Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:13])[C@H:4]([CH3:12])[NH:5][C:6](=[O:11])[CH2:7][CH:8]1[CH2:10][CH2:9]1>CO.ClCCl>[CH:8]1([CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:13])=[O:2])[CH3:12])=[O:11])[CH2:10][CH2:9]1
Reactant: COC(=O)[C@H](C)NC(=O)CC1CC1
Solvent: ClCCl
Solvent: CO
Product: C[C@H](NC(=O)CC1CC1)C(=O)O

Procedure:
Following General Procedure II-A above using N-(cyclopropylacetyl)-L-alanine methyl ester (from Step A), the title compound was prepared as an oil. The reaction was monitored by tlc on silica get (Rf=0.27 in 10% methanol/dichloromethane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[O:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][C:35]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[O:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CCN(CC)C(=O)CS(=O)(=O)c1ccccc1Br
Product: CCN(CC)C(=O)CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)-N,N-diethylacetamide. MS (ESI): mass calcd. for C22H23FN4O3S, 442.52; m/z found, 443.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55 (d, J=1.4, 2H), 8.13 (dd, J=8.0, 1.3, 1H), 7.81-7.73 (m, 1H), 7.71-7.63 (m, 1H), 7.62-7.55 (m, 1H), 7.44 (dd, J=7.6, 1.3, 1H), 7.39 (dd, J=4.5, 1.7, 1H), 7.37 (dd, J=8.0, 1.3, 1H), 3.29-3.27 (m, 4H), 1.07 (t, J=7.2, 3H), 1.04 (t, J=7.2, 3H).
Reaction SMILES: Br[C:2]1[C:5](=[O:6])[C:4]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]=1[NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=2[Cl:33])=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15].O.Cl.[C:37](OCC)(=[O:39])[CH3:38]>C(N(CC)CC)C>[O:6]=[C:5]1[C:4]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:14]([O:16][CH2:38][CH2:37][OH:39])=[O:15])=[CH:2]1
Reactant: CCOC(C)=O
Reactant: O=C(Nc1ccc(C[C@H](NC2=C(Br)C(=O)C23CCCCC3)C(=O)O)cc1)c1c(Cl)cncc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(C[C@H](NC2=CC(=O)C23CCCCC3)C(=O)OCCO)cc1)c1c(Cl)cncc1Cl
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
Intermediate 2 (31.0 g) was introduced dropwise to a well-stirred solution of Intermediate 16 (50.0 g) in ethyl acetate (500 mL) and triethylamine (25 mL). The reaction temperature was kept below 25° C. throughout by external cooling. Acylation of the starting material was complete after a 1.5 hour stir-out. Water (150 mL) was charged at the end of this period, followed by sufficient 2M hydrochloric acid to lower the pH to 1-1.5. Following separation, the organic phase was washed with water (2×150 mL), 5% sodium carbonate solution (150 mL) and 10% brine (2×150 mL) then dried (MgSO4), filtered and evaporated in vacuo to afford the title compound as a yellow-brown foam (71.1 g, 95.6% yield). 1H NMR D6-DMSO: δ1.1-1.73 (10H, b,m); 2.98 (1H, dd); 3.20 (1H, dd); 3.64 (2H, m); 4.13 (2H, t); 4.24 (1H, m); 4.39 (1H, s); 4.87 (1H, t); 7.28 (2H, d); 7.59 (2H, d); 8.37 (1H, d); 8.81 (2H, s); 10.88 (1H, s) ppm. Mass Spectrum: ESI+ m/z 532/534
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].N#N.[CH3:13][CH2:14][OH:15].[Li][CH:17](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:10])=[C:2]([CH2:13][C@H:14]([OH:15])[CH3:17])[CH:7]=1
Reactant: CCO
Reactant: [Li]C(C)CC
Reactant: COc1ccc(C)c(I)c1
Agent: FB(F)F
Agent: N#N
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(C)c(C[C@@H](C)O)c1
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
