Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3].Cl.[CH3:9][C:10]([O:13][C:14]([NH:16][C@H:17]([C:20](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:21])[CH2:18][OH:19])=[O:15])([CH3:12])[CH3:11].ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)(Cl)Cl>[NH:16]([C:14]([O:13][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:15])[C@H:17]([C:18]([NH:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3])=[O:19])[CH2:20][OH:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C

Procedure:
25 g of H-Ala-OMe, HCl and 66 g. of Boc-Ser-ONb are dissolved in 500 ml DMF. The product is cooled in an ice bath and 25 ml of NEM, 24 g of N-hydroxy benzotriazole are added with magnetic stirring and the pH is maintained at 6.5 or 7 by addition of NEM. The product is stirred for 18 hrs. at ambient temperature. After TLC monitoring, the medium is evaporated to 90% (0.1 mm Hg-35° C.). The oil obtained is dissolved in 1.500 ml of chloroform, the product is washed with a solution of saturated sodium chloride (twice), 5% sulfate/potassium bisulfate solution (3 times), saturated sodium bicarbonate (5 times). The solution is dried over Na2SO4 and evaporated to dryness. An oil is obtained which is dried to constant weight (30°-0.1 mm Hg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[S:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.C([O:27][C:28]([CH2:30][C:31](O)=[O:32])=O)C.C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:20]4[CH:23]=[CH:24][C:17]([N:14]5[CH2:15][CH2:16][S:11][CH2:12][CH2:13]5)=[CH:18][CH:19]=4)[C:28](=[O:27])[CH2:30][C:31]3=[O:32])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=Cc1ccc(N2CCSCC2)cc1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCSCC2)cc1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.963 g, 7.24 mmol), 4-thiomorpholinobenzaldehyde (1.5 g, 7.24 mmol), 2-(ethoxycarbonyl)acetic acid (0.957 g, 7.24 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (1.13 g, 7.24 mmol) and sodium tert.-butoxide (0.77 g, 6.87 mmol) according to method 3.
Reaction SMILES: [CH2:1]([B-:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Li+].[Br-].[CH3:26][S+:27]([CH3:38])([CH2:29]C(C1C=CC=CC=1)=O)=[O:28]>O.CO>[CH3:26][S+:27]([CH3:38])([CH2:29][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:28].[CH2:1]([B-:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[S+](C)(=O)CC(=O)c1ccccc1
Agent: CCCC[B-](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: C[S+](C)(=O)Cc1ccccc1

Procedure:
An aqueous solution of 8.90 g of lithium butyltriphenylborate in 100 ml of water was added to a solution of 7.24 g of dimethylphenacyloxosulfonium bromide in 100 ml of methanol, and the resultant mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was filtered, and the resultant crystal was washed with water and dried to give 10.61 g of dimethylbenzyloxosulfonium-butyltriphenylborate as a white crystal.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH:6]([C:11]([O:13]CC)=O)[CH2:5]1)(=[O:3])[CH3:2].Cl.[C:17]([NH2:23])(=[NH:22])[CH2:18][CH2:19][CH2:20][CH3:21].C[O-].[Na+]>C(O)C.CO>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:22]=[C:17]([CH2:18][CH2:19][CH2:20][CH3:21])[NH:23][C:11](=[O:13])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)C1CN(C(C)=O)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCCCc1nc2c(c(=O)[nH]1)CN(C(C)=O)CC2
Yield: 96.9 %

Procedure:
A mixture of 1.5 g of ethyl 1-acetyl-4-oxo-3-piperidinecarboxylate and 1.0 g of valeramidine hydrochloride in 15 ml of anhydrous ethyl alcohol is treated with 7.5 ml of a 1M solution of sodium methoxide in methanol. The resulting mixture is stirred and heated at reflux for one hour. The reaction mixture is allowed to cool over 30 minutes then filtered. The filtrate is evaporated to a colorless syrup which is stirred with 50 ml of ether for 2 hours then filtered. The tacky cake is dried under high vacuum at 56° C. to afford 1.7 g of the desired product, m.p. 106°-113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=2)=[C:4]([F:23])[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:37])[CH2:33][C:34](O)=[O:35])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[F:23][C:4]1[CH:3]=[C:2]([NH:1][C:34](=[O:35])[CH2:33][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:37])[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cc2F)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)ncn1
Yield: 80.1 %

