Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[N+:14]([O-])([OH:16])=[O:15].O.N>S(=O)(=O)(O)O>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])O
Reactant: COCc1cc2ccccc2cn1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: COCc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Methoxymethylisoquinoline (68.8 g) is dissolved in 95% sulphuric acid (density 1.83; 300 cc). The solution is cooled to 0° C. and a mixture of 70% nitric acid (density 1.42; 25 cc) and 95% sulphuric acid (density 1.83; 100 cc) is added dropwise in the course of 30 minutes so as not to exceed 10° C. Stirring is continued for 16 hours, whilst allowing the temperature to return to about 20° C. The mixture is then poured into a mixture of ice and water (2 liters), and an ammonia solution containing 20% of NH3 (density 0.9) is added, without exceeding 30° C., until a pH of about 10 is obtained. The resulting yellow solution is extracted with methylene chloride (4×400 cc). The organic extracts are combined, washed with water (2×50 cc), dried over magnesium sulphate and filtered, and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). 3-Methoxymethyl-5-nitroisoquinoline (78 g), m.p. 91° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1.[OH:26][C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:30]1[CH2:31][CH2:32][C:27]([OH:26])([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:28][CH2:29]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reactant: OC1(c2ccccc2)CCNCC1
Product: Cc1nc2ccc(N3CCC(O)(c4ccccc4)CC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 29 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 4-hydroxy-4-phenylpiperidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 29%; MS: m/z=491 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Yield: 85.3 %

Procedure:
To a mixture of methyl 5-bromo-2-hydroxybenzoate (150 g, 0.65 mol) in concentrated H2SO4 (320 mL) below 0° C. was added dropwise a mixture of concentrated HNO3 (69.2 g, 0.71 mol) and concentrated H2SO4 (97 mL) with stirring below 5° C. After the addition, the mixture was stirred at this temperature for 3 hr. The reaction mixture was poured into crash ice and the precipitate was collected, washed with cold water, hot ethanol and dried to give methyl 5-bromo-2-hydroxy-3-nitrobenzoate (153 g, yield 85%). 1H-NMR (400 MHz, CDCl3-d) δ 4.04 (s, 3H), 8.25 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 11.92 (s, 1H); LC-MS (ESI) m/z 278 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C:13]([CH2:23][NH:24]C(=O)C)([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:28](=[O:30])[NH:29][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:31])[O:4][N:3]=1.Cl>O1CCCC1.O>[NH2:24][CH2:23][C:13]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:12]2[C:28](=[O:30])[NH:29][C:10]3=[CH:9][CH:8]=[C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:31])[C:16](=[C:11]23)[O:15][CH2:14]1
Reactant: CC(=O)NCC1(c2ccccn2)COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3(CN)c1ccccn1
Temperature: 100 °C

Procedure:
N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl}acetamide (10 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL) and concentrated hydrochloric acid (200 μL, 6 mmol) in water (800 μL). The reaction was heated to 100° C. for 4 h and was then purified without workup by prep HPLC on a C-18 column eluting a water:acetonitrile gradient buffered at pH 2 with TFA to give 4-(aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as off white solid (0.0045 g, 40%). LCMS calculated for C20H20N5O3 (M+H)+: m/z=378.1. found: 378.1. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.68-8.58 (m, 1H), 8.20 (bs, 2H), 7.84 (td, J=7.8, 1.8 Hz, 1H), 7.48-7.37 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.73 (d, 1H), 4.41 (d, 1H), 4.12-3.97 (m, 1H), 3.75-3.58 (m, 1H), 2.18 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:23]([OH:25])=[O:24])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH:6]=2.C(=O)([O-])O.[Na+].[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>O1CCCC1.O>[C:31]([N:13]([CH2:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([OH:1])[C:3]([C:23]([OH:25])=[O:24])=[CH:4]2)=[CH:9][CH:8]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)(=[O:33])[CH3:32]
Reactant: CC(C)c1ccc(NCc2ccc3cc(O)c(C(=O)O)cc3c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccc2cc(O)c(C(=O)O)cc2c1)c1ccc(C(C)C)cc1
Yield: 79.5 %