A solution of 2-iodo-4-methoxy-1-methylbenzene (3.70 g, 14.9 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (11.3 mL, 15.8 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.35 mL, 19.4 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (3.14 mL, 22.5 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.50 in EtOAc/hexane 3:7) to give (2R)-1-(5-methoxy-2-methylphenyl)propan-2-ol (0.49 g, 18%) as pale oil. 1H NMR (300 MHz, CDCl3): δ 7.08 (d, J=8.31 Hz, 1H), 6.73 (m, 2H), 4.02 (m, 1H), 3.78 (s, 3H), 2.64-2.80 (m, 2H), 2.26 (s, 3H), 1.54 (d, J=3.39 Hz, 1H), 1.27 (d, J=6.03 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1C(C#N)=[N:6][C:5](CNC2C=CC(C(N[C@H](C(OC(C)(C)C)=O)CCC(OC(C)(C)C)=O)=O)=CC=2)=[CH:4][N:3]=1.[C:38]([OH:41])(=O)[CH3:39].[CH:42]([NH2:44])=[NH:43].C(OCCO)C.C(Cl)(Cl)Cl>CO>[NH2:43][C:42]1[NH:44][C:38](=[O:41])[C:39]2[C:2](=[N:3][CH:4]=[CH:5][N:6]=2)[N:1]=1
Reactant: N=CN
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc(N)c(C#N)n2)cc1)C(=O)OC(C)(C)C
Reactant: CC(=O)O
Solvent: CCOCCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc2nccnc2c(=O)[nH]1
Yield: 163.1 %

Procedure:
A mixture of the product described in the preceding paragraph (a) (2.55 g, 0.005 mol), formamidine acetate (Aldrich, 2.08 g, 0.02 mol), and 2-ethoxyethanol (30 mL) was refluxed for 45 min, the solvent was evaporated under reduced pressure, and the dark residue was partitioned between CHCl3 and H2O. The emulsion was allowed to settle, and the residue after evaporation of the CHCl3 layer was passed through a silica gel column (70 g, 3×35 cm), which was eluted first with 19:1 CHCl3 --MeOH to sequentially remove a brown impurity and yellow impurity, and then with 15:1 CHCl3 --MeOH to obtain the product. TLC homogeneous fractions (Rf 0.5, Analab silica gel plates, 9:1 CHCl3 --MeOH) were combined, care being taken to exclude a colored impurity immediately following the product, and the solvent was evaporated to obtain 2-desaminoaminopterin as a tan powder (1.33 g, 58% yield); mp 103°-110° C., with sintering at lower temp; IR (KBr) 3370, 2980, 2940, 1730 (ester C=O), 1635, 1610, 1565, 1555, 1515, 1455, 1420, 1395, 1370, 1325, 1310, 1265 cm-1; UV: λ max (95% EtOH) 248 nm (ε18,200), 289 (23,000), 338 (7,390); NMR (CDCl3 δ1.40, (s, γ-t-OBu, 1.47 (s, α-t-OBu), 2.32 (m, CH2CH2, 4.70 (m, CH2NH), 5.58 (m, α-CH), 6.60 (d, J=8 Hz, 3'- and 5'-H), 6.8-7.3 (m, 4--NH2 and CONH), 7.67 (d, J=8 Hz, 2'- and 4'-H), 8.73 (s, 2--H), 9.05 (s, 7--H). Anal. (C27H35N7O5.0.25H2O) Calcd: C, 59.82; H, 6.60; N, 18.09. Found: C, 59.74; H, 6.54; N, 17.90. Acidolysis of this di-tert-butyl ester product was carried out as follows to provide 2-desamino-aminopterin having the structural formula given above in which R1 and R2 are both hydrogen.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH:15]([C:17]([CH3:19])=O)=[CH2:16]>>[CH3:11][O:10][C:9]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:8]=1[C:17]([CH3:19])=[CH:15][CH:16]=[N:7]2
Reactant: C=CC(C)=O
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OC
Yield: 27 %

Procedure:
A Skraup reaction of 4,5 -dimethoxy-2-nitroaniline with methyl vinyl ketone gave a 27% yield of 5,6-dimethoxy-4-methyl-8-nitroquinoline. The yellow compound crystallized well from methanol; mp 126°-127.5°.
