Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:28][CH2:29][C@@H:30]([OH:36])[CH2:31][C:32](OC)=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O>[C:21]1([C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:28][CH2:29][C@@H:30]([OH:36])[CH2:31][C:32](=[O:33])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
125 mL of THF and 24 g of diisopropylamine were charged and cooled to −15° C. 168 mL of 1.2 N n-BuLi was added at −15 to −5° C. and was stirred for 30 minutes. 21.56 g of tert-butyl acetate in 45 mL of THF, which was pre-cooled to −45° C., was added maintaining the temperature between −45 to −25° C. for 60 minutes. The reaction mixture was cooled to −45° C. and 30 g of methyl 4 -triphenylmethyloxy-3(S)-hydroxybutyrate in THF was added over a period of 20 minutes and the stirring was continued at −25° C. for 90 minutes. Water was added and the layers were separated. The aqueous layer was extracted using EtOAc and the combined organic layers were washed with brine, water, dried and concentrated to give the title compound which was used as such for the next step.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl[CH2:14]Cl.[C:16](Cl)(Cl)=[O:17]>N1C=CC=CC=1>[C:6]([O:17][CH3:16])(=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:14])=[O:11])=[CH:10][CH:9]=1
Reactant: ClCCl
Reactant: O=C(Cl)Cl
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)OC)cc1
Yield: 100 %

Procedure:
Following the general procedure of Example 9, a slurry of 8.28 parts terephthalic acid in 80 parts dry dichloromethane was added to a stirred mixture of 8.72 parts pyridine and 10.84 parts phosgene in 210 parts dry dichloromethane at 24° to 30° C. The ratio of equivalents of pyridine base/COOH acid groups was 1.10. After carrying out the reaction and esterifying the resulting diacid chloride by the procedure described in Example 1, there was obtained a 100% yield of dimethyl terephthalate, corresponding to a 100% yield of terephthaloyl chloride, formed initially in the reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18](O)=[O:19])[CH:13]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:19])[CH:13]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)ccn1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
174 mg (1.27 mmol) 5-fluoro-2,3-dihydro-1H-indole were added to 200.0 mg (1.27 mmol) 4-chloropyridine-2-carboxylic acid, 351 μL (2.50 mmol) triethylamine and 434.0 mg (1.35 mmol) TBTU in 3 mL DMF. The reaction mixture was stirred overnight at RT. Purification was carried out by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30]Br>CN(C=O)C.CCOC(C)=O>[F:21][C:18]([F:19])([F:20])[CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:2]([C:3]2([C:4]([O:6][CH3:7])=[O:5])[CH2:30][CH2:29]2)=[O:1])=[CH:9][CH:10]=1
Reactant: BrCCBr
Reactant: COC(=O)CC(=O)c1ccc(OCCCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)c2ccc(OCCCC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
To a solution of Intermediate 14A (6.0 g, 19.7 mmol) in DMF (197 mL) was added K2CO3 (8.18 g, 59.2 mmol) followed by 1,2-dibromoethane (2.6 mL, 30 mmol). The reaction mixture was stirred at rt for 2 days. The reaction was reduced in volume in vacuo, then diluted with EtOAc, washed with a 1:1 solution of sat'd aq NaCl and water, dried over anhydrous MgSO4, filtered and concentrated. The product was isolated by silica gel chromatography (220 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 14B (4.2 g, 61%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.45-1.49 (m, 2H), 1.56-1.61 (m, 2H), 2.03-2.14 (m, 2H), 2.26-2.39 (m, 2H), 3.60 (s, 3H), 4.09 (t, J=6.05 Hz, 2H), 6.90-6.94 (m, 2H), 7.86-7.93 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:9][C:10]([C:12]1[CH:17]=CC(F)=C[CH:13]=1)=[O:11])[C:6](=[O:8])[CH3:7])[CH3:2].Cl[CH2:21]C(=O)C(C)(C)C>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6](=[O:8])[CH3:7])[CH2:9][C:10](=[O:11])[C:12]([CH3:13])([CH3:17])[CH3:21])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Reactant: CC(C)(C)C(=O)CCl
Product: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O

Procedure:
Prepared in analogy to that of 2-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester from 1-chloro-3,3-dimethyl-butan-2-one. The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=4.19 (q, 2H, J=7.2 Hz), 4.02 (m, 1H), 3.23 (dd, 1H, J=8.2 Hz, 18.4 Hz), 3.00 (dd, J=6.0 Hz, J=18.4 Hz), 2.37 (s, 3H), 1.8 (t, 3H, J=7.2 Hz), 1.17 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:35][C:36]([CH2:38]Cl)=[CH2:37]>CN(C=O)C.C(Cl)Cl>[Cl:35][C:36](=[CH2:37])[CH2:38][O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:16](=[O:25])[C:17]4=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]4[C:19]3=[O:20])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: C=C(Cl)CCl
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)c(=O)oc2c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C(Cl)COc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 25 °C