Procedure:
3-Hydroxy-7-[(4-(2-propyl)phenylamino)methyl]naphthalene-2-carboxylic acid (25 mg, 0.07 mmol) (example 363) was suspended in tetrahydrofuran (200 μL). A solution of sodium hydrogencarbonate (23 mg, 0.27 mmol) in water (200 μL) was added followed by acetic anhydride (14 μL, 15 mg, 0.15 mmol). The reaction mixture was stirred vigorously for 65 hours at room temperature before 6 N hydrochloric acid (4 mL) was added. The precipitate was filtered off and rinsed with water (3×1 mL) to yield the title compound (21 mg). No further purification was necessary.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[S:31]([CH3:34])(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:27]4[CH:28]=[CH:29][C:30]([S:31]([CH3:34])(=[O:32])=[O:33])=[C:25]([F:24])[CH:26]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1F
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)c(F)c4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-4-(methanesulfonyl)phenylboronic acid acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.71 min; Mass spectrum (ESI+): m/z=477 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14]CC2C=CC=CC=2)[C@H:10]([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Yield: 85.9 %

Procedure:
A mixture of (+/−)-(cis)-tert-butyl-4-(benzylamino)-3-fluoropiperidine-1-carboxylate (100 mg, 0.32 mmol) and 10% Pd/C (10 mg) in methanol (20 mL) was stirred under a balloon of hydrogen for 2 h at room temperature. The reaction mixture was purged with argon, filtered over Celite, rinsed with methanol (10 mL) and the resulting filtrate was concentrated under vacuum to give the title compound as a colorless oil (60 mg, 85%). 1H-NMR (400 MHz, CDCl3) δ ppm: 4.49-4.61 (d, J=48.4 Hz, 1H), 4.30 (s, 1H), 4.07 (s, 1H), 2.84-3.08 (m, 3H), 1.67-1.69 (m, 2H), 1.47 (s, 9H), 1.32 (s, 2H). 19F-NMR (400 MHz in CDCl3): δ ppm: −205.75-206.03 (1F).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14]Br.Cl>CN(C)C=O.O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1
Reactant: COC(CBr)OC
Reactant: Oc1cccc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1cccc(Br)c1)OC
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a suspension of 60% sodium hydride. (60 g) in N,N-dimethylformamide (1.4 l) was added dropwise 3-bromophenol (260 g) under ice-cooling. After stirring for 10 minutes, to the solution was added dropwise bromoacetaldehyde dimethyl acetai (318 g) and the mixture was heated with stirring for 3 hours at 90° C. After cooling, water was added to the resulting solution and acidified with 1 M hydrochloric acid and then extracted with ether (3l). The organic layer was washed with successive water, saturated aqueous sodium bicarbonate solution and saturated aqueous NaCl solution. After drying over anhydrous sodium sulfate, ether was removed in vacuo and the residue was purified by silica gel column chromatography to give 363.3 g of the objective compound.
Reaction SMILES: S(=O)(=O)(O)O.COC(=O)[NH:9][CH2:10][C@H:11]([CH2:16][C:17](=[O:27])N[C@H](C1C=CC=CC=1)C)[CH2:12][CH:13]([CH3:15])[CH3:14].[OH-:29].[Na+]>>[CH3:15][CH:13]([CH2:12][C@H:11]([CH2:10][NH2:9])[CH2:16][C:17]([OH:27])=[O:29])[CH3:14]
Reactant: COC(=O)NC[C@H](CC(=O)N[C@@H](C)c1ccccc1)CC(C)C
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 117.5 °C
Yield: 50.4 %

