Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:47])[C@H:33]([CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:34][CH3:35]>>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:47])[C@H:33]([CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[N:34]([C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:35]
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CN(C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1
Yield: 57.6 %

Procedure:
Boc-tyrosine (400 mg) and Nδ-Boc-Nα-methylornithine β-naphthylamide (454 mg) were coupled (Procedure B) to afford titled compound (447 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.50 (m, 21H), 1.77 (m, 1H), 2.73 (s, 3H), 2.76 (m, 2H), 2.99 (dd, J=10.8; 6.8 Hz, 1H), 3.09 (dd, J=12.8; 13.2 Hz, 1H), 4.70 (m, 1H), 4.87 (m, 1H), 6.89 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 7.41 (m, 2H), 7.75 (m, 4H), and 8.26 (s, 1H).
Reaction SMILES: N#N.[SH:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C(N(CC)CC)C.[C:24](Cl)(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CCCCCC>[C:24]([S:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCO[Si](CCCS)(OCC)OCC
Agent: N#N
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Yield: 99.2 %

Procedure:
Into a 12-liter, three-necked round bottom flask equipped with mechanical stirrer, addition funnel, thermocouple, heating mantle, N2 inlet, and temperature controller were charged 3-mercaptopropyltriethoxysilane (1,021 grams, 3.73 moles purchase as SILQUEST® A-1891 silane from General Electric Company), triethylamine (433 grams), and hexane (3,000 ml). The solution was cooled in an ice bath, and octanoyl chloride (693 grams, 4.25 moles) were added over a two hour period via the addition funnel. After addition of the acid chloride was complete, the mixture was filtered two times, first through a 0.1 μm filter and then through a 0.01 μm filter, using a pressure filter, to remove the salt. The solvent was removed under vacuum. The remaining yellow liquid was vacuum distilled to yield 1,349 grams of octanoylthiopropyltriethoxysilane as a clear, very light yellow liquid. The yield was 87 percent.
Reaction SMILES: FC1C=CC(F)=C(C(O)=O)C=1N.[F:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:15]=1[C:16](=O)[NH:17][C:18]([CH3:25])=[N:19]2.P(Cl)(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(OC(=O)C)(=O)C.P(Cl)(Cl)(Cl)=O.[Pd].C(O)(=O)C>[F:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:15]=1[CH:16]=[N:17][C:18]([CH3:25])=[N:19]2
Reactant: Cc1nc2c(F)ccc(F)c2c(=O)[nH]1
Agent: [Pd]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: Nc1c(F)ccc(F)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ncc2c(F)ccc(F)c2n1
Reaction time: 72 h
Yield: 58.2 %