Procedure:
A slurry of 7-hydroxy-4,8-dimethyl-3-phthalimidomethylcoumarin (649 mg, 1.86 mmol), potassium carbonate (320 mg, 2.60 mmol), potassium iodide (15 mg, 0.093 mmol), and 2,3-dichloro-1-propene (0.20 mL, 2.23 mmol) in DMF (15 mL) was stirred at 55-65° C. for 8 hours, allowed to cool to room temperature, then chilled in an ice water bath. The solid was filtered off to obtain the first crop of crude product (1.09 g). Half of the solvent was removed from the filtrate and after chilling, a second crop of crystals was obtained (33 mg). The solids were combined, dissolved in CH2Cl2, and washed with water several times. The organic layer was dried and evaporated to give 7-(beta-chloroallyloxy)-4,8-dimethyl-3-phthalimidomethylcoumarin, a white solid (690 mg, 87%). 1H NMR (CDCl3): δ7.66-7.83 (m, 4H), 7.49 (d, J=9.1 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 5.56 (s, 1H), 5.47 (s, 1H), 4.91 (s, 2H), 4.67 (s, 2H), 2.59 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:43]=[CH:42][C:27]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:26][CH:25]=2)[N:14]=1.C(N(CC)CC)C>CN(C=O)C.[OH-].[OH-].[Pd+2].C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:43]=[CH:42][C:27]([CH2:28][N:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Yield: 66 %

Procedure:
tert-Butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I95) (190 mg, 0.312 mmol) was stirred vigorously with 10% Pd/C (100 mg) in DMF (10 mL) under an atmosphere of hydrogen. After two the reaction was transferred to a Parr tube with the aid of ethyl acetate (10 mL) and the mixture was hydrogenated at 45 psi. After 18 hours Pearlman's catalyst (100 mg) and triethylamine (0.2 mL) were added, and the mixture agitated under hydrogen at 40 psi. After three hours the mixture was diluted with ethyl acetate (50 mL) and filtered through celite, washing the celite with ethyl acetate (2×25 mL). The filtrate was diluted with ethyl acetate (100 mL) and washed with 5% lithium chloride solution (3×100 mL). The organic phase was dried over sodium sulfate and evaporated to give the title compound (I96) (127 mg, 66% yield) as a yellow syrup; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.63-7.56 (m, 2H), 7.46 (s, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.26-7.17 (m, 4H), 3.75 (s, 2H), 3.68 (s, 3H), 3.50 (s, 2H), 3.46-3.40 (m, 4H), 3.17-3.05 (m, 4H), 2.45-2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 5.63 min; m/z 614.2 [M+H]+; m/z 612.1 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.OC1C2N=NNC=2C=CC=1.CNC(N=C=NCC)CCNC.C(NC(C)C)(C)C>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NC(CCNC)NC
Agent: Oc1cccc2[nH]nnc12
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.98 g of para-nitrobenzoic acid in 50 mL of dichloromethane are successively added under argon, at 0° C., 0.781 mL of pyrrolidine, 0.13 g of hydroxybenzotriazole, 2.3 g of 1,3-dimethylaminopropyl-3-ethyl carbodiimide and 3.43 mL of diisopropylamine. The reaction mixture is then stirred at room temperature for 15 hours and then washed with water. The organic phase is then washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 1.9 g of (4-nitrophenyl)pyrrolidin-1-yl-methanone, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][C:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:23]3)=[N:18][N:17]2[CH:40]=1)=O)C>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:23][CH2:24][N:25]([C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]([F:36])([F:38])[F:37])[CH2:26][CH2:27]4)=[N:18][N:17]3[CH:40]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Reactant: Nc1ccc(F)cc1
Product: O=C(Nc1ccc(F)cc1)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 57 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to 4-fluoroaniline in place of isoamylamine to react with 6-[4-(2-trifluoromethyl-benzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 57% yield (0.065 g). m.p. 115-117° C. 1H NMR (300 MHz, CDCl3) δ 9.1 (s, 1H), 8.22 (s, 1H), 7.74-7.5 (m, 6H), 7.35-7.33 (m, 1H), 7.08-6.95 (m, 2H), 6.9 (d, J=7.6 Hz, 1H), 4.06-3.94 (m, 1H), 3.93-3.81 (m, 1H), 3.7-3.53 (m, 2H), 3.51-3.4 (m, 2H), 3.6-3.27 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 160.8, 160.2, 157.6, 154.9, 137.8, 135.7, 134.3, 134.2, 134.1, 134.0, 132.4, 129.5, 127.2, 126.9, 126.8, 126.7, 126.5, 125.4, 121.2, 121.1, 118.7, 115.8, 115.5, 112.2, 46.2, 46.1, 45.6, 41.2. MS (ES+) m/z 513.3 (M+1).
Reaction SMILES: [F:1]C1C=C(C=CC=1)C[Br:6].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:29]1([CH3:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Br-:6].[F:1][C:32]1[CH:33]=[CH:34][C:29]([CH2:35][P+:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:30][CH:31]=1
Reactant: Fc1cccc(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1
Product: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]

