Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:32])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:32])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Cc1ncc2c(N)cccc2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 135 mg (0.46 mmol) of (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal, 100 mg (0.63 mmol) of 5-amino-2-methylquinazoline and 0.23 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 260 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 5 ml (5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 56 mg of product.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C@H:7]([C:20]1[CH:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:8]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]([CH3:42])([CH3:41])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>CS(C)=O>[C:1]([Si:5]([CH3:27])([CH3:28])[O:6][C@H:7]([C:20]1[CH:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:8][NH:29][C:30]([CH3:42])([CH3:41])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Solvent: CS(C)=O
Product: CC(C)(Cc1ccc([N+](=O)[O-])cc1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Yield: 63.5 %

Procedure:
A solution of (R)-toluene-4-sulfonic acid 2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl ester (12.0 g) and 11.4 g of 2-amino-2-methyl-1-(4-nitrophenyl)propane (prepared by the method described in J. Milecki, et al. J. Med. Chem., 30, 1563 (1987)) in DMSO (30 mL) was stirred at 100° C. for 48 h. The reaction solution was partitioned between ethyl ether/water, the resulting organic layer washed with water (3×), brine, dried over sodium sulfate and concentrated in vacuo to afford an oil. Flash chromatography on silica gel (20% to 50% ethyl acetate/hexanes) afforded 8.0 g of the title compound (I-2f) as a golden oil.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[CH:13]([N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])=[CH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:20]=[C:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH:13]([C:11]1[NH:10][N:9]=[N:8][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])[CH3:14]
Reactant: Cc1ccccc1-c1c[nH]nn1
Reactant: C=CN1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1nn[nH]c1C(C)N1CCCC1=O
Temperature: 25 °C

Procedure:
A mixture of tolyltriazole (26.6 g; 0.2 moles), 1-vinyl-2-pyrrolidinone (22.2 g; 0.2 moles) and para toluene sulphonic acid (0.14 g) is heated in toluene (200 ml), under reflux, for 7 hours. The mixture is then cooled to ambient temperature and washed with 5% sodium bicarbonate solution (50 ml), water (2×50 ml) and finally, dried over anhydrous magnesium sulphate. The dried extract is filtered and then evaporated to yield a yellow oil. Short-path distillation of the crude product yields a pale yellow viscous oil (34.9 g; 71%), bp 175°/0.05 mbar.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](O)=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[CH3:22][NH:23][C:24]1[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C>COCCOC>[CH2:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:19]3[N:23]([CH3:22])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N:30]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: CNc1ccccc1N
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nc4ccccc4n3C)n2)CC1
Temperature: 150 °C
Yield: 62.1 %

Procedure:
A mixture of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (100 mg, 0.3171 mmol), N-methylbenzene-1,2-diamine (42.61 mg, 39.64 μL, 0.3488 mmol), diethoxyphosphorylformonitrile (56.89 mg, 51.72 μL, 0.3488 mmol) and triethylamine (64.17 mg, 88.39 μL, 0.6342 mmol) in DME (3.000 mL) was heated in the microwave at 150° C. for 20 mins. The reaction mixture was allowed to cool and concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (79 mg, 60% Yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Fc1ccc(-c2noc(-c3cccc(Br)c3)n2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1ccc(-c2noc(-c3cccc(-c4cccnc4)c3)n2)nc1
Yield: 50.2 %

Procedure:
A mixture of 3-(5-fluoro-pyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (100 mg, 0.313 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (102 mg, 0.624 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 50.8 mg, 0.044 mmol), in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a sealed vial at 110° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 50 mg (50.2%) 3-(5-fluoro-pyrid-2-yl)-5-[3-(3-pyridyl)phenyl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.91 (d, 1H), 8.69 (d, 1H), 8.64 (d, 1H), 8.49 (s, 1H), 8.28 (m, 2H), 8.00 (m, 1H), 7.84 (dd, 1H), 7.69 (t, 1H), 7.60 (td, 1H), 7.44(dd, 1H).
Reaction SMILES: [CH2:1]([C:6]1[O:10][CH:9]=[N:8][C:7]=1[C:11]([O:13]C)=[O:12])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].CO>O>[CH2:1]([C:6]1[O:10][CH:9]=[N:8][C:7]=1[C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ocnc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCc1ocnc1C(=O)O
Yield: 79.9 %

