluoride (0.50 g, 2.4 mmol) and sodium methanesulfinate (0.25 g, 2.4 mmol) in anhyd DMF (1.0 mL) was heated at 120° C. with stirring. After 18 h the reaction mixture was cooled, concentrated and chromatographed (silica, EtOAc/Hex, 0:100 to 40:60) to give 2-methanesulfonyl-5-nitro-benzotrifluoride (0.41 g, 64%) as a white solid: 1H-NMR (CDCl3) δ 8.76 (1H, d, J=2.0), 8.62 (1H, dd, J=2.0, 8.8), 8.57 (1H, d, J=8.8), 3.26 (3H, s). The title compound was prepared from 2-methanesulfonyl-5-nitro-benzotrifluoride in a manner similar to that described in Example 3A: 1H-NMR (DMSO-d6) δ 10.14 (1H, s), 8.50 (1H, d, J=2.0), 8.35 (1H, dd, J=2.0, 8.6), 8.16 (1H, d, J=8.8), 8.02 (1H, d, J=7.8), 7.92 (1H, app t, J=7.8), 7.82 (1H, app t, J=7.8), 7.52 (1H, d, J=7.8), 6.69 (1H, s), 3.26 (3H, s), 2.15 (3H, s), 1.89 (3H, s); MS (ESI): 505 (MH+). B. In a manner similar to that described for Example 5A, the following compound was prepared by replacing 2-fluoro-5-nitro-benzotrifluoride with 3-chloro-4-fluoro-nitrobenzene:
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH3:15][C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:22]([C:19]1[CH:20]=[N:21][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:24]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCNC[C@@H]2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1394.9 %

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (1 g, 4.99 mmol) in DMF (5 ml) was added 6-methyl-3-pyridinecarboxylic acid (0.685 g, 0.340 mmol), HOBT.H2O (0.765 g, 4.99 mmol) and HBTU (1.894 g, 4.99 mmol). Finally DIPEA (2.62 ml, 14.98 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. Solvent was removed by evaporation and EtOAc was added to the residue and the solution was extracted with saturated aqueous sodium bicarbonate and sodium chloride solutions. The organic layer was evaporated to dryness and dissolved in dioxane (100 ml) and stirred with 4M HCl in dioxane (15 ml) and water (0.25 ml) overnight. The solution was evaporated to dryness and purified using an ion exchange column (SCX, Biotage) to give the title compound as an oil (1.04 g)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:5]1[C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])=[CH:3][CH:4]=1
Reactant: O=C(O)c1nc(Br)ccc1F
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1nc(-c2ccccc2F)ccc1F
Yield: 81 %

Procedure:
Method 1 was followed using 6-bromo-3-fluoropicolinic acid (1.0 equiv.) and 2-fluorophenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 3-fluoro-6-(2-fluorophenyl)picolinic acid in 81% yield. LC/MS=236.1 (M+H), Rt=0.72 min.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:13]C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].CCOCC.[Na+].[Cl-]>Cl.C(O)C.O>[N:1]([CH2:4][C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NC[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The compound from step 3 (4.3 g, 15.6 mmol) is dissolved in 30 mL of 4 N HCl in ethanol, and the reaction mixture is stirred for 1.5 hours at room temperature. The solvent is stripped and chased with ether. The residue is dissolved in water, NaCl is added, and the mixture is extracted with ethyl ether, which is discarded. The aqueous layer is adjusted to pH 12 with K2CO3, saturated with NaCl, then extracted with CHCl3. The organic extract is washed with brine, dried (Na2SO4) and filtered. The solvent is removed under vacuum to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18](Cl)=[O:19])[CH3:2].[Cl:21][C:22]1[C:23]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[C:37]2[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=2)=[CH:24][C:25]([F:29])=[C:26]([NH2:28])[CH:27]=1>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]1[C:23]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[C:37]2[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=2)=[CH:24][C:25]([F:29])=[C:26]([NH:28][C:18]([C:5]2[C:6](=[O:17])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:19])[CH:27]=1
Reactant: Cn1cc(-c2cnccc2Oc2cc(F)c(N)cc2Cl)cn1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccncc2-c2cnn(C)c2)cc1F
Yield: 37.7 %