Reaction SMILES: [C:1]([C:3]1[O:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:8][C:9]1[S:10][C:11]([CH2:19][CH3:20])=[CH:12][C:13]=1[C:14](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:14]1[C:13]2[CH:12]=[C:11]([CH2:19][CH3:20])[S:10][C:9]=2[N:8]=[C:1]([C:3]2[O:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: N#Cc1ccno1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 5-cyanoisoxazole and 2-amino-5-ethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[CH:10]=[C:9]([OH:22])[CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[CH:10]=[C:9]([O:22][CH2:1][CH:3]2[CH2:4][O:5]2)[CH:8]=1
Reactant: O=c1c2ccccc2sc2cc(O)cc(O)c12
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2ccccc2sc2cc(OCC3CO3)cc(O)c12
Temperature: 57.5 °C
Yield: 18.6 %

Procedure:
Epichlorohydrin (0.24 mL, 3.05 mmol) was added dropwise to a mixture of 1,3-dihydroxy-9H-thioxanthen-9-one (137 mg, 0.61 mmol) and K2CO3 (169 mg, 1.22 mmol) in anhydrous acetone (15 mL) in a dry round-bottom flask, followed by stirring under reflux at a temperature of 55 to 60° C. for one day. Solid of the reaction mixture was filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: CH2Cl2) to give the title compound (34 mg, 18.6%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3′-chloroacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) was heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract was concentrated in vacuo and the desired product, as a 1:1 mixture of E- and Z-isomers, was isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether. The purified oil solidified on standing at room temperature
Reaction SMILES: NO.C([N:6](CC)C(C)C)(C)C.[Br:12][C:13]1[C:14]([NH:19][C:20]([NH:22]C(OCC)=O)=S)=[N:15][CH:16]=[CH:17][CH:18]=1>CO.C(O)C>[Br:12][C:13]1[C:14]2[N:15]([N:6]=[C:20]([NH2:22])[N:19]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ncccc1Br
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2c(Br)cccn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 mL, 505 mmol) were dissolved in methanol (200 mL) and ethanol (200 mL). N-(3-Bromo-pyridin-2-yl)-N′-ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 3 hours. The white precipitate was filtered off and triturated with water for 25 minutes, filtered and triturated two times with diethyl ether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:29]([O:28][C:27]([NH:26][CH:23]1[CH2:24][CH2:25][N:21]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:22]1)=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 95.4 %

Procedure:
A suspension of 49.5 g (0.175 mole) of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3-carboxylic acid, 37.3 g (0.2 mole) of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate, 40.4 g (0.4 mole) of triethylamine in 1.5 l of acetonitrile was refluxed for three hours. The precipitate was removed by filtration, washed with acetonitrile, then ethyl ether, and dried in vacuo to give 75.0 g of the title compound, mp 239°-240° C.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.O.C(N(CC)CC)C.Cl[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][C:26]=1[N+:35]([O-:37])=[O:36]>O1CCOCC1>[N+:35]([C:26]1[CH:27]=[C:28]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:29]=[CH:30][C:25]=1[NH:15][CH:12]1[CH2:13][CH2:14][N:9]([CH:6]2[CH2:5][CH2:4][O:3][CH2:8][CH2:7]2)[CH2:10][CH2:11]1)([O-:37])=[O:36]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(NC2CCN(C3CCOCC3)CC2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
A mixture of EXAMPLE 49B (22.12 g), water (43 mL), and triethylamine (43.6 mL) in 1,4-dioxane (300 mL) was stirred at room temperature until EXAMPLE 49B completely dissolved. The solution was then treated with 4-chloro-3-nitrobenzenesulfonamide (20.3 g), heated at 90° C. for 16 hours, cooled and concentrated. 10% Methanol in dichloromethane was added, and the solution was stirred vigorously at room temperature until a fine suspension existed and then the mixture was filtered.
Reaction SMILES: [OH-:1].[Li+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]3[CH2:22][CH:21]([C:23]([O:25]C)=[O:24])[NH:20][C:19]3=[O:27])=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.O1CCCC1>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([C:19]([OH:1])=[O:27])[CH2:22][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:20])=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1CC(Oc2ccc(CCCCc3ccccc3)cc2)C(=O)N1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc(CCCCc2ccccc2)cc1)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A mixture of lithium hydroxide (0.072 g) in water (0.9 ml) and tetrahydrofuran (2.9 ml) was treated with methyl 3-[4-(4-phenylbutyl)phenoxy]-2-pyrrolidone-5-carboxylate (0.370 g), and heated to 60° C. After about 4.0 hours, the reaction mixture was allowed to cool to room temperature. After approximately 2.25 hours at room temperature, the reaction mixture was treated with 5N HCl (604 ml). The resulting biphasic solution was cooled to 5° C. for approximately 18 hours. The biphasic solution was treated with water (2 ml). The resulting milky solution was sonicated resulting in crystal formation. The crystals were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (10 ml). The crystals were then dried overnight in at vacuum oven at 60° C. to afford the title compound (106 mg).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>C(O)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([N:13]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:15][CH:16]=1)(=[O:22])[CH3:21]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CC(=O)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 104.3 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g, 2.94 mmol) and 1-(4-aminophenyl)ethanone (1.19 g, 1.19 mmol) in ethanol (3 mL). 1-(4-acetylphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.307 g (42%) was obtained as a bright yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.Cl.[CH2:26]([NH:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][NH:34][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=2)[CH:5]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NNCc1ccccc1
Agent: Cl
Product: COc1ccc(C(=O)NNCc2ccccc2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and benzylhydrazine hydrochloride in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]1[C:13](Cl)=[O:14].Cl.[NH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([CH2:20][CH2:21][CH2:22][NH:23][C:13]([C:6]1[N:5]([CH2:4][CH2:3][CH:2]([CH3:16])[CH3:1])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)=[O:14])#[N:18]
Reactant: N#CCCCN
Reactant: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)NCCCC#N
Temperature: 50 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a mixture of the acid chloride 45 (0.6 g, 2.45 mmol) and 3-aminopropylcyanide hydrochloride (0.31 g, 2.57 mmol) in anhydrous toluene was added 1.5 ml of anhydrous pyridine. The reaction mixture was stirred at 50° C. overnight and then evaporated to dryness. The product was purified by chromatography using toluene-ethyl acetate (2:1) to yield white crystals (0.623 g, 87%). 1H NMR (DMSO-d6) δ8.46 (t, 1H), 8.17 (d, 1H), 7.39 (d, 1H), 4.37 (t, 2H), 3.27 (quintet, 2H), 2.53 (d, 2H), 1.77 (quintet, 2H), 1.60-1.42 (q and quintet, 3H), 0.87 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:79])[C:71]1[CH:76]=[CH:75][C:74]([NH2:77])=[CH:73][C:72]=1[F:78])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:79])[C:71]1[CH:76]=[CH:75][C:74]([NH:77][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[CH:73][C:72]=1[F:78])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich, 147 mg, 0.39 mmol) was added followed by the addition of DIPEA (0.225 mL, 1.29 mmol) and 4-amino-2-fluoro-benzoic acid t-butyl ester (Aldrich, 44 mg, 0.32 mmol). The mixture was stirred at rt for 5.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 0-15% EtOAc/hexanes) to give a white solid. 19 mg.