Procedure:
The 3,6-difluoroanthranilic acid is heated in 8 ml of acetic acid anhydride for 45 minutes to 100° C. After cooling, the acetic acid that is produced and excess acetic acid anhydride are removed azeotropically with toluene in a vacuum. The residue is mixed with 40 ml of a 25% ammonia solution while being cooled with ice, and it is stirred for 72 hours. It is diluted with water and acidified with acetic acid. It is extracted with ethyl acetate, the organic phase is washed with water, dried on sodium sulfate and concentrated by evaporation. The thus obtained 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus pentachloride are heated in 20 ml of phosphoryl chloride over 12 hours to 125° C. After cooling, it is poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried, and the solvent is removed. 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline, which is dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine, is obtained quantitatively. 600 mg of palladium on carbon is added, and it is shaken for 2 hours (480 ml of hydrogen absorption) under hydrogen atmosphere at normal pressure. Catalyst is removed from the solution by means of filtration on Celite, whereby it was rewashed with 100 ml of ethanol and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline is obtained. 890 mg (13.7 mmol) of sodium azide is added to 240 mg (1.3 mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-crown-6 in 10 ml of DMF, and the mixture is heated for 8 hours to 125° C. The solvent is removed in a vacuum and chromatographed on silica gel with ethyl acetate, and 52 mg of product is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C1COCC1.C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCCCCC.O>[CH2:17]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: c1ccsc1
Reactant: CCCCCCCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCc1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
Thiophene (59.9 g, 0.713 mol) and dehydrated tetrahydrofran (hereinafter referred to as “THF”) (200 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. The solution was cooled to −78° C., and a solution (200 ml) of n-butyllithium (2.6 M) in n-hexane was added dropwise to the cooled solution over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred at −78° C. for about one hr. Thereafter, the reaction temperature was raised to room temperature. At that temperature, the mixture was again stirred for one hr, and 1-bromooctane (91.8 g, 0.475 mol) was added dropwise thereto at 0° C. over a period of about one hr. After the completion of the dropwise addition, the reaction temperature was raised to room temperature, and, at that temperature, the mixture was stirred overnight. After the completion of the reaction, water (200 ml) was added, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (n-hexane) to give an objective compound 2-octylthiophene as a yellow liquid (99.9 g, yield 97.8%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.28 (m, 10H), 1.67 (m, 2H), 2.81 (t, 2H, J=7.32 Hz), 6.77 (dd, 1H, J=0.976 Hz, J=3.90 Hz), 6.91 (dd, 1H, J=3.90 Hz, J=4.88 Hz), 7.10 (dd, 1H, J=0.976 Hz, J=4.88 Hz).
Reaction SMILES: [BH3-]C#N.[Na+].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:15])=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2.[OH-].[K+].C([O-])(O)=O.[Na+]>C(O)(=O)C.CCOC(C)=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:15])=[C:10]2[C:14]=1[NH:13][CH2:12][CH2:11]2
Reactant: Fc1ccc(Br)c2[nH]ccc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Fc1ccc(Br)c2c1CCN2
Reaction time: 8 h

Procedure:
NaCNBH3 (2.4 g, 38.2 mmol) was added portionwise to a solution of 7-bromo-4-fluoro-1H-indole (1 g, 4.7 mmol) in acetic acid at −10° C. (bath temp). The reaction was stirred overnight, cooled to 0° C. (bath temp), and solid KOH was added. Saturated NaHCO3 and EtOAc were added, the layers were separated, and the organic layer evaporated. The crude product was purified by flash chromatography, giving the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.O>ClCCl>[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]([N:3]([O:4][CH3:5])[CH3:2])=[O:21])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 250-mL round-bottom flask containing N,O-dimethyl hydroxylamine hydrochloride (3.5 g, 35.9 mmol) and triethylamine (15.0 mL, 108 mmol) was added a solution of 6-fluoropyridine-3-carbonyl chloride (5.70 g, 35.7 mmol, Intermediate 21, step a) in dichloromethane (200 mL) dropwise. The resulting mixture was stirred for 12 hours at room temperature, and 20 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×100 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography (silica gel column, 100:1 CHCl3/MeOH) to give the title compound as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:18][N:19]=[C:14]2[C@H:13]([NH:25]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:18][N:19]=[C:14]2[C@H:13]([NH2:25])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 1 h

Procedure:
Hydrochloric acid (4.0 M in dioxane; 2.0 mL, 8.0 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (100 mg, 0.224 mmol) in dioxane (1 mL). After 1 h, the reaction mixture was concentrated to give the hydrochloride salt of the title compound. MS 346.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([O:30][CH3:31])=[CH:21][C:22]([O:28][CH3:29])=[C:23]([N:25]=[C:26]=[O:27])[CH:24]=1>C(#N)C>[Cl:18][C:19]1[C:20]([O:30][CH3:31])=[CH:21][C:22]([O:28][CH3:29])=[C:23]([NH:25][C:26](=[O:27])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[CH:6][CH:7]=2)[CH:24]=1
Reactant: COc1cc(OC)c(N=C=O)cc1Cl
Reactant: Nc1ccc(NC(=O)c2ccccc2F)cc1
Solvent: CC#N
Product: COc1cc(OC)c(NC(=O)Nc2ccc(NC(=O)c3ccccc3F)cc2)cc1Cl
Reaction time: 12 h