Procedure:
The title compound was prepared from tert-butyl 6-(4-amino-2-fluorophenoxy)pyrimidin-4-ylcarbamate (8 mg, 0.025 mmol) and (4-fluorophenylamino)-3-oxopropanoic acid (6 mg, 0.031 mmol, Compound B of Example 1), TBTU (11 mg, 0.034 mmol), and DIPEA (6 μL, 0.030 mmol) using a similar procedure described for the preparation of Compound C, Example 1. Flash chromatography using 1-1.5% MeOH in CH2Cl2 as the eluent gave the title compound as a white solid (10 mg, 80%). 1H NMR (DMSO-d6) δ 10.48 (s, 1H), 10.46 (s, 1H), 10.25 (s, 1H), 8.39 (s, 1H), 7.74-7.77 (m, 1H), 7.62 (d, 1H, J=5.5 Hz), 7.61 (d, 1H, J=4.9 Hz), 7.36-7.30 (m, 2H), 7.17-7.13 (m, 2H), 3.48 (s, 2H), 1.46 (s, 9H); MS (ESI+) m/z 500.12 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:25]([CH2:30][CH2:31][CH2:32][C:33]([NH:35][NH:36]C(OC(C)(C)C)=O)=[O:34])[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N:25]([CH2:30][CH2:31][CH2:32][C:33]([NH:35][NH2:36])=[O:34])[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NNC(=O)CCCN(c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CCCC(=O)NN)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A solution of tert-butyl 2-(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)benzofuran-6-yl)methylsulfonamido)butanoyl)hydrazinecarboxylate (40 mg, 0.065 mmol) in anhydrous CH2Cl2 (0.5 mL) under nitrogen was cooled to 0° C., and treated with trifluoroacetic acid (0.5 mL). The reaction was stirred at 25° C. for 1 hour. The mixture was concentrated by rotary evaporation, and the residue was diluted with ethyl acetate (50 mL), and washed with 5% aqueous NaHCO3 (2×10 mL) and brine (10 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The crude material was purified by SiO2 flash chromatography (Alltech Extract-Clean™ column, 5 g bed) eluting with a step gradient of 5% methanol/CH2Cl2 to 10% methanol/CH2Cl2 to afford the title compound as a white solid (16 mg, 0.031 mmol, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.64 (m, 1H), 0.80-0.90 (m, 1H), 0.92-1.08 (m, 2H), 1.59-1.75 (m, 2H), 2.02-2.17 (m, 2H), 2.34-2.42 (m, 1H), 3.15 (s, 3H), 3.55-3.77 (m, 2H), 4.12 (d, J=4.12 Hz, 2H), 7.08 (s, 1H), 7.18 (s, 1H), 7.28-7.43 (m, 3H), 7.85 (s, 1H), 8.02 (dd, J=9.00, 5.53 Hz, 2H), 8.93 (t, J=3.36 Hz, 1H), 12.41 (s, 1H); MS (ESI+) m/z 512 (M+H)+, 1023 (2M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH2:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.O>[CH2:1]([N:8]1[CH2:9][C@@H:10]([OH:11])[C@H:12]([NH:22][CH2:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccccc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1NCCc1ccccc1

Procedure:
19.4 g (0.1 mol) of 90% strength 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane are heated under reflux with 14.5 g (0.12 mol) of benzylmethylamine in 100 ml of dioxane and 200 ml of water overnight. The mixture is extracted with CHCl3, the extracts are dried with K2CO3 and concentrated and the residue is subjected to incipient distillation up to 160° C. (oil bath temperature).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:10])C1C=CC=CC=1.O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:26]
Reactant: COc1cccc(C(=O)NN2CCC[C@H]2C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NN2CCC[C@H]2C(=O)O)c1
Yield: 97.9 %

