Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[CH:6][S:7][CH:8]=1)([CH3:3])[CH3:2].[Li]CCCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].O>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cscn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C(C)C)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred solution of 4-isopropylthiazole (9 g, 71 mmol) in anhydrous THF (100 mL) at −78° C. was added nBuLi (40 mL, 99 mmol). The reaction was stirred for 1 hr and the temperature reached −40° C. The reaction mixture was cooled to −78° C. and tri-n-butyltinchloride (23 g, 71 mmol) was added. The reaction mixture was stirred at room temperature for 48 hrs. Water was added and solvent was evaporated under reduced pressure. The residue was partioned between water and EtOAc. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 219 as colorless oil in 55% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.88-1.62 (m, 27H), 1.40 (s, 3H), 1.42 (s, 3H), 3.17-3.24 (m, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[C:7]([OH:24])=[C:8]2[C:13]3=[C:14]([C:16](=[O:22])[C:17]([C:19]([OH:21])=[O:20])=[CH:18][N:12]3[N:11]([CH3:23])[CH2:10][CH2:9]2)[CH:15]=1.[CH3:25]O>>[F:5][C:6]1[C:7]([OH:24])=[C:8]2[C:13]3=[C:14]([C:16](=[O:22])[C:17]([C:19]([O:21][CH3:25])=[O:20])=[CH:18][N:12]3[N:11]([CH3:23])[CH2:10][CH2:9]2)[CH:15]=1
Reactant: CN1CCc2c(O)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn2c3c(c(O)c(F)cc3c1=O)CCN2C
Reaction time: 0.5 h

Procedure:
To 100 ml of methanol, while cooling on ice, 9 ml of thionyl chloride was added, and the solution was stirred for 30 minutes at the same temperature. 2.60 g of the compound (166) obtained in Example 43 was added to the solution, and the solution was heated at reflux for 24 hours. After air-cooling, insoluble matter was removed by filtering, and the filtrate was removed by distillation. To the residue, chloroform was added, and the formed solid matter was filtered off to obtain 2.20 g of the subject compound (167).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=[O:7])C.CO.O.O[Li].O>C1COCC1>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][C:4]([OH:23])=[O:3])[CH2:13][CH2:12]1
Reactant: CCOC(=O)CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a stirred solution of malonic acid monoethyl ester (0.5 g, 0.00377 mole) in DMF (10 mL) was added DIPEA (1.18 g, 0.0094 mole), HOBt (0.608 g, 0.0045 mole) and EDCI.HCl (0.865 g, 0.0045 mole). After 2 minutes 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (1 g, 0.003 7 mole) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to get afford 0.9 g (70%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 344.78 (M+1)+, 82.56%. To a stirred solution of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (0.9 g, 0.0026 mole) in a mixture of THF (10 mL), methanol (3 mL) and H2O (2 mL) was added LiOH.H2O (0.218 g, 0.0052 mole) at ambient temperature and the resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The product was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.6 g (73%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid. LC-MS purity: 316.72 (M+1)+, 75.8%.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16](CC#N)[CH:17]=[CH:18][CH:19]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2].[OH-].[Na+].Cl.[C:26]([O:29]CC)(=[O:28])[CH3:27]>C(O)C.O>[CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16]([CH2:27][C:26]([OH:29])=[O:28])[CH:17]=[CH:18][CH:19]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:10])([CH3:11])[CH3:12])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CC#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CC(=O)O)c1

Procedure:
195 mg of the resulting nitrile compound was dissolved in 6 ml of ethanol, and a 3N aqueous solution (2ml) of sodium hydroxide was added. The mixture was refluxed for 3 hours, and then acidified with 1N hydrochloric acid. Ethyl acetate and water were added, and the organic layer separated was worked up in a customary manner. The product was purified by silica gel column chromatography [ethyl acetate / methanol=20/1] to give 176 mg of the captioned compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:9]([C:23]([OH:25])=O)[CH2:10][CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][C:35]([CH3:38])([OH:37])[CH3:36].C(N(CC)C(C)C)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CCO>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:13][N:14]([CH2:34][C:35]([OH:37])([CH3:38])[CH3:36])[C:23](=[O:25])[C@H:9]([N:8]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]1
Reactant: CC(C)(O)CCl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCO
Product: CC(C)(O)CN1C[C@H](c2cccc(F)c2F)CC[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1=O
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A mixture of (5S) —N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.569 g, 1.24 mmol, described in Intermediate 4), 1-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol) and N,N-diisopropylethylamine (0.713 mL, 4.10 mmol) in EtOH (5 mL) was heated at 75° C. for 18 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in CH2Cl2 (20 mL), then EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) and N,N-diisopropylethylamine (0.650 mL, 3.73 mmol) were added. The resulting mixture was stirred at ambient temperature for 18 h, then aqueous NaHCO3 was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 65:35, to give the title compound. MS: m/z=513 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Li+].Cl>O1CCCC1.O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)CCCCn1ccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCn1ccnc1
Yield: 130.1 %