Procedure:
A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) in acetonitrile (4 mL) is treated with 5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture becomes a solution and is allowed to stand for 12 hours. A white solid forms and is collected by filtration (0.79 g). [M+H] 444.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C.[Cl-].C([O:27][C:28](=O)[C:29](O)=[O:30])C>O1CCCC1>[N+:8]([C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[N:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:28](=[O:27])[C:29](=[O:30])[NH:1]2)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1NCCC(=O)O
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
At a bath temperature of +4° C., under argon and with exclusion of moisture, 211 mg (0.9 mmol) of 3-(2-amino-4-nitrophenylamino)propionic acid is combined with 200 mg (2 mmol) of triethylamine in 20 ml of dry tetrahydrofuran. A solution of 270 mg (2 mmol) of oxalic acid ethyl ester chloride and 5 ml of dry tetrahydrofuran is added dropwise to the batch, and the latter is stirred for 2 hours at room temperature. Furthermore, 0.05 ml of triethylamine and 0.05 ml of oxalic acid ethyl ester chloride are added to the mixture and the latter stirred for one hour at room temperature. The batch is filtered and the filtrate concentrated and distributed in water and ethyl acetate. The organic phase is concentrated. The residue is taken up in 15 ml of ethanol and 15 ml of 1N hydrochloric acid and refluxed for 2 hours at a bath temperature of 110° C. The batch is concentrated, taken up in a small amount of water, and suctioned off, yielding 120 mg of 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)propionic acid, mp: 148-156° C. with decomposition.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[F:10][CH:11]([F:27])[O:12][C:13]1[C:18]2[N:19]=[C:20]([CH2:22][CH3:23])[O:21][C:17]=2[C:16]([C:24]([OH:26])=O)=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH3:35][C:36]1[C:40]([NH2:41])=[CH:39][O:38][N:37]=1>ClCCl.C(OCC)C.CCCCCC>[CH3:35][C:36]1[C:40]([NH:41][C:24]([C:16]2[C:17]3[O:21][C:20]([CH2:22][CH3:23])=[N:19][C:18]=3[C:13]([O:12][CH:11]([F:10])[F:27])=[CH:14][CH:15]=2)=[O:26])=[CH:39][O:38][N:37]=1
Reactant: Cc1nocc1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3conc3C)c2o1
Reaction time: 2 h
Yield: 3.8 %

Procedure:
Cyanuric chloride (24 mg) was added to a suspension of 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (0.1 g) in dichloromethane (20 ml) at room temperature under an atmosphere of nitrogen. Triethylamine (0.07 ml) was added dropwise, followed by 3-methylisoxazol-4-ylamine (46 mg) in dichloromethane (5 ml). The reaction was left to stir for 2 hours before evaporation of the solvent in vacuo. Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane afforded, after trituration with diethyl ether-hexane, the title compound as a white solid (5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@H:17]3[N:8]([C:9](=O)[C@@H:10]4[C@H:15]([CH2:16]3)[N:14]([C:21]([NH:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[O:22])[CH2:13][CH2:12][CH2:11]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@H:17]3[N:8]([CH2:9][C@@H:10]4[C@H:15]([CH2:16]3)[N:14]([C:21]([NH:23][C@@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])=[O:22])[CH2:13][CH2:12][CH2:11]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN(C(=O)N[C@H](C)c4ccccc4)[C@H]3C[C@@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCN1C[C@H]3CCCN(C(=O)N[C@H](C)c4ccccc4)[C@H]3C[C@@H]21

