Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH3:12])[NH:7][C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][CH2:30]Cl>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:11][CH3:12])[N:7]([CH2:28][O:29][CH3:30])[C:6]=2[CH:21]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(Br)cc2[nH]1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(Br)cc2n1COC
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
To a solution of (S)-tert-butyl (1-(6-bromo-1H-benzo[d]imidazol-2-yl)propyl)carbamate (Preparation 18, 0.97 g, 2.7 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.35 g, 9.77 mmol) and chloromethyl methyl ether (0.40 mL, 5.3 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (580 mg, 53%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][N:13]2[C:19](=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.I[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1>>[OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][N:13]2[C:19](=[O:20])[CH2:18][CH2:17][N:16]([C:26]3[CH:27]=[CH:22][CH:23]=[C:24]([O:28][C:29]([F:30])([F:31])[F:32])[CH:25]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6][C:3]21[CH2:4][CH2:5]2
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: O=C1CCNCCN1CCCN1CCC2(CC2)[C@H](O)C1
Product: O=C1CCN(c2cccc(OC(F)(F)F)c2)CCN1CCCN1CCC2(CC2)[C@H](O)C1

Procedure:
The title compound was prepared from 4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one and 1-iodo-3-trifluoromethoxy-benzene in analogy to example 33. MS: 442.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)oc1ccccc12
Reaction time: 0.5 h
Yield: 56 %

Procedure:
3-nitrodibenzofuran (30 g, 141 mmol) was stirred in 500 mL ethyl acetate and 3 g of 10% Pd/C were added to the slurry. Reaction mixture was hydrogenated for 30 minutes at 50 psi H2 pressure. Reaction mixture was filtered through a small Celite pad. Filtrate was concentrated under reduced pressure and performed silica gel column using 9:1 DCM/Hexanes as eluent. Final isolated amount was 14.5 g (56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[C:9]([O-])(=O)[CH3:10].[Na+]>[Pd].CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 52.2 %

Procedure:
2 ml of the stock solution described in Example 23 are added to 18 ml of DMF. 9.77 g (50 mmols) of 4-chlorobromobenzene and 4.52 g (55 mmols) of anhydrous sodium acetate are then added. The reaction mixture is then placed under ethylene in a pressure apparatus and is stirred for 6 hours at 10 bar and 130° C. 3.62 g (26.1 mmols) of 4-chlorostyrene are obtained, corresponding to a yield of 52% of theory (conversion figure 5200; Pd content 0.01 mol %).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][C@H:3]1[OH:14].C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>CN(C=O)C>[CH2:7]([N:5]1[CH2:4][C@@H:3]2[C@@H:2]([NH:1][C:20](=[O:21])[O:14]2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1N[C@H]2CN(Cc3ccccc3)C[C@H]2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
(3R,4S)-4-Amino-1-benzylpyrrolidin-3-ol (6 g, 31.4 mmol) in DMF (100 mL) was treated with CDI (5 g, 31.4 mmol) and the reaction mixture was stirred at r.t. for 18 h. The reaction was concentrated in vacuo and azeotroped with heptane. The residual oil was chromatographed on silica with a mixture of dichloromethane and methanol (gradient elution 0-10% methanol), yielding a colourless oil (6 g) which crystallized on standing. δH (DMSO-d6) 7.58 (1H, s), 7.29 (5H, m), 4.96 (1H, dd, J 7.9, 4.5 Hz), 4.16 (1H, dd, J 7.7, 4.9 Hz), 3.59 (2H, m), 3.00 (1H, d, J 11.1 Hz), 2.76 (1H, m), 2.19 (1H, dd, J 11.3, 4.5 Hz), 2.08 (1H, dd, J 10.2, 4.9 Hz).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36]([OH:39])([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
Diisopropylamine (25.2 mL, 0.18 mol) in anhydrous THF (500 mL) was cooled to 0° C. and n-butyllithium (112.5 mL of a 1.6 M solution in THF, 0.18 mol) was added dropwise over 20 minutes to the cooled solution. The reaction mixture was stirred for an additional 15 minutes at 0° C. and then tri-n-butyltinhydride (48.4 mL, 0.18 mol) was added dropwise over 30 minutes. The reaction mixture was then stirred for one hour and then cooled to −78° C. N-(t-butoxycarbonyl)-4-piperidone (30.0 g, 0.15 mol) in THF (500 mL) was then added dropwise to the cooled solution over one hour. After addition was complete, the reaction was stirred for 2 hours at −78° C. and then quenched with buffer (pH 6). The mixture was extracted with ethyl acetate, the organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (5% ethyl acetate/hexane to provide 1-(t-butoxycarbonyl)-4-hydroxy-4-tributylstannyl piperidine (36.06 g).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[ClH:18].[H][H].C>[Pd].CO>[ClH:18].[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NC1CCNCC1
Reaction time: 1 h