Procedure:
Stir a solution of methyl 5-imidazol-1-ylpentanoate (0.60 g; 1.0 equiv; 3.29 mmoles) and lithium hydroxide (0.553 g; 4 equiv; 13.17 mmoles) in tetrahydrofuran (20 mL) and water (15 mL) for 18 hours. Add 3 ml of 5N hydrochloric acid then concentrate the mixture. Purify the crude product by column chromatography (0 to 15% methanol in dichloromethane) to afford 5-imidazol-1-ylpentanoic acid (0.72 g; 19%) as a yellow oil: MS (m/z): 169(M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1N.[H][H]>[Rh]>[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1[NH:2][CH2:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccnc1
Reactant: [H][H]
Reactant: Nc1ccc(F)cc1F
Agent: [Rh]
Product: Fc1ccc(NCc2cccnc2)c(F)c1

Procedure:
A mixture of 3-cyanopyridine (10.4 g), 2,4-difluoroaniline (129.1 g) and a 5% rhodium on carbon catalyst (1.0 g) was treated with hydrogen at 60 psig and 25-30 deg C. until two equivalents of hydrogen had reacted. The hydrogen pressure was incrementally increased to 400 psig during the course of the reaction. After cooling, venting and purging with nitrogen, the catalyst was removed by filtration. The filtrate analyzed and found to contain 10.4 g of N-(2,4-diflourophenyl)-N-(3-pyridylmethyl)amine which could be isolated by distillation (158-164 deg. C. @ 3mm Hg) and recrystallization (cyclohexane) to give a white solid with a melting point of 88.5-90 deg C.
Reaction SMILES: CO[CH:3]1[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[Cl-:17].[NH4+:18]>CO>[ClH:17].[C:11]1([CH2:10][CH:9]2[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]2=[NH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1NCCCCC1Cc1ccccc1
Solvent: CO
Product: Cl
Product: N=C1NCCCCC1Cc1ccccc1

Procedure:
The title product of Example 4 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]([O:9][Si](C)(C)C)=[O:8])[N:5]2[C:14](=[O:21])[C@@H:15]([NH:16][Si](C)(C)C)[C@H:4]2[S:3]1.C1OC1C.ClC(Cl)C([O:31][N:32]=[C:33]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:34](Cl)=[O:35])=O.CS(C)=O>ClCCl>[CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]([OH:9])=[O:8])[N:5]2[C:14](=[O:21])[C@@H:15]([NH:16][C:34](=[O:35])[C:33](=[N:32][OH:31])[C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[C@H:4]2[S:3]1
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1
Reactant: CC1(C)S[C@@H]2[C@H](N[Si](C)(C)C)C(=O)N2[C@H]1C(=O)O[Si](C)(C)C
Agent: CC1CO1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)C(=NO)c3cccs3)C(=O)N2[C@H]1C(=O)O

Procedure:
A solution of trimethylsilyl 2,2-dimethyl-6β-trimethylsilylaminopenam-3α-carboxylate [prepared from the corresponding amino-acid (0.864 g.)] and propylene oxide (1 ml.) in dichloromethane (20 ml.) was cooled to 0° and treated dropwise with a solution of 2-dichloroacetoxyimino(thien-2-yl)acetyl chloride syn-isomer; [prepared from the corresponding acid (0.753 g.)] in dichloromethane (12 ml.). The resulting solution was maintained at 0° for 1 hour and was then evaporated to a small bulk and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous phase was washed with ethyl acetate, acidified with 2N-hydrochloric acid, and extracted with ethyl acetate. The dried organic solution was evaporated to a small bulk and added dropwise to stirred petroleum spirot (b.p. 40°-60° ). The resulting precipitate was collected, washed, and dried to afford the title acid (0.337 g., 24% based on amine), [α D + 224° (c 0.57, DMSO), λmax. (pH 6 buffer) 288 nm (ε 6,400), λ inf. 270 nm (ε 5,800), νmax. (Nujol), 2600 and 1730 (COH), H), 1776 (β-lactam), 1670 and 1526 cm.-1 (CONH), τ (d6 -DMSO) values include 0.44 (d, J 6 Hz; NH), 2.45 and 2.9 (multiplets, aromatic protons), 5.78 (s; C-3H), 8.46 and 8.55 (2 s; CH3 groups).
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[C:19](=[O:21])[CH3:20])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:8]=2[O:7][CH2:6]1)(=[O:3])[CH3:2].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].N1C=CC=CC=1>C(Cl)(Cl)Cl.O>[C:1]([O:4][C:5]1([CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[C:19](=[O:21])[CH3:20])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15][C:8]=2[O:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1(CN(C(C)=O)C(C)C)COc2ccc(N)cc2OC1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(c1)OCC(CN(C(C)=O)C(C)C)(OC(C)=O)CO2

