Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[NH2:23])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:15]1[C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:30]1=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C[C@H](CCc1ccccc1)Nc1cc(C)ccc1N
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C[C@H](CCc1ccccc1)n1c(=O)[nH]c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of (S)-3-(2-Amino-5-methyl-phenylamino)-5-phenyl-pentanoic acid ethyl ester (0.84 g, 2.6 mmol) in THF (15 mL) was added CDI (0.50 g, 3.1 mmol). The reaction mixture was stirred at room temperature for 16 h. When the reaction was complete, the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 0.75 g of the desired product as a dark brown solid. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: [CH3:1]COC(C1N(C(OC(C)(C)C)=O)C2=NC=C(OC(=O)C3C=CC=CC=3)C=C2C=1)=O.[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@H:52]([O:54][CH3:55])[CH3:53])=[C:44](Br)[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@H:52]([O:54][CH3:55])[CH3:53])=[C:44]([CH3:1])[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Reactant: CO[C@H](C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Product: CO[C@H](C)c1nc2c(cc1C)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 14, intermediate c) from (4R,9aR)-7-bromo-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 47, intermediate).
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].[CH2:5]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1)=[O:9])[CH3:6]>>[CH2:5]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:3]([CH2:1][CH3:2])[CH3:4])[N:11]=1)=[O:9])[CH3:6]
Reactant: CCNC(=O)c1cccc(Br)n1
Reactant: CCNC
Product: CCNC(=O)c1cccc(N(C)CC)n1

Procedure:
prepared by reaction of ethyl-methyl-amine with 6-bromo-pyridine-2-carboxylic acid ethylamide
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:18])[CH2:14][C:15](=O)[CH3:16])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH3:30]>O1CCCC1>[CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:18])/[CH:14]=[C:15](\[NH2:30])/[CH3:16])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)CC(=O)N1CCN(C2CCCCC2)CC1
Reactant: N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: C/C(N)=C/C(=O)N1CCN(C2CCCCC2)CC1
Reaction time: 8 h

Procedure:
0.1 mol of crude 3-oxo-butyric acid 4-cyclohexylpiperazide is dissolved in 150 ml of tetrahydrofuran and, under reflux, after addition of 0.5 g of p-toluenesulphonic acid, ammonia is passed in for 4 hours. The mixture is allowed to stand at room temperature overnight, the solvent is removed by distillation in vacuo, and the residue is crystallized from toluene/petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 93.3 %

Procedure:
To a solution of 4-fluoro-2-nitrobenzoic acid (1 g, 5.4 mmol), N,O-dimethylhydroxylamine hydrochloride (0.58 g, 5.95 mmol) and N-methylmorpholine (0.65 mL, 5.91 mmol) in dichloromethane (20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.14 g, 5.95 mmol). The mixture was stirred for 80 minutes at room temperature. The mixture was concentrated under reduced pressure and then diluted with EtOAc and water. The organic layer was washed with 3 N HCl, saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fluoro-2-nitro-benzamide (1.15 g, 95%).
Reaction SMILES: [CH3:1][P:2]([CH2:12][C:13]([OH:15])=[O:14])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[N+](=[CH2:18])=[N-].C(OCC)(=O)C>CCOCC>[CH3:1][P:2]([CH2:12][C:13]([O:15][CH3:18])=[O:14])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: CP(=O)(CC(=O)O)OCc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)CP(C)(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of [methyl(phenylmethoxy)phosphinyl]acetic acid in ethyl acetate-ether is treated with an excess of diazomethane in ether and stirred for three hours. The excess diazomethane is destroyed by the addition of acetic acid. The solution is washed with sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give an 87% yield of [methyl(phenylmethoxy)phosphinyl]acetic acid, methyl ester as a clear oil (TLC Rf =0.18 (ethyl acetate)).
Reaction SMILES: C1COCC1.[C:6]1([C@H:12]2[CH2:16][O:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[O:20][CH2:21][C:22](OCC)=[O:23])=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[BH4-].O>C(OCC)C>[C:6]1([C@H:12]2[CH2:16][O:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[O:20][CH2:21][CH2:22][OH:23])=[N:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCCOc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Reaction time: 4 h
Yield: 39.4 %