Procedure:
(2S)-1-(3-Methoxybenzoylamino)pyrrolidine-2-carboxylic acid benzyl ester (654 mg, 1.93 mmol) was dissolved in THF/H2O (9:1, 10 ml). Lithium hydroxide monohydrate (243 mg, 5.79 mmol) was added. After 18 h at room temperature the reaction mixture was diluted with ethyl acetate (50 ml). This solution was washed with 1M KHSO4, water and brine, dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as the title compound (470 mg, 1.89 mmol, 98%).
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[Br:16]Br>C(O)(=O)C>[Br:16][C:12]1[CH:13]=[CH:14][C:9]2[NH:8][C:7](=[O:15])[O:6][C:10]=2[CH:11]=1
Reactant: BrBr
Reactant: O=c1[nH]c2ccccc2o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
To a solution of glacial acetic acid (1500 ml) was added sodium acetate (222 g, 2.70 mole) and 2-benzoxazolinone (300 g, 2.22 mole). The suspension was cooled to 15° C. bromine (118 ml, 2.29 mole) added dropwise over 1 h and the mixture stirred for 12 h at ambient temperature. The solids were then filtered, washed with H2O (3×500 ml) and dried under vacuum to give the title compound as a white solid (374 g, 89.7%): mp 186.0-187.0° C.: 1H NMR (DMSO-d6) δ 11.8 (s, 1 H), 7.6 (s, 1 H), 7.3 (d, J=8.0 Hz, 1 H), 7.0 (d, J=8.0 Hz, 1 H).
Reaction SMILES: ClC(OC(Cl)=O)C.C([N:15]([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:16][CH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=2)=[CH:20][CH:19]=1)C1C=CC=CC=1.ClCCCl.N>CO>[C:37]1([CH2:36][CH2:35][CH2:34][NH:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)=[CH:32][CH:33]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCN(CCCc3ccccc3)Cc3ccccc3)cc2)nc1
Agent: CC(Cl)OC(=O)Cl
Agent: N
Solvent: CO
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CCNCCCc3ccccc3)cc2)nc1
Yield: 66.9 %

Procedure:
Add 1-chloroethylchloroformate (0.056 mL, 0.52 mmol) to a stirred solution of 6-(4-{2-[benzyl-(3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide (0.1211 g, 0.2603 mmol) (Example 3) and 1,2-dichloroethane (5 mL). Heat the reaction to reflux under nitrogen for 1.5 h. Add methanol (7 mL) and heat at reflux under nitrogen for 1 h. Cool the reaction to room temperature and add 2 M ammonia in methanol (5 mL). Concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 1% concentrated ammonium hydroxide/10% ethanol/chloroform to yield 0.0654 g (67%) of 6-{4-[2-(3-phenyl-propylamino)-ethyl]-phenoxy}-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 7.48 minutes, Purity: 99.2%; mass spectrum (ion spray): m/z=376.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:36]=[CH:35][C:22]2[NH:23][C:24]([C@@H:26]([NH2:34])[CH2:27][CH2:28][C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:36]=[CH:35][C:22]2[NH:23][C:24]([C@@H:26]([NH:34][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][CH2:28][C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: N[C@@H](CCc1nnn[nH]1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](CCc2nnn[nH]2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12](OCC3C=CC([N+]([O-])=O)=CC=3)[C@H:11]([C:25]([OH:27])=O)[CH2:10]2)=[CH:5][CH:4]=1.[N+:30]([C:33]1[CH:51]=[CH:50][C:36]([CH2:37][O:38][C:39]([NH:41][C:42]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[NH:43])=[O:40])=[CH:35][CH:34]=1)([O-:32])=[O:31]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:39]([O:38][CH2:37][C:36]3[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:51][CH:50]=3)=[O:40])[C@H:11]([C:25]([N:47]3[CH2:46][CH2:45][N:44]([C:42](=[NH:43])[NH:41][C:39]([O:38][CH2:37][C:36]4[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:51][CH:50]=4)=[O:40])[CH2:49][CH2:48]3)=[O:27])[CH2:10]2)=[CH:28][CH:29]=1
Reactant: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=N)NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.6 %