Procedure:
3-Acetoxy-3-N-acetylisopropylaminomethyl-7-amino-3,4-dihydro-2H-1,5-benzodioxepin (0.1 mole) from Example 86, Step B, in chloroform is treated with 0.11 mole of ethyl chloroformate and pyridine in chloroform. The mixture after stirring and heating in a water bath for several hours is diluted with water, extracted with ether, the combined ethereal extracts washed, dried and evaporated to give 3-acetoxy-3-(N-acetylisopropylaminomethyl)-7-carbethoxyamino-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:18])=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:9])[F:10]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)s2)noc1C(F)(F)F
Yield: 85 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a saturated aqueous NaHCO3 solution followed by water to afford product as a pale yellow solid (88 mg, 85%). 1H NMR (CDCl3) 1.76 (m, 4 H), 1.96-2.10 (m, 4 H), 2.37 (d, J=1.3, 3 H), 2.56-2.64 (m, 6 H), 3.80 (m, 2 H), 4.48 (m, 1 H), 7.50 (d, J=4.0, 1 H), 7.57 (br, 1 H). 19F NMR −63.2. LC/MS 4.66 min, [M+1]+ 414.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4O[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH2:24].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:24]([C:23]5[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:22]=5[Cl:21])[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1
Reactant: Nc1ccc(F)cc1Cl
Reactant: Brc1ccc2c(c1)-c1sc(-c3nnco3)cc1CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2cnnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(Cl)c1
Temperature: 160 °C
Yield: 67.6 %

Procedure:
A microwave tube was charged with 2-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-[1,3,4]oxadiazole (0.64 g; 1.83 mmol), 2-chloro-4-fluoroaniline (0.44 ml; 3.68 mmol), TFA (0.27 ml; 3.63 mmol) and toluene (5 ml). The mixture was heated in a microwave at 160° C. for 30 min., diluted with EtOAc (150 ml) and washed with satd. NaHCO3. The organic layer was dried (MgSO4), concentrated and purified by ISCO to give 267 as a cream-coloured solid (0.59 g; 68%). δH (400 MHz, CDCl3) 3.14 (t, J=5.2, 2H), 4.29 (t, J=5.2, 2H), 6.91 (d, J=8.4, 1H), 6.93 (s, 1H), 7.22-7.27 (m, 2H), 7.43-7.51 (m, 2H), 7.65 (d, J=2.4, 1H), 8.22 (s, 1H). [M+H]+: 478
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=1>C1C=CC=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([SH:1])=[CH:3][CH:4]=2)=[O:10])[CH:12]=1
Reactant: O=C=Nc1ccc(S)cc1
Reactant: NCc1cccnc1
Solvent: c1ccccc1
Product: O=C(NCc1cccnc1)Nc1ccc(S)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To 4-mercaptophenyl isocyanate (0.9 g., 0.006 mol) in 50 ml. of anhydrous benzene was added 3-pyridylmethylamine (0.65 g., 0.006 mol). An exothermic reaction caused the temperature to rise to 40° C. and a white precipitate formed. The reaction mixture was momentarily heated to reflux, then cooled to room temperature and filtered to give 1.2 g. melting at 155°-159° C. The product was a 77.5% yield of 1-(3-pyridylmethyl)-3-(4-mercaptophenyl)urea.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][C:8]=1[Cl:22])[CH3:6])=[O:4].[C:23]([O:27][C:28](=[O:45])[CH2:29][NH:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[C:23]([O:27][C:28](=[O:45])[CH2:29][N:30]([CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][C:8]=1[Cl:22])[CH3:6])=[O:4])([CH3:24])([CH3:25])[CH3:26]
Reactant: CN(C(=O)CCl)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Reactant: CC(C)(C)OC(=O)CNCc1cccc(C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C(=O)CN(CC(=O)OC(C)(C)C)Cc1cccc(C(=O)OC(C)(C)C)c1)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 2-chloro-N-(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methylacetamide (500 mg) in acetonitrile (8.95 mL) were added tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (441 mg), potassium carbonate (285 mg), and potassium iodide (22.8 mg), followed by stirring at 60° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl){2-[(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)(methyl)amino]-2-oxoethyl}amino]methyl}benzoate (809 mg).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Br:9][C:10]1[C:11]([NH:22][NH2:23])=[N:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>C1COCC1.CCOC(C)=O>[Br:9][C:10]1[C:11]2[N:12]([C:29](=[O:30])[NH:23][N:22]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1
Reactant: NNc1ncc(-c2ccccc2)nc1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Br)nc(-c3ccccc3)cn12
Reaction time: 1.5 h