Procedure:
40 g of 5-n-pentyl-4-methoxycarbonyloxazole, 27 g of potassium hydroxide, 1000 ml of methanol and 50 ml of water are treated in the same manner as described in Preparation 1-(2). 29.7 g of 5-n-pentyl-4-oxazolecarboxylic acid are thereby obtained. Yield: 80%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:15]([NH:17][C@@H:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C:20](=[O:23])[O:21][CH3:22])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]#[N:14]>C(O)=O>[NH2:1][C@@H:2]([C:15]([NH:17][C@@H:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C:20](=[O:23])[O:21][CH3:22])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]#[N:14]
Reactant: COC(=O)C[C@@H](NC(=O)[C@@H](Cc1c(C#N)[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=CO
Product: COC(=O)C[C@@H](NC(=O)[C@H](N)Cc1c(C#N)[nH]c2ccccc12)C(=O)OC(C)(C)C
Yield: 84.4 %

Procedure:
A solution of Boc-DTrp(2-CN)-DAsp(OMe)-OtBu (78 mg, prepared in Example (9-a)) in formic acid (3 mL) was stirred at room temperature for 1 h and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), and the solution was washed with sat. aq. NaHCO3 (20 mL×2), dried over MgSO4 and evaporated under reduced pressure to give the product (53 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][NH:8][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2n[nH]c(=O)c3cc(Cl)ccc23)cc1
Product: COc1ccc(-c2nnc(Cl)c3cc(Cl)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-chloro-4-(4-methoxyphenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[N:14]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 22.7 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (1.6 g, 8.64 mmol) (Example 113, Step B) in 25 mL of DMSO was added, 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (2.6 g, 13 mmol), and K2CO3 (3.6 g, 26 mmol). The mixture was heated to 130° C. for 24 h. The mixture was then poured into 400 mL of H2O and extracted with EtOAc. The product was isolated by flash chromatography to give the title compound of step A (0.7 g, 1.96 mmol, 22%). 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 6.66 (d, J=4.58 Hz, 1H), 3.87 (s, 3H), 3.40-3.52 (m, 4H), 3.33 (d, J=9.34 Hz, 2H), 3.24 (d, J=4.58 Hz, 2H), 2.19 (s, 3H), 1.80-1.90 (m, 2H), 1.36 (s, 5H), 1.30 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([NH:39][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:29])([F:30])[F:31])[C:9]=3[CH:17]=2)[CH:19]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCc1ccccc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=536.96 (M+H+); retention time=0.92 minutes.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH2:18][N:19]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:48](Cl)(=[O:50])[CH3:49]>ClCCl>[C:48]([N:38]1[CH2:39][CH2:40][CH:35]([CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[CH:16][CH:15]=2)[CH2:18][N:19]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:36][CH2:37]1)(=[O:50])[CH3:49]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(=O)N(CCc1ccccc1)CC(c1ccc(-c2cccc3ccccc23)cc1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(CCc1ccccc1)CC(c1ccc(-c2cccc3ccccc23)cc1)C1CCN(C(C)=O)CC1
Reaction time: 1 h

Procedure:
A room temperature solution of Example 47A (50.0 mg, 0.094 mmol) in dichloromethane (2 mL) was treated with triethylamine (26.2 μL, 0.19 mmol) and acetyl chloride (10.0 μL, 0.14 mmol), stirred for 1 hour, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: Cl[CH:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:15][C:16]1[C:17]([F:56])=[C:18]([C@@H:22]2[C@:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:25]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:24][C@H:23]2[C:42]([NH:44][C:45]2[CH:53]=[CH:52][C:48]([C:49]([OH:51])=[O:50])=[CH:47][C:46]=2[O:54][CH3:55])=[O:43])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C@@:26]2([C:27]#[N:28])[C@H:25]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:24][C@@H:23]([C:42]([NH:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([O:51][CH:2]([O:4][C:5]([N:7]4[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9][CH2:8]4)=[O:6])[CH3:3])=[O:50])=[CH:47][C:46]=3[O:54][CH3:55])=[O:43])[C@@H:22]2[C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[C:17]=2[F:56])=[C:30]([F:36])[CH:31]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(Cl)OC(=O)N1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(=O)N2CCS(=O)(=O)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 87.4 %