Procedure:
A 0.2 l reactor was loaded with 70% sulfuric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120° C. for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25° C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 50 ml of isopropanol, the organic layer was separated, and NH4OH was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of isobutanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 50.4% yield. Purity: 99.05% area by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])=[CH:20][CH:19]=1.Cl>ClCCCl.O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:25]2([OH:32])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]([CH2:22][C:21]3[CH:34]=[CH:35][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:24]2=[O:33])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(O)(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (8.00 g, 58.3 mmol) in 1,2-dichloroethane (500 mL) and tetrahydrofuran (50 mL) was added isopropylmagnesium chloride (29.2 mL, 2.0 M solution in tetrahydrofuran, 58.4 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h. 1-(4-methoxybenzyl)-1H-indole-2,3-dione (15.0 g, 56.1 mmol) was added and the reaction mixture was stirred at reflux for 156 h. The mixture was cooled to 0° C. and 10% w/v hydrochloric acid was added. The phases were separated and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/1) to afford 2-fluoro-4-hydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (12.30 g, 54%): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J=9.0 Hz, 1H), 7.34-7.32 (m, 2H), 7.17-7.11 (m, 1H), 6.91-6.76 (m, 7H), 4.78 (ABq, 2H), 3.72 (s, 3H); MS (ES+) m/z 404.9 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][CH2:15][NH:16][CH3:17]>>[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][CH2:15][N:16]([CH3:17])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNCCCN(C)C
Product: CN(C)CCCN(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and 1-dimethylamino-3-methylamino-propane
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([NH:19][CH2:20][CH:21]([F:23])[F:22])=[CH:14][C:13]=2[N:24]2[CH2:28][CH2:27][C@@H:26]([F:29])[CH2:25]2)=[CH:6][CH:5]=1.[Cl:33][C:34]1[C:47]([N:48]=[C:49]=S)=[C:46]([Cl:51])[CH:45]=[CH:44][C:35]=1[CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].CC(C)N=C=NC(C)C>C1COCC1>[F:32][C:2]([F:31])([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:12]2[C:13]([N:24]3[CH2:28][CH2:27][C@@H:26]([F:29])[CH2:25]3)=[CH:14][C:15]3[N:19]([CH2:20][CH:21]([F:23])[F:22])[C:49]([NH:48][C:47]4[C:46]([Cl:51])=[CH:45][CH:44]=[C:35]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42])[C:34]=4[Cl:33])=[N:18][C:16]=3[CH:17]=2)=[O:30])=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: Nc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)c(N2CC[C@@H](F)C2)cc1NCC(F)F
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)Nc4ccc(OC(F)(F)F)cc4)c(N4CC[C@@H](F)C4)cc3n2CC(F)F)c1Cl

Procedure:
The title compound is prepared in analogy to 6c from (R)—N-(4-trifluoromethoxyphenyl)-2-[3-fluoro-pyrrolidinyl]-4-(2,2-difluoro-ethylamino)-5-amino-benzoic acid amide (94 mg, 0.20 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (64 mg, 0.20 mmol), DIC (62 μL, 0.40 mmol) and THF (10 mL).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl.Br[C:9]1[CH:14]=[CH:13][NH+:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(O)C>[N:12]1[CH:13]=[CH:14][C:9]([N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)=[CH:10][CH:11]=1
Reactant: Brc1cc[nH+]cc1
Reactant: OC1CCNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(c2ccncc2)C1
Temperature: 150 °C