Procedure:
To a THF (40 ml) solution of ethyl 3-(4,5-dihydro-4(S)-phenyloxazol-2-yl)phenoxyacetate (2.77 g, 8.5 mmol) was added LiBH4 (0.37 g, 17 mmol) in one portion. After stirring for 4 h, water (40 ml) was added and the mixture diluted with diethyl ether (40 ml). The aqueous layer was separated and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with 0.5 N aqueous HCl (20 ml), brine (20 ml), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (=2:1) to afford title compound (0.95 g, 40%) as a colorless liquid.
Reaction SMILES: [N:1]#[N:2].C([O:5][C:6](=[O:42])[CH2:7][N:8]([C:14](=[O:41])[C@H:15]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39])[NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[CH2:9][CH:10]([O:12][CH3:13])[CH3:11])C>CO.[OH-].[Na+]>[N:1]#[N:2].[CH3:31][O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:32][CH3:33])[CH:21]=[C:20]([S:17]([NH:16][C@H:15]([C:14]([N:8]([CH2:9][CH:10]([O:12][CH3:13])[CH3:11])[CH2:7][C:6]([OH:42])=[O:5])=[O:41])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:40])(=[O:18])=[O:19])[CH:29]=[CH:28]2
Reactant: CCOC(=O)CN(CC(C)OC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)O)CC(C)OC)cc2cc1OC
Reaction time: 10 h
Yield: 82 %

Procedure:
A solution of 2.3 g of N2 -(6, 7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxypropyl)glycine ethyl ester in 15 ml of methanol and 5 ml of 2N sodium hydroxide solution was warmed at 40° C and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH4OH (10:9:1). The main fraction was evaporated to dryness and washed with ether to give 1.8 g of N2 -(6, 7-dimethoxy-2-naphthylsulfonyl)L-arginyl-N-(2-methoxypropyl)glycine as an amorphous solid.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH:11](OCC)=[O:12].Cl>CO.C(Cl)Cl.O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH:11]=[O:12]
Reactant: CCOC=O
Reactant: Nc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=CNc1ccccn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of sodium methoxide (176 mL, 25 wt %, 0.81 mol) in 500 mL of methanol was added 2-aminopyridine (30.0 g, 0.32 mol) and the resulting solution was stirred at 40° C. for 30 minutes. Ethyl formate (220 mL, 2.76 mol) was then added dropwise and the reaction mixture was stirred overnight at 40° C. After cooling to room temperature, 250 mL of H2O and 250 mL of CH2Cl2 were added and conc. HCl (˜40 mL) was added dropwise until pH ˜5. Most of the methanol was evaporated and the resulting mixture was extracted with 3×150 mL of CH2Cl2. The combined organic portions were washed with 250 mL of H2O and 150 mL of brine and dried over Na2SO4. After evaporation of the solvent, 20.2 g of crude solid was obtained and distilled on a Kugelrohr at an oven temperature of 140° C. to yield 18.98 g of a white solid as the product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH2:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH2:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[CH2:25]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1
Temperature: 40 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Triphenylphosphine (2.9 g, 11.0 mmol) was added portionwise to a solution of 5-(S)-azidomethyl-3-[4′-aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one (2.8 g, 10.0 mmol) in THF (75 ml) under nitrogen atmosphere. The solution was stirred at 40° C. for 2 h, water (2.0 ml) added, and the reaction mixture was stirred at 40° C. overnight. Solvent was removed under vacuum, and the resulting solid was triturated with ether. Precipitated material was filtered, washed with ether and ethanol and dried under vacuum to afford the product as white crystals (1.7 g, 69%). HPLC Rt=5.0 min. MS (m/z): [M+H]+=254.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([NH2:13])=[S:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[C:2]1([C:1]2[N:9]=[N:10][C:11](=[S:12])[N:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)NNC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=C1N=NC(c2ccccc2)=N1