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood, 1.32 g, 1 mL, 9.27 mmol) was reacted with thiomorpholine 1,1-dioxide (1.1638 g, 8.61 mmol) and pyridine (783 mg, 801 μl, 9.9 mmol) in methylene chloride (15 mL) at room temperature for 3 h to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester. A portion of 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester (577 mg, 1.614 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.5 mg, 0.244 mmol) in the presence of cesium carbonate (598.4 mg, 1.84 mmol) in dimethylformamide (7 mL) overnight to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoyloxy)-ethyl ester as an off-white solid (175.3 mg, 87% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O8S: [(M+H)+]: 821, found: 821
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>[OH-].[Na+].O1CCOCC1>[CH2:20]([O:19][C:17]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
L-Pyroglutamic acid (2.02 g, 13.83 mmol) was dissolved in 1 N NaOH (13.84 mL) and the solution was cooled to 0° C. After 30 min stirring, Na2CO3 (3.63 g) and benzyl chloroformate (4.82 mL) in dioxane (21.23 mL) were gradually added in equal portions. Stirring was continued at 0° C. for 1 h, then the solution was stirred overnight at room temperature and extracted with ethyl ether (2×20 mL). The aqueous solution was acidified with 2N HCl to pH 5 and extracted with ethyl acetate (3×50 mL). The ethyl acetate layer was dried over sodium sulfate and evaporated to give an oil, which crystallized overnight. Recrystallization of the crude product gave white crystalline material (2.86 g, 87%): FABMS 240.1 (M+H): HRFABMS Calcd for C13H14NO5 (M+H) 264.0872, Found 264.0866; Calcd for C13H13NaNO5 (M+Na) 286.0691, Found 286.0694.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([NH2:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=1>CC#N>[N:1]1([C:8]2[N:13]=[C:12]([NH2:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC#N
Product: Nc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Morpholine (4 eq) was added to a suspension of 6-chloro-3-nitropyridin-2-amine (1 eq) in CH3CN, and the reaction mixture was stirred at 70° C. for 5 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with ether to afford the desired compound as a bright yellow powder. LC/MS m/z 225.0 (MH+), Rt 1.79 minutes.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12>CN(C)C=O>[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH:68][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
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: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 46.6 %

Procedure:
DIEA (0.035 mL, 0.20 mmol) was added to 8-(trifluoromethoxy)-3-carboxy-coumarin (0.050 g, 0.18 mmol) and HATU (0.076 g, 0.20 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-imidazo[1,2-a]pyridin-2-yl-phenylamine (0.038 g, 0.18 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.039 g of 1541B in a 46% yield: LCMS (ESI) m/z 466 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH2:15]O)[CH:3]=1.O=S(Cl)[Cl:19]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH2:15][Cl:19])[CH:3]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(Br)cc1CCl
Yield: 75.1 %

Procedure:
To ethyl [4-bromo-2-(hydroxymethyl)phenoxy]acetate (Example 7, 5.00 g, 17.4 mmol) in 150 mL CH2Cl2 under Ar, was added SOCl2 (4.13 g, 34.7 mmol) dropwise with stirring. The mixture was then heated to reflux for 4 hours, cooled, and the volatiles were removed under reduced pressure. The crude oil was then subjected to flash chromatography (15% EtOAc/hexanes) to provide 4.02 g (76%) of the desired product as a clear oil. 1H-NMR (acetone-d6, δ): 1.25 (t, 3H), 3.50 (ddd, 2H), 4.22 (q, 2H), 5.37 (dd, 1H), 6.77 (d, 1H), 7.29 (m, 1H), 7.37 (m, 1H); LRMS (GC/MS/EI) 270 [M]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1>[C:21]([NH:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 7-amino-1-phenyl-5-trifluoromethylbenzimidazole (300 mg, 1 mmol), benzoylchloride (0.23 ml, 2 mmol) and triethyl amine (0.3 ml, 2 mmol) in tetrahydrofurane (10 ml) was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and hydro chloric acid (4M). The aqueous phase was rendered alkaline with saturated, aqueous sodium carbonate and extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure and the resultant gum was triturated with a mixture of diethyl ether and petroleum ether to leave the solid, off-white product (145 mg, 38%), m/z, 382.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[Br:14][C:15]1[CH:16]=[C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[C:19]([Br:21])[CH:20]=1>C(N(CC)CC)C>[Br:21][C:19]1[CH:18]=[C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:24][CH2:23]2)[CH:16]=[C:15]([Br:14])[CH:20]=1
Reactant: Brc1cc(Br)cc(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3cc(Br)cc(Br)c3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with (3,5-dibromophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(3,5-dibromophenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[CH:1]1([NH:7][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(C(=O)O)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: NC1CCCCC1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 20, Step B, but using cyclohexylamine (0.020 mL, 0.12 mmol), 4,5-di-(4-chlorophenyl)-1-methylimidazole-2-carboxylic acid (20 mg, 0.060 mmol) from Example 20, Step A was converted to the title compound. HPLC/MS: 428 (M+1), 430 (M+3); Rt=4.53 min.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:17])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
4′-Trifluoromethyl-biphenyl-carboxylic acid (5.0 g) was dissolved in dimethylformamide (50 mL), and to this solution were added at room temperature 4-amino-1-benzylpiperidine (3.55 g), 1-hydroxybenzotriazole hydrate (3.0 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (3.58 g). The mixture was stirred at room temperature overnight, and the reaction solution was concentrated in vacuo to precipitate crystals. The crystals were washed successively with saturated aqueous sodium bicarbonate and water, and dried in vacuo to give the title compound (7.42 g).