Procedure:
740 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxy)pyrrolidine-2-carboxylic acid was dissolved in 7.4 ml of dry acetonitrile, and 330 mg of N,N'-carbonyldiimidazole were added to the resulting solution, after which the mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 525 mg of 1-(4-nitrobenzyloxycarbonylamidino)piperazine [prepared as described in step (c) above] dissolved in 10 ml of acetonitrile was added to the resulting mixture, and the mixture was left to stand overnight under the same conditions. The reaction mixture was then diluted with ethyl acetate, after which it was washed with an aqueous solution of sodium hydrogencarbonate, with water and with an aqueous solution of sodium chloride, in that order, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted first with ethyl acetate alone and then with a 4:1 by volume mixture of ethyl acetate and acetonitrile, in that order. The fractions containing the desired compound were concentrated by evaporation under reduced pressure, to obtain 890 mg of the title compound, as a powder.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.NC1OC2C=CC=CC=2N=1.C1(C[C@@H:66]([N:75]2[CH2:83]C3C(=CC=CC=3)C2=O)[C:67]([NH:69][C:70]2SC=C[N:74]=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:74][C:70]2[CH:83]=[N:75][CH:66]=[CH:67][N:69]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nc2ccccc2o1
Product: O=C(Nc1cnccn1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 144 mg; 0.50 mmol) and 2-aminobenzoxazole (67 mg; 0.50 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 50% ethyl acetate/hexanes) 161 mg (96%)of (S)-N-Benzdoxazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a white foam: EI-HRMS m/e calcd for C24H25N3O3 (M+) 403.1896, found 403.1895.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([S:15](O)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=3[Cl:19])[N:7]=[CH:6][C:5]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>O=P(Cl)(Cl)Cl>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([S:15]([Cl:26])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=3[Cl:19])[N:7]=[CH:6][C:5]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(-c2cc(S(=O)(=O)O)ccc2Cl)c1C1CC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn(-c2cc(S(=O)(=O)Cl)ccc2Cl)c1C1CC1
Temperature: 95 °C
Yield: 95.1 %

Procedure:
A mixture of ethyl 5-cyclopropyl-1-(2-chloro-5-{hydroxysulfonyl}phenyl)-1H-pyrazole-4-carboxylate (1.48 g, 4.0 mmol) and PCl5 (1.79 g, 8.6 mmol) in POCl3 (6 mL) under a nitrogen atmosphere was heated at 95° C. for 30 min, cooled to 23° C. and poured slowly over ice. The resulting mixture was extracted with EtOAc. The organic layer was washed three times with cold water, brine, dried over MgSO4, filtered and concentrated in vacuo to afford 1.48 g (95% yield) of ethyl 5-cyclopropyl-1-(2-chloro-5-{chlorosulfonyl}phenyl)-1H-pyrazole-4-carboxylate as a yellow oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(O)(=O)C>ClCCl>[CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: C[Si](C)(C)c1cccc(CO)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[Si](C)(C)c1cccc(C=O)c1
Reaction time: 0.33 h