Procedure:
A solution of 11.5-g of (8aS,12aS,13aS) 3-methoxy 12-[(R)-(+)-1-phenylethylamino]carbonyl-5,6,8a,9,10,11,12,12a,13,13a decahydroisoquino[2,1-g][1,6]naphthyridin-8-one, in 50 ml of tetrahydrofuran was added slowly to a solution of 2.0-g of lithium aluminum hydride in 75 ml of tetrahydrofuran. The resulting mixture was stirred at reflux for 2 hours, cooled, and treated sequentially with 2.5 ml of water, 2.5 ml of 15% sodium hydroxide, and 7.5 ml of water. The mixture was filtered and the filtrate was evaporated to afford 8.8-g of (8aR,12aS,13aS) 3-methoxy 12-[(R)-(+)-1 phenylethylamino]carbonyl-5,6,8a,9,10,11,12,12a,13,13a decahydro-8H-isoquino[2,1-g][1,6]naphthyridine, a compound of formula (I).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54](=[O:61])[N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:47][CH:46]=1>CN(C=O)C.O>[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:46]=[CH:47][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54]([N:55]2[CH2:56][CH2:57][N:58]([C:23](=[O:25])[C:22]3[CH:26]=[C:27]([F:31])[C:28]([Cl:30])=[CH:29][C:21]=3[Cl:20])[CH2:59][CH2:60]2)=[O:61])=[CH:49][CH:50]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1Cl
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)c(Cl)cc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
HOBt (23 mg, 0.17 mmol) and DIPEA (44.8 mg, 0.35 mmol) were added to a stirred solution of 2,4-dichloro-5-fluorobenzoic acid (29 mg, 0.14 mmol) in DMF (1 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (33 mg, 0.17 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (50 mg, 0.14 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered to afford 50 mg (70%) of N-biphenyl-4-yl-3-[4-(2,4-dichloro-5-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 514.11 (M+1)+ 100%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 7H), 7.44 (t, 2H), 7.34 (t, 1H), 7.14 (d, 1H), 3.96 (bs, 2H), 3.72 (m, 4H), 3.54 (d, 2H), 3.34 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[N:26]1[C:31]2[CH2:32][CH2:33][NH:34][CH2:35][C:30]=2[C:29](=[O:36])[NH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:34]3[CH2:33][CH2:32][C:31]4[N:26]=[CH:27][NH:28][C:29](=[O:36])[C:30]=4[CH2:35]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=c1[nH]cnc2c1CNCC2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCc4nc[nH]c(=O)c4C3)n2n1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 52 mg, 0.151 mmol), 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (78 mg, 0.395 mmol), and N,N-diisopropylethylamine (60 mg, 0.467 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was filtered and the crude material recrystallized from hot methanol, providing the titled compound as a white solid (26.9 mg, 39%). 1H NMR (DMSO-d6) δ: 8.13 (br. s., 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.45 (s, 1H), 6.18 (s, 1H), 5.18 (s, 1H), 4.49 (br. s., 2H), 4.10 (t, J=6.7 Hz, 2H), 2.87 (t, J=6.7 Hz, 2H), 2.40 (s, 3H), 1.45 (s, 6H); ESI-MS: m/z 460.2 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[CH:2]1.[O:6]1[C:10]2([CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1>>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:13]1([OH:16])[CH2:14][CH2:15][C:10]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:11][CH2:12]1
Reactant: c1nncs1
Reactant: O=C1CCC2(CC1)OCCO2
Product: OC1(c2nncs2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from [1,3,4]thiadiazole (3B Scientific) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[CH3:30][N:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.ClCCl>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:36][C:32]3[N:31]([CH3:30])[CH:35]=[CH:34][CH:33]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: Cn1cccc1C=O
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccn2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccn2C)c1