Procedure:
10% w/w Palladium on charcoal (1.5 g) was added to a solution of the product from step (i) (10.0 g), 1 molar hydrochloric acid (21.5 ml) and methanol (150 ml) and the mixture hydrogenated at room temperature and pressure until the theoretical amount of hydrogen had been taken up. Charcoal was added, the mixture stirred for 1 hour then filtered through diatomaceous earth and the filtrate evaporated to dryness giving 4-acetylaminopiperidine hydrochloride, 8.64 g, as a sticky foam: NMR (CDCl3 +d6DMSO). δ 9.72(1H,b), 9.02(1H,b), 7.40(1H,bd), 3.87(1H,m), 3.30(2H,m), 2.81(2H,m), 1.86(4H,m), 1.80(3H,s); m/e 143 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1>C(OCC)(=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:2]3[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:22][CH:23]=1
Reactant: NCC1CCN(C(=O)OCc2ccc(F)cc2)CC1
Reactant: Clc1nccnc1Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc(F)cc1)N1CCC(CNc2nccnc2Cl)CC1
Temperature: 110 °C

Procedure:
To 2,3-dichloropyrazine (0.160 gm, 0.00107 mol) was added 4-fluorobenzyl 4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2C) (0.86 gm, 0.00322 mol) and the resulting mixture heated under nitrogen at 110° C. for 30 min. The reaction was cooled, diluted with ethyl acetate (50 mL), and washed with 10% aqueous sodium/citric acid pH=5.2 (3×30 mL), and 10% aqueous sodium bicarbonate (30 mL). The ethyl acetate extract was dried over sodium sulfate, filtered through a pad of silica and concentrated to an oil. Crystallization from ether/hexane gave 4-[(3-chloro-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid 4-fluoro-benzyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]4=[CH:17][CH:18]=3)[NH:13][C:12](=[O:24])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]4=[CH:17][CH:18]=3)[NH:13][C:12](=[O:24])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CC(c2cccc([N+](=O)[O-])c2)c2ccc3ccccc3c2N1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Yield: 85 %