Procedure:
To a mixture of 3-trimethylsilylbenzylalcohol (3.60 g, 20 mmol) and pyridium dichromate (11.29 g, 30 mmol) in dichloromethane (60 ml) at 0° C. was added 3 Å molecular sieve powder (16 g) and anhydrous acetic acid (2 ml). Then the reaction was allowed to react 30 min at room temperature, stirred 20 min with celite (10 g), filtered and evaporated under reduced pressure. The residue was treated with diethyl ether (50 ml), filtered through MgSO4 and concentrated. 3-trimethylsilylbenzaldehyde was purified by distillation.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:6][CH2:5][CH:4]([OH:7])[O:3]1.[CH2:9](N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].[Cl-].[NH4+]>O1CCCC1>[CH3:16][S:17]([O:7][CH:4]1[CH2:5][O:6][C:2]([CH3:8])([CH3:1])[O:3][CH2:9]1)(=[O:19])=[O:18]
Reactant: CCN(CC)CC
Reactant: CC1(C)OCC(O)O1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OCC(OS(C)(=O)=O)CO1
Reaction time: 0.5 h

Procedure:
A 2,2-dimethyl-1,3-dioxolan-5-ol (743 mg) solution in tetrahydrofuran (10 mL) was cooled to 0° C. in nitrogen atmosphere. To the reaction mixture, triethylamine (1.87 mL) and methanesulfonyl chloride (520 μL) were successively added at 0° C., followed by 30 minutes' stirring. After addition of saturated aqueous ammonium chloride solution, the reaction mixture was extracted with ethyl acetate. The extract washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was removed by distillation to provide 837 mg of crude title compound as a colorless solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4]C.C([Li])(C)(C)C.CON(C)[C:14](=[O:24])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23].[Cl-:26].[NH4+]>C1COCC1.CCOCC>[Cl:26][CH2:4][CH2:3][CH2:2][CH2:1][C:14]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])=[O:24]
Reactant: COc1ccc(Cl)cc1C(=O)N(C)OC
Reactant: [Cl-]
Reactant: CCCCC
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(Cl)cc1C(=O)CCCCCl
Temperature: -65 °C

Procedure:
A mixture of 5-chloro-1-iodobutane (30 g, 137.6 mmol), ether (300 mL) and pentane (500 mL) was cooled to approximately -65° C. and then tert-butyllithium (1.7M, 160 mL, 0.27 moles) was added over 30 minutes such that the reaction mixture remained below approximately -55° C. The mixture was cooled 1 hour with stirring at -65° C. to -60° C. and then N-methoxy-N-methyl-5-chloro-2-methoxybenzamide (25 g, 0.11 mol), prepared as in Example 4, in THF (approximately 80 mL) was added. The mixture was diluted with additional ether (300 mL), allowed to warm to 10° C. and then combined with saturated ammonium chloride. The organic layer was separated, dried (K2CO3), filtered and concentrated. The residue was purified by column chromatography eluding with hexane/ethyl acetate (9:1 to 85:15) to give 5-chloro-1-(5-chloro-2-methoxy-phenyl)-1-pentanone, m.p. 52°-54° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Product: COc1nc2cc(C)c(C)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 71 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 71%). 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.40 (s, 3H), 3.23-3.30 (m, 4H), 3.74-3.77 (m, 3H), 4.13 (s, 4H), 6.80-6.91 (m, 3H), 7.15-7.20 (m, 1H), 7.36 (br s, 1H), 7.53 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][NH2:8].[N:9]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:10]=[S:11]>C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][NH:8][C:10]([NH:9][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:11]
Reactant: S=C=NCCc1ccccc1
Reactant: Cn1cccc1CN
Solvent: CCOC(C)=O
Product: Cn1cccc1CNC(=S)NCCc1ccccc1
Reaction time: 12 h
Yield: 60.1 %

Procedure:
(1-methyl-1H-pyrrol-2-yl)methylamine (65 mg) and (2-isothiocyanatoethyl)benzene (100 mg) were dissolved in ethyl acetate (20 ml) and the solution was stirred for 12 hours. After the completion of the reaction, the resulting mixture was purified by column-chromatography (ethyl acetate/hexane=1/3) to yield the compound 17-3 (97 mg, 60%) as a brown liquid.