Procedure:
A mixture of 3-hydroxypyrrolidine (9.9 g, 113.64 mmol), 4-bromopyridinium hydrochloride (22.098 g, 113.64 mmol), triethylamine (47.5 mL, 341.0 mmol) and 3:1 ethanol:water (150 mL), in a pressure tube reaction vessel, was purged with nitrogen and sealed. The mixture was heated to 150° C. for 96 hours and cooled. The solvent was evaporated and ethyl acetate (50 mL) was added. After trituration, the organic solvent was decanted off and saved. Methylene chloride (80 mL) and 2 N sodium hydroxide (60 mL) were added to the solid. The mixture was shaken vigorously and was filtered with water and methylene chloride wash to give the title compound as an off-white solid. The organic supernatant and the methylene chloride and water washes were combined. This mixture was extracted with methylene chloride. The organic layer was sodium sulfate dried and concentrated. The residue was triturated with methylene chloride and the solid was filtered. This solid was combined with the solid from above and vacuum dried (100° C. at 133 Pa for 14 hours) to give the title compound as an off-white solid (8.52 g, 46%).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:31][C@H:32]([CH2:36][CH3:37])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:31][C@H:32]([CH2:36][CH3:37])[C:33]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5]1)=[O:34]
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Reactant: CC[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.82 mmol) in CH2Cl2 (6 mL) was added triethylamine (227 μL, 1.63 mmol) followed by the addition of (R)-2-hydroxybutanoic acid (110 mg, 1.06 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one (280 mg, 88%). LC/MS: m/z 393.3 (M+H)+ at 2.17 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (m, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.89 (m, 2H), 7.57 (m, 1H), 7.40 (m, 1H), 6.96 (m, 2H), 4.92 (d, J=7.1 Hz, 1H), 3.88 (m, 8H), 1.67 (m, 1H), 1.51 (m, 1H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using 5-bromo-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 70.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.01 min, m/z=461.1 [M+H]+, m/z=459.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.94 (d, J=11.74 Hz, 2H) 3.37-3.45 (m, 2H) 3.85 (d, J=2.69 Hz, 2H) 5.04 (br. s, 2H) 7.35 (d, J=8.31 Hz, 2H) 7.51 (dd, J=7.09, 4.89 Hz, 1H) 7.81 (d, J=7.83 Hz, 1H) 7.86 (d, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.59 (dd, J=4.77, 1.59 Hz, 1H) 8.64 (d, J=1.96 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([CH2:41][NH2:42])[CH2:40][CH2:39]1>>[CH:38]1([CH2:41][NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NCC1CC1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and cyclopropylmethylamine according to conditions described in general procedure C. Mp: 117-119° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.10-0.30 (m, 4 H), 0.90 (bs, 1 H), 1.58-1.60 (m, 6H), 3.00 (bs, 2H), 3.27-3.28 (m, 4 H), 6.29 (bs, 1 H), 6.96 (d, 1 H), 7.15 (d, 1 H), 7.20 (s, 1 H), 7.38 (d, J=8.0 Hz, 1 H), 7.45 (s, 1 H), 7.54-7.58 (m, 3 H), 7.80 (d, 1 H), 7.96 (d, 1 H), 8.20 (s, 1 H), 10.41 (s, 1 H).
Reaction SMILES: [N+:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:3])=[O:2].[F:15]F>>[CH2:8]([O:7][C:5](=[O:6])[C:4]([F:15])([N+:1]([O-:3])=[O:2])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9]
Reactant: CCOC(=O)C(C(=O)OCC)[N+](=O)[O-]
Reactant: FF
Product: CCOC(=O)C(F)(C(=O)OCC)[N+](=O)[O-]
Yield: 76 %

Procedure:
An experiment was carried out as described in Example 2 using diethyl nitromalonate instead of diethyl malonate. Thus, 4.1 gm. (20 mmol.) diethylnitromalonate was treated with fluorine to give diethylfluoronitromalonate {δH 1.40 (6H, t, JHH 7.11, CH3), 4.47 (4H, q, JHH 7.12, CH2); δF 127.3 δC 13.7 (s, CH3), 65.2 (s, CH2), 106.3 (d, 1JCF 261.7, CF), 157.9 (d. 2JCF 25.2, CO).} in 76% yield. The conversion was 97%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:26][C:25]=1[CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:25]2[N:26]=[C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)Oc1ccccc1

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester, shown below, were reacted, as described in Example 1, Step D, to provide 2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester, shown below, as a colorless oil (30%). 1H NMR (300 MHz, CDCl3): δ 7.59 (d, 1H), 7.37 (d, 1H), 7.24 (t, 2H), 7.13 (d, 2H), 7.09 (t, 1H), 6.96 (t, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 4.21 (t, 2H), 4.19 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 2.95 (t, 2H), 2.35 (s, 3H), 1.39 (s, 3H), 1.21 (t, 3H). MS [EI+] 492 (M+H)+, [EI−] 490 (M−H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18].C(N(C(C)C)C(C)C)C.[CH3:28][O:29][CH2:30]Cl>COCCOC>[CH3:28][O:29][CH2:30][O:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18]
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CC(O)C1=O
Reactant: COCCl
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COCOC1CC(c2ccccc2)([N+](=O)[O-])CN(C)C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 50 mg (0.2 mmol) rac-3-hydroxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one and 52 ul (0.3 mmol) N-ethyl diisopropylamine in 1,2-dimethoxyethane were added 23 ul (0.3 mmol) chloromethyl methyl ether at room temperature. After 1 hour, the solution was heated in a 60° C. oil bath for 20 hours. The mixture was cooled to room temperature. 52 ul (0.3 mmol) N-ethyl diisopropylamine and 23 ul (0.3 mmol) chloromethyl methyl ether were added. The mixture was heated in a 60° C. oil bath for 4 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed once with water. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 30 mg (51%) of the title compound as a yellow oil. MS (m/e): 295.2 (MH+).