Procedure:
To a stirred suspension of 4-(3-Nitro-phenyl)-3,4-dihydro-1H-benzo[h]quinolin-2-one (1.0 g, 3.14 mmol) and 10% Pd/C (0.10 g) in ethanol (50 ml) was slowly added hydrazine hydrate (0.40 g, 12.6 mmol). The solution was refluxed for 2 hr and the catalyst separated by filtration. The filtrate was concentrated in vacuo to 20 ml and the solution stored in a refrigerator overnight. The precipitate was separated by filtration, washed with small amount of ethanol and vacuum dried to afford the product (0.77 g, 2.67 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[OH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1>>[OH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:27]1
Reactant: OC1CCCNC1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: O=c1[nH]c2cc(CN3CCCC(O)C3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 3-hydroxypiperidine to give a yellow solid. MS m/z: 419.2 (M+1).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]1[CH:14]2[CH2:15][C:16](=O)[CH:12]([CH2:13]2)[CH2:11]1.C([N-]C(C)C)(C)C.[Li+]>C1C=CC=CC=1.O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:9][C:1]1[C:2]2[C:3]([N:4]=[C:11]3[C:10]=1[CH:14]1[CH2:13][CH:12]3[CH2:16][CH2:15]1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1CC2CCC1C2
Reactant: N#Cc1ccccc1N
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Nc1c2c(nc3ccccc13)C1CCC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
A solution of anthranilonitrile (3.6 g, 30.0 mmole), norcamphor (3.3 g, 30.0 mmole) and para-toluenesulfonic acid (50 mg) in benzene (50 ml) was heated to reflux using a Dean Stark apparatus. After heating for 18 hours, the reaction mixture was then cooled (25° C.) and the separated water (about 1.5 ml) was withdrawn. The excess benzene was then removed under vacuum (1 mm Hg, 15 minutes). The oily residue thus obtained was dissolved in tetrahydrofuran (THF, 10 ml) and was cooled to 0° C. and a solution of lithium diisopropylamide in THF (1M, 36 ml, 36 mmole) was then added. This reaction mixture was then stirred at 0° C. for 3 hours. At the end of this period, the reaction mixture was quenched with 40 ml of water and was extracted with methylene chloride (200 ml). The resulting organic phase was washed with water (2×50 ml) and dried (anhydrous MgSO4). The methylene chloride was removed under vaccum to afford a residue which was loaded on a silica gel flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine afforded the title compound 1.6 g, 25%) as an oil which solidified on standing (m.p. 185°-186° C.). 1H-NMR (CDCl3, 300 MHz, δ): 2H, m, 1.22-1.42 ppm; 1H, d, 1.64 ppm (J=7.0 Hz); 1H, d, 1.86 ppm (J=6.0 Hz); 2H, m, 1.9-2.04 ppm; 2H, bd, 3.46 ppm; 2H, bs, 4.49 ppm; 1H, t, 7.38 ppm (J=6.0 Hz); 1H, t, 7.55 ppm (J=6.0 Hz); 1H, d, 7.67 ppm (J=6.0 Hz); 1H, d, 7.92 ppm (J=6.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[C@@H:13]([CH3:15])[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Br)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([O:14][C@H:13]([CH3:15])[C@@H:12]([C:16]([OH:18])=[O:17])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:21])[CH3:20]
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)Br
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of N-benzyloxycarbonyl-L-threonine (5 g) in acetic acid (50 ml) was added acetyl bromide (1.75 ml) at room temperature. After stirring for an hour at room temperature, the reaction mixture was concentrated and the residue was diluted with ethyl acetate and washed successively with water (2 times) and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated to give O-acetyl-N-benzyloxycarbonyl-L-threonine (3.64 g).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O1CC[N:21]([CH:24]=[CH:25][CH2:26][CH3:27])CC1.[NH4+].[Cl-]>CO.C(O)(=O)C>[CH2:26]([C:25]1[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:21][CH:24]=1)[CH3:27]
Reactant: CCC=CN1CCOCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of diethyl ethoxymethyleneoxalacetate (43.2 g, 0.16 mol) dissolved in CH3OH (150 mL) at -10° under N2 is added 1-morpholinobutene (25 g, 0.16 mol). The reaction is slowly warmed to room temperature over three hours, after which the CH3OH is removed in vacuo. The residue is dissolved in acetic acid (100 mL) and this solution slowly added to NH4Cl (34.2 g, 0.64 mol) dissolved in acetic acid (200 mL) at 50°-70°. The reaction is then heated to 90°-95° for two hours and 30 minutes, concentrated in vacuo, partitioned between water and the CH2Cl2, and the organic phase chromatographed over silica gel with CH2Cl2 -CH3CN (95:5) elution to give the product as an oil. Distillation at 123°-155° at 0.15mm gives the product (23.4 g, 83% pure, 55%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[S:17]([NH:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]1)(=[O:19])=[O:18].C([N:35](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[F:32][C:2]([F:31])([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:7][C:6]=1[S:17]([NH:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([NH2:35])=[O:30])[CH2:24][CH2:23]1)(=[O:18])=[O:19]
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)CC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@H](CNS(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of trans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylic acid (2.78 g, 5.63 mmol) and triethylamine (1.9 mL, 13.6 mmol) in THF (25 mL) was cooled to 0° C. To the mixture was added ethyl chloroformate (0.586 mL, 6.2 mmol) in THF (5 mL) over 10 min. After stirring at 0° C. for 15 min, 25% aqueous ammonia (10 mL) was added dropwise. The mixture was stirred at ambient temperature for 2 hr. The resulting mixture was concentrated under reduced pressure and the concentrate was diluted with water to give a solid. The solid was filtered and washed with water and hexanes to give trans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylic acid amide as a white solid (2.7 g, 