Procedure:
A solution of 3-fluorobenzyl bromide (4.73 g) in dry toluene (5.0 cm3) was added to a stirred suspension of triphenylphosphine (4.87 g) in dry toluene (5.0 cm3) and after 30 minutes the resultant precipitate was collected by filtration and washed with toluene to yield 4-fluorobenzyltriphenylphosphonium bromide (7.1 g) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:17][C:18]1[C:19]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(Cl)(Cl)[Cl:54]>O.CO>[ClH:54].[CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:31]2[CH2:32][CH2:33][N:28]([C:19]3[C:18]([CH3:17])=[CH:23][C:22]([C:24]([F:27])([F:25])[F:26])=[CH:21][N:20]=3)[CH2:29][CH2:30]2)=[O:14])=[CH:15][CH:16]=1
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: ClC(Cl)Cl
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (664 mg) described in Preparation Example 37, 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (736 mg) described in Preparation Example 51 and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.2 g) were added chloroform (5 mL) and methanol (5 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate). The obtained compound was dissolved in ethyl acetate (20 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was filtered to give the title compound (310 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][N:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(#N)C.C(N(CC)CC)C>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:24][C:25]3[CH:26]=[C:27]([CH:33]=[CH:34][N:35]=3)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccnc(CCl)c1
Reactant: COc1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(CN2CCC(OC(c3ccccc3)c3ccc(OC)cc3)CC2)c1
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 297 mg of a known compound (±)-4-[(4-methoxyphenyl)phenylmethoxy]piperidine, 240 mg of a known compound ethyl 2-chloromethylisonicotinate, 2.3 mL of acetonitrile, and 0.28 mL of triethylamine was stirred overnight. The mixture was poured into salt water and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over sodium sulfate. The solvent was distilled off, and then the residue was purified by p-TLC to give the title compound (309 mg (67%)).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13]>C(O)CO>[F:10][C:7]1[CH:6]=[C:3]2[C:4]([NH2:5])=[N:13][NH:12][C:2]2=[N:9][CH:8]=1
Reactant: NN
Reactant: N#Cc1cc(F)cnc1Cl
Solvent: OCCO
Solvent: O
Product: Nc1n[nH]c2ncc(F)cc12
Reaction time: 4 h

Procedure:
A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml, 2.459 mol) was then added. The mixture was heated under reflux with stirring for 4 h. The product precipitated on cooling. Water (380 ml) was added to the yellow crystals, and the mixture was subjected to extractive stirring at RT for 10 min. The suspension was then filtered with suction over a frit, and the filter product was washed with water (200 ml) and with −10° C. cold THF (200 ml). The residue was dried under high vacuum over phosphorus pentoxide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:21][CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:7]([CH:20]=1)[CH2:8][N:9]1[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:10]1)#N.[OH-:28].[Na+].C[OH:31]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:21][CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:7]([CH:20]=1)[CH2:8][N:9]1[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:10]1)([OH:31])=[O:28]
Reactant: CCC(CC)COc1ccc(C#N)cc1Cn1nc(CCC(=O)O)cc1C
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: CCC(CC)COc1ccc(C(=O)O)cc1Cn1nc(CCC(=O)O)cc1C
Temperature: 140 °C