Procedure:
The starting material 2-bromo-5-nitrothiazole was prepared by treating 2-amino-5-nitrothiazole (Aldrich) with sodium nitrite and hydrogen bromide (Fr. Demande 2,015,434, 1970). 3-Phenyl-1,2,4-triazole-5-thione (E. Hogarth, J. Chem. Soc. (1949) 1163) was prepared by first reacting benzoyl chloride with thiosemicarbazide in pyridine at 0° C. to give benzoyl thiosemicarbazide. Benzoyl thiosemicarbazide was treated with potassium hydroxide in ethanol to give 3-phenyl-1,2,4-triazole-5-thione. 3-Phenyl-1,2,4-triazole-5-thione (1.77 g) was then dissolved in 50 mL of methanol and treated with 0.57 g of 95% sodium methoxide, and then with 2-bromo-5-nitrothiazole (2.09 g). The mixture was stirred at room temperature for 2 hours and the precipitated sodium bromide was removed by filtration. The methanol was evaporated and the product crystallized from ethanol and water to give 1.5 g of 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole, a white solid, MP 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@@H:34]([O:36][CH3:37])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@@H:34]([O:36][CH3:37])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H](C)OC)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@H](C)OC)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
387 mg (0.66 mmol) of tert-butyl 4-({(4S)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 2. Yield: 245 mg (70% of theory)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[N:7]2.[F:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][C:21]=1[C:35]1[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[F:18])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:22][C:21]=1[C:35]1[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Fc1ccccc1-c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(-c2ccnc3nc(-c4ccccc4F)ccc23)ccc1F
Yield: 62 %

Procedure:
This was prepared in 62% yield from 5-chloro-2-(2-fluorophenyl)-[1,8]naphthyridine (from step a) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (from Example 2, step e) using a similar procedure to that described in step a. δH (400 MHz, CDCl3) 7.20 (1H, ddd, J 11.7, 8.2 and 1.2), 7.34 (1H, td, J 7.4, 1.2), 7.42-7.48 (2H, m), 7.50 (1H, d, J 4.3), 7.54 (1H, td, J 7.4, 1.2), 7.60-7.65 (3H, m), 7.71 (1H, td, J 7.4, 1.2), 7.84 (1H, dd, J 7.8, 0.8), 8.09 (1H, dd, J 8.6 and 2.3), 8.42 (1H, td, J 7.8, 2.0), 8.49 (1H, d, J 8.6), 9.18 (1H, d, J 4.7). m/z (ES+) 420 [MH]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][OH:8])[C:3]([OH:5])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O.C1COCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][CH:2]2[CH2:6][CH2:7][O:8][C:3]2=[O:5])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: NC(CCO)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1OCCC1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
(RS)-2-amino-4-hydroxybutanoic acid (2.0438 g) was dissolved in water (20 ml). The solution was cooled to 0° C., and potassium carbonate (5.217 g) and ethyl acetate (20 ml) were added. Then, p-chlorobenzenesulfonyl chloride (9.0536 g) and THF (2 ml) were added, and the whole was stirred overnight. After the reaction was completed, the ethyl acetate layer was separated. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The combined ethyl acetate layers were concentrated to give a crude product. The crude product was purified by silica gel column chromatography (silica gel 50 g, hexane/ethyl acetate=2/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-4-butanolide (2.8674 g).
Reaction SMILES: N(OCCCCC)=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](N)=[CH:13][CH:12]=1.OS(O)(=O)=O.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:25]=[CH:24][C:23]([O:27][CH3:28])=[O:26])=[CH:13][CH:12]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCON=O
Solvent: CO
Product: COC(=O)C=Cc1ccc(OC)cc1
Temperature: 55 °C
Yield: 87 %