Reaction SMILES: FC1C=C(OC)C=C(F)C=1[C:11]1=[C:12]([CH:42]=[CH:43][C:44]2[C:52]([CH3:54])([CH3:53])[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([S:55]([O-:58])(=[O:57])=[O:56])[CH:50]=3)[N+:45]=2[CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH2:13][CH2:14][CH2:15]/[C:16]/1=[CH:17]\[CH:18]=[C:19]1\[N:20]([CH2:34][CH2:35][CH2:36][CH2:37][S:38]([O-:41])(=[O:40])=[O:39])[C:21]2[C:26]([C:27]\1([CH3:29])[CH3:28])=[CH:25][C:24]([S:30]([O-:33])(=[O:32])=[O:31])=[CH:23][CH:22]=2.[Na+:67].[Na+].[Na+].B([C:73]1[C:74]([F:87])=[C:75]([CH:83]=[CH:84][C:85]=1[F:86])[O:76][CH2:77][CH2:78][CH2:79][C:80]([OH:82])=[O:81])(O)O>>[C:80]([CH2:79][CH2:78][CH2:77][O:76][C:75]1[C:74]([F:87])=[C:73]([C:11]2=[C:16]([CH:17]=[CH:18][C:19]3[C:27]([CH3:29])([CH3:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([S:30]([O-:33])(=[O:31])=[O:32])[CH:25]=4)[N+:20]=3[CH2:34][CH2:35][CH2:36][CH2:37][S:38]([O-:41])(=[O:40])=[O:39])[CH2:15][CH2:14][CH2:13]/[C:12]/2=[CH:42]\[CH:43]=[C:44]2\[N:45]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[C:46]3[C:51]([C:52]\2([CH3:54])[CH3:53])=[CH:50][C:49]([S:55]([O-:58])(=[O:56])=[O:57])=[CH:48][CH:47]=3)[C:85]([F:86])=[CH:84][CH:83]=1)([OH:82])=[O:81].[Na+:67].[Na+:67].[Na+:67]
Reactant: O=C(O)CCCOc1ccc(F)c(B(O)O)c1F
Reactant: COc1cc(F)c(C2=C(C=CC3=[N+](CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC/C2=C\C=C2\N(CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c(F)c1
Agent: CC1(C)C(/C=C/C2=C(c3c(F)ccc(OCCCC(=O)O)c3F)/C(=C/C=C3/N(CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Agent: COc1cc(F)c(C2=C(/C=C/C3=[N+](CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC/C2=C\C=C2\N(CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c(F)c1
Agent: [Na+]
Product: CC1(C)C(C=CC2=C(c3c(F)ccc(OCCCC(=O)O)c3F)/C(=C/C=C3/N(CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 37 is prepared analogously to compound 17, except with 4-(3-borono-2,4-difluorophenoxy)butanoic acid as a starting material.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClCCl.[N:20]1([C:26]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:27]=2[NH2:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O>[N:20]1([C:26]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][C:27]=2[NH:28][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
Benzoyl chloride (50.0 μl, 0.430 mmol, commercially available product) and triethylamine (170 μl, 1.21 mmol) were sequentially added at 0° C. to a dichloromethane (3 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (102 mg, 0.417 mmol), obtained as described in Referential Example 1-2. The resulting mixture was warmed to room temperature and stirred for 18 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=10/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]benzamide (GIF-0344) (126 mg, 86.7%) was yielded as a colorless solid.