Procedure:
To a solution of hydroxyamine 55 (0.80 g, 2 mmol) in anhydrous ethyl alcohol (5 mL) and toluene (20 mL) was added 1-methyl-2-pyrrolecarboxaldehyde (66) (0.22 g, 2 mmol) and Na2SO4 (0.30 g). The resulting mixture was heated at reflux for 48 h. The mixture was diluted with dichloromethane (100 mL) and dried (MgSO4), and the solvent was removed with a rotary evaporator. The crude product was purified by flash chromatography with 9:1 ethyl acetate/methanol as the eluant to obtain 0.40 g (0.8 mmol, 40%) of 77 as a light yellow solid: mp 173°-175° C.; IR (CH2Cl2) 3440, 2940, 1695, 1622, 1575, 1470, 1300, 1212, 1100 cm-1 ; 1H NMR (CDCl3) δ 1.10 (d, J=6.2 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H), 2.26 (s, 6H), 3.31 (s, 3H), 3.55 (t, J=4.8 Hz, 2H), 3.71 (s, 3H), 4.11-4.20 (m, 2H), 4.94 (septet, J=6.2 Hz, 1H), 5.08 (s, 1H), 6.30-7.98 (m, 9H); 13C NMR (CDCl3) δ 19.17, 19.32, 22.01, 22.23, 34.34, 39.98, 58.79, 62.76, 67.04, 70.71, 102.63, 103.45, 109.56, 117.39, 118.95, 121.24, 124.21, 125.59, 128.01, 128.23, 129.62, 145.20, 146.02, 148.30, 149.91, 167.12, 167.60; mass spectrum, m/e (relative intensity) 495 (M+, 3.1), 481 (15.5), 296 (100), 254 (86.1), 184 (90.2), 108 (48.3); high resolution mass spectrum, m/e 495.2362 (calcd. for C27H33N3O6, 495.2369).
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+].OC(CC(=O)[O-])C[N+](C)(C)C>CC(O)=O.O.C(OCC)(=O)C>[OH:1][C@H:2]([CH2:8][C:9](=[O:10])[O-:11])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6]
Reactant: C[N+](C)(C)C[C@@H](O)CC(=O)[O-]
Agent: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Temperature: 4 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a mixture of (S)-carnitine inner salt (100 g; 0.62 moles) in glacial CH3COOH (100 g) 100% HNO3 is added (117.2 g; 1.86 moles) keeping the temperature at 10° C. and in the space of 1 hour and 5 minutes. Then, the temperature was lowered to 0-5° C. and acetic anhydride was added (76 g; 0.744 moles) in 2 hours and 10 minutes. After keeping the reaction mixture cool (3-5° C.) for further 3 hours from the end of addition, the reaction mass was left at 5° C. overnight. The following morning, temperature was left to rise up to 19° C. and ethyl acetate was added (835 ml) to precipitate nitriloxy-carnitine nitrate. After stirring the suspension for 30′, it was filtered washing with ethyl acetate (330 ml). The wet solid on the filter (164,6 g) was dissolved in water (760 ml) and NaHCO3 (94.53 g; 1.125 moles) was added to the solution. Temperature was kept at 80° C. for 9 hours, the solution was diluted with water (760 ml) and passed through IR 120 (H+) (1320 ml) with the purpose to block carnitine. After washing with water, to completely eliminate acidity, elution was made with 1N NH3 and the ammonia solution was concentrated and eliminated with an azeotrope with isobutyl alcohol, giving (R)-carnitine inner salt, having an enantiomeric excess higher than 98% (70.8 g; yield 70.2%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:10][CH2:11][CH2:12][CH3:13])[C:5](=[O:9])[O:6][CH2:7][CH3:8].S(Cl)([Cl:16])=O>C(Cl)Cl>[CH2:7]([O:6][C:5](=[O:9])[N:4]([CH2:3][CH2:2][Cl:16])[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCN(CCO)C(=O)OCC
Solvent: ClCCl
Product: CCCCN(CCCl)C(=O)OCC

Procedure:
52 g of ethyl (2-hydroxyethyl)-n-butylcarbamate are placed in 125 ml of methylene chloride and treated dropwise with 41.6 g of thionyl chloride during 45 minutes at 20°-25° C. Then the mixture is allowed to react for an additional 1 hour at room temperature. After removing the solvent, the residue is distilled to yield pure ethyl(2-chloroethyl)-n-butylcarbamate; b.p. 91° C./0.07 Torr.