Procedure:
117 g of amyl nitrite are added slowly to a solution, cooled to about 10° C., of 123 g of p-anisidine and 100 ml of conc. H2SO4 in 400 ml of methanol and the mixture is stirred without cooling for a further 40 minutes after addition is complete It is treated with 95 g of methyl acrylate and 112 mg of Pd(OAc)2 and heated to about 55° C. until evolution of gas has ended. After cooling, the solid is filtered off with suction, washed with water and dried at 40° C. 167 g (87%) of methyl p-methoxycinnamate are obtained, m.p. 88°-89° C., Lit 89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)=[CH:4][CH:3]=1>C(OCC)(=O)C.O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)cc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCNC(c2ccc(F)cc2)C1
Yield: 99.9 %

Procedure:
A solution of benzyl 2-(4-fluorophenyl)-4-oxopiperidine-1-carboxylate (4.75 g, 14.50 mmol) in a mixture of ethyl acetate and tetrahydrofuran (1:1, 100 mL) was hydrogenated in the presence of 10% Pd/C at atmospheric pressure over 12 h. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate (250 mL) and washed twice with saturated aqueous bicarbonate (100 mL), brine, then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dried to give 2-(4-fluorophenyl)piperidin-4-one (2.8 g, quantitative). MS (EI) for C11H12FNO: 194 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:23]=[CH:22][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:24][O:25][CH2:26][CH2:27]Br.O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=1)[CH2:27][CH2:26][O:25][CH3:24])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N(CCOC)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 165 mg) in N,N-dimethylformamide (1 ml) was added dropwise a solution of ethyl 4-(tert-butoxycarbonylamino)cinnamate (1.00 g) in N,N-dimethylformamide (5 ml) in ice water bath under nitrogen and stirred for 1 hour under same condition. To the mixture was added 2-bromoethyl methyl ether (602 mg) and stirred for 1 hour at same condition and at ambient temperature for 20 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting to a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 4-[N-tert-butoxycarbonyl-N-(2-methoxyethyl)amino]cinnamate (935 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[NH2:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:18][C:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(Cl)cc1
Yield: 44.8 %

Procedure:
Ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate (10.0 g) and 1-aminomethylnaphthalene (7.0 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-chlorophenyl)-2-(1-naphthyl)imidazole-4-carboxylate (6.6 g). 6.0 g therefrom was dissolved in ethyl alcohol (120 ml), and 1 M sodium hydroxide solution (45 ml) was added. The reaction mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-chlorophenyl)-2-(1-naphthyl)-imidazole-4-carboxyic acid (4.1 g), melting point 210° C. (decomposition).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:14]=[C:13]([O:28][CH3:29])[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>CO.C1COCC1>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][NH:17][C:15]1[N:14]=[C:13]([O:28][CH3:29])[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[CH:16]=1
Reactant: COC(=O)C1CCN(c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(N2CCC(C(=O)O)CC2)n1
Yield: 38.2 %

Procedure:
A solution of 1-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-piperidine-4-carboxylic acid methyl ester [70 mg, 0.16 mmol] and a 2 M solution of lithium hydroxide (1 mL, 2 mmol) in MeOH (1 mL) and THF (1 mL) is stirred at ambient temperature for 15 hours. The mixture is concentrated, and the residue is taken up with water, acidified to pH 2 with the addition of 10% HCl and extracted twice with EtOAc (20 mL). The organic extracts from the acidic layer are combined and dried over magnesium sulfate, filtered and concentrated to afford 1-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-piperidine-4-carboxylic acid [26 mg, 38%, Example 97] as a solid. LCMS RT=2.02 minutes, MS: 425 (M+H). IC50=7 nM
Reaction SMILES: [CH:1]([N:4]([CH3:34])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].Br.CC(O)=O>CCOCC>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:34])[CH2:6][C@H:7]2[CH2:28][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[C:12]1=[O:27]
Reactant: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.4 %

Procedure:
The entirety of benzyl (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate prepared in Step 2 (250 mg) was charged with 30% HBr/AcOH (5 mL). The reaction vessel warms and a vigorous gas evolution occurs. The mixture was stirred for 25 min at RT and then the flask was placed in a cool water bath before the addition of 20 mL of Et2O. The resulting solid was collected, washed with Et2O twice, and concentrated in vacuo to give (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (150 mg). MS found: (M+H)+=360.