Procedure:
A mixture of 15.3 g of NaH (60% suspension in mineral oil) and 80.0 g of 3-bromo-5-phenyl-pyrazin-2-ol (J Het. Chem., 665 (1978)) was stirred together for 15 min. After gas evolution ceased, 90.0 g of trifluoromethanesulfonic anhydride was added dropwise over one h. The mixture was stirred an additional 30 min. and was filtered through a pad of silica gel and the solids were washed with methylene chloride. Concentration of the filtrate provided 3-bromo-5-phenyl-pyrazin-2-trifluoromethansulfonate that was dissolved in IPA (200 mL) and stirred as 4.48 g of hydrazine was added. The mixture was stirred at ambient temperature for 16 h. The resulting solid was collected, washed with methylene chloride, and dried under reduced pressure. The filtrate was re-subjected to the above reaction conditions a second and third time to provide (3-bromo-5-phenyl-pyrazin-2-yl)-hydrazine as the trifluoromethane sulfonate salt. A solution of 265 mg of (3-bromo-5-phenyl-pyrazin-2-yl)-hydrazine trifluoromethane sulfonate in THF (5.0 mL) was stirred as 243 mg of CDI was added in portions over 15 min. The resulting solution was stirred for 1.5 h and was diluted with EtOAc and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated to provide 8-bromo-6-phenyl-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a tan solid. MS (M+H−)=290.2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[OH-].[Na+].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C1COCC1.O>[CH:16]1([C:19]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)=[O:20])[CH2:18][CH2:17]1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C2CC2)cc1[N+](=O)[O-]

Procedure:
6 g (0.033 mol) of 4-amino-2-nitrobenzoic acid were dissolved in a mixture (100 ml) of THF and water (1:1). The solution was adjusted to pH 8.5 with 2 N NaOH and reacted at room temperature with 3.78 g (0.0363 mol) of cyclopropanecarboxylic acid chloride in 25 ml of THF. The pH value of the reaction solution was kept at 8.0 - 8.5 to the end by further addition of 2 N sodium hydroxide solution. After a reaction time of 3.5 hours, the solvent was next distilled off. The residue was diluted with water and the aqueous solution was extracted by shaking once with ethyl acetate and was finally acidified with 2 N HCl to pH 2.0. The oil which precipitated was isolated by extraction with ethyl acetate. After washing and drying the ethyl acetate phase, the solution was concentrated to dryness. The product was crystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[NH2:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C@@H:22]([NH2:24])[CH3:23])[C:13]=2[N:25]=1>>[C:1]([NH:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C@@H:22]([NH2:24])[CH3:23])[C:13]=2[N:25]=1)(=[O:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Product: CC(=O)Nc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)N
Yield: 63 %

Procedure:
xxxi-a (44 mg, 0.104 mmol) was deprotected using the TFA conditions detailed in the preparation of 30 to afford the title compound (66, 29 mg, 63%). NH4OAc standard conditions. DAD
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[C:4]([NH:6][C:7]1[N:8]=[CH:9][C:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:25]([F:28])([F:27])[F:26])=[N:11][CH:12]=1)=[O:5].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[CH2:47]([O:49][CH:50]([O:53][CH2:54][CH3:55])[CH2:51][NH2:52])[CH3:48]>C(Cl)Cl.CN(C=O)C>[CH2:47]([O:49][CH:50]([O:53][CH2:54][CH3:55])[CH2:51][NH:52][C:22]([C:20]1[CH:19]=[CH:18][C:17]2[N:13]([C:10]3[CH:9]=[N:8][C:7]([NH:6][C:4](=[O:5])[C:3]4[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:2]=4[F:1])=[CH:12][N:11]=3)[C:14]([C:25]([F:28])([F:27])[F:26])=[N:15][C:16]=2[CH:21]=1)=[O:23])[CH3:48]
Reactant: O=C(O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Reactant: CCOC(CN)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(CNC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (xiii) (50 mg, 0.11 mmol, 1.00 equiv) in DCM (15 ml) and DMF (1 drop). To the above stirred solution was added oxalyl dichloride (70 mg, 0.55 mmol, 5.00 equiv) dropwise at 0° C. The resulting solution was allowed to stir at 0° C. for 4 hours then was concentrated by evaporation under vacuum using a rotary evaporator. The residue was then taken up by DCM (10 ml) and then add dropwise to a stirred solution Of Et3N (40 mg, 3.00 equiv) and 2,2-diethoxyethanamine (15 mg, 0.11 mmol, 1.00 equiv) in DCM (10 mL) at 0° C. The resulting solution was allowed to stir overnight at room temperature, then was washed with H2O (2×100 mL) and dried over Na2SO4. Removal of the solvent and volatile components afforded the crude product 1-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid (2,2-diethoxy-ethyl)-amide (xiv) (50 mg, 64% yield) as a yellow solid that was used directly in the next step.