Procedure:
The title compound was prepared from 1 3-{1-[5-Cyano-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid following the methods described in example 64, but replacing LiOH with NaOH and adding MeOH as co-solvent while heating in a microwave reactor at 140° C. in a microwave reactor for 30 min.
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[O:13][C:14]([C:17]2[C:18]([O:27][CH3:28])=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:39](C)=O.[Na+].C=O.O>ClC(Cl)C.C(Cl)Cl>[CH2:29]([N:1]([CH3:39])[C@H:2]([C:12]1[O:13][C:14]([C:17]2[C:18]([O:27][CH3:28])=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCC(=O)CCCCC[C@H](N)c1ncc(-c2cc3ccccc3nc2OC)o1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCC(=O)CCCCC[C@@H](c1ncc(-c2cc3ccccc3nc2OC)o1)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
(S)-9-amino-9-(5-(2-methoxyquinolin-3-yl)oxazol-2-yl)nonan-3-one (0.21 mmol, 1 eq), prepared as described above, was solubilized in dichloroethane (2.1 mL) and treated with benzaldehyde (0.17 mmol, 0.8 eq). The mixture was stirred 1 h at room temperature then treated with NaBH(AcO)3 (0.21 mmol, 1 eq). After stirring 30 min at room temperatures, a 37% solution of HCHO in water (3 eq) and NaBH(AcO)3 (0.21 mmol, 3 eq). After 10 minutes, the mixture was diluted with DCM and washed with water and brine. The organic phase was dried, filtered and concentrated. Residue was purified by flash chromatography using EtOAc/Petroleum Ether in a linear gradient from 4% to 40% of EtOAc. The product was obtained as a colorless oil in 53% yield. MS (ES) C30H35N3O3 requires: 485.62, found: 486. 1H-NMR (300 MHz, DMSO-d6) δ: 8.58 (1 H, s), 8.05 (1 H, d, J=5.4 Hz), 7.81 (1 H, d, J=6.3 Hz), 7.71 (2 H, m). 7.49 (1 H, t, J=5.4 Hz), 7.34-7.30 (4 H, m), 7.27-7.22 (1 H, m), 4.17 (3 H, s), 3.95 (1 H, t, J=5.7 Hz), 3.72 (1 H, d, J=10.2 Hz), 3.49 (1 H, d, J=10.2 Hz), 2.41-2.34 (2 H, m), 2.18 (3 H, s), 1.99-1.93 (2 H, m), 1.50-1.41 (4 H, m), 1.27-1.23 (4 H, m), 0.89 (3 H, t, J=5.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])C.[CH3:16]C(OC(O[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:11]1[CH:12]=[CH:13][C:16]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1.[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cc1
Product: Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 178.5 %

Procedure:
4-(Pyridin-4-yl)aniline (20) was prepared in three steps: To a mixture of 4-bromoaniline (950 mg, 5.6 mmol), triethylamine (678 mg, 6.7 mmol) and DMAP (73 mg, 0.56 mmol) in DCM (30 mL) was added Boc2O (1.22g, 5.6 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hr. After the reaction was quenched with 5% NaHCO3, the mixture was extracted with DCM (3×20 mL). The organic layer was combined and dried over anhydrous MgSO4. tert-Butyl 4-bromophenylcarbamate (1.36 g, 90%) was obtained after flash column chromatography (hexane:ethyl acetate, 4:1). Suzuki coupling reaction of tert-butyl 4-bromophenylcarbamate (800 mg, 2.95 mmol) with 4-pyridineboronic acid (300 mg, 2.46 mmol) in the presence of Pd(PPh3)4 (57 mg, 0.05 mmol) and K2CO3 (678 mg, 4.9 mmol) in dioxane- H2O (4:1, 10 mL) at 90° C. for 14 hr. tert-Butyl 4-(pyridin-4-yl)phenylcarbamate (600 mg, 75%) was obtained after flash column chromatography (DCM:MeOH, 20:1). Compound 20 (380 mg, 99%) was obtained after treatment of tert-butyl 4-(pyridin-4-yl)phenylcarbamate (600 mg, 2.2 mmol) with DCM:TFA (1:1, 1 mL) for 2 hr at room temperature followed by solvent removal. To a mixture of 4-(pyridin-4-yl)aniline 20 (380 mg, 2.24 mmol) and pyridine (3 mL) in DCM (3 mL) was added phenyl chloroformate (366 mg, 2.35 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 hr. After DCM and pyridine were removed under reduced pressure, the residue was purified by flash column chromatography (DCM:MeOH, 20:1). Compound 21 (400 mg) was obtained in 65% yield.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH:12]([OH:18])[C:13](=[NH:17])[O:14]CC)[CH3:3].[O:19]1CCC[CH2:20]1>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH:12]1[O:18][C:20](=[O:19])[NH:14][C:13]1=[O:17])[CH3:3]
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1c(F)cccc1OCC
Agent: Cl
Product: CCOc1cccc(F)c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 66, using a reaction time of 3 hours at room temperature, ethyl 1-(2-ethoxy-6-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (0.56 g., 2 mmoles) in 55 ml. of tetrahydrofuran was converted to crude product. Recrystallization from toluene afforded purified 5-(2-ethoxy-6-fluorophenyl)oxazolidine-2,4-dione. (147 mg., m.p. 127°-128° C.).