Procedure:
To a solution of 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (0.275 g, 0.929 mmol) in CH2Cl2 (2 mL) was added a suspension of 5-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (0.148 g, 0.464 mmol) in pyridine (2.00 mL) at 0° C. The resultant mixture was stirred at ambient temp for 30 min. The solvent was completely evaporated and the residue was stirred in water. The precipitate was collected by filtration and was re-crystallized from acetonitrile to provide N-(5-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.101 g, 37.6% yield) as an off-white solid. The mesylate salt was prepared by treatment with one equivalent of methanesulfonic acid. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.20 (s, 1H), 8.62 (d, J=5.5 Hz, 1H), 8.51 (m, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.75 (d, J=11 Hz, 1H), 7.50 (m, 2H), 7.41 (m, 2H), 7.25 (d, J=2.5 Hz, 1H), 6.60 (d, J=5.5 Hz, 1H), 4.30 (q, J=6 Hz, 2H), 3.92 (s, 3H), 2.30 (s, 3H), 1.30 (t, J=6 Hz, 3H); MS (ESI) m/z: 578.2 (M+H+).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].[C:5]([O:10][CH2:11][CH3:12])(=[O:9])[C:6]([CH3:8])=O.C(#N)C.[CH:16](=[N:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:11]([O:10][C:5]([C:6]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]=[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=1)=[O:9])[CH3:12]
Reactant: Oc1ccc(N=Cc2ccccc2)cc1
Reactant: CCOC(=O)C(C)=O
Agent: [Cl-]
Agent: [In+3]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2ccccc2)nc2ccc(O)cc12
Temperature: 90 °C
Reaction time: 0.45 h
Yield: 20 %

Procedure:
Indium chloride (0.4977 g, 2.25 mmol) and ethyl pyruvate (1.3064 g, 11.3 mmol) were added to an acetonitrile (15.0 mL) solution of 4-benzylideneaminophenol (0.8875 g, 4.50 mmol), and the mixture was heated with stirring at 90° C. for 27 minutes with microwave irradiation. To the reaction solution, water and saturated saline were added. The mixture was subjected to extraction with dichloromethane and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography, and the solvent was distilled off to obtain 6-hydroxy-2-phenyl-4-quinolinecarboxylic acid ethyl ester (0.264 g, 0.900 mmol) as a pale yellow powder.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:5]([OH:7])=O)([CH3:4])[CH3:3].C(N1[CH:26]=[CH:25]N=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].C(O)(=O)[CH2:31][C:32]([OH:34])=[O:33].C([K])C>CCOC(C)=O.C1COCC1>[C:11]([O:10][C:8]([NH:1][C:2]([CH3:3])([CH3:4])[C:5](=[O:7])[CH2:31][C:32]([O:34][CH2:25][CH3:26])=[O:33])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(=O)O
Agent: CC[K]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.3 %

Procedure:
To a 1-liter, 3 neck, round-bottomed flask equipped with a mechanical stirrer and internal temperature probe was added Boc-Aib-OH (Bachem) (20 g, 98 mmol) and THF (500 mL). To the mixture at RT was added 1,1′-carbonyldiimidazole (Sigma-Aldrich) (23.9 g, 148 mmol) in portions. The solution was stirred for 2.5 h at RT. To the solution was added magnesium chloride (18.7 g, 197 mmol) and ethyl potassium malonate (Sigma-Aldrich) (33.5 g, 197 mmol). The solution was stirred at 50° C. for 17 h and then the solution was cooled to RT. The solution was diluted with EtOAc (400 mL) and filtered and the filter cake was washed with EtOAc. The filtrate was concentrated and the resulting material was diluted with EtOAc and hexanes. The solution was filtered and the filtrate was concentrated onto silica. Purification by silica gel chromatography (0-20% EtOAc/hexanes) afforded the title compound as a white solid (4.65 g, 17.0 mmol, 17% yield). m/z (ESI, +ve ion) 296.1 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22]([N:42]3[CH2:43][CH2:44][NH:39][C:40](=[O:45])[CH2:41]3)=[O:23])=[C:15]2[CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCNC(=O)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 82 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), piperazin-2-one (60 mg, 0.6 mmol), bis(2-oxo-3-oxazolidinyl) phosphonic chloride (0.138 g, 0.54 mmol), triethylamine (0.25 mL, 1.62 mmol) and 8 mL of dichloromethane were added into the reaction flask, and 10 mL of N,N-dimethylformamide was then added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(3-oxo-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 19a (140 mg, yield 82%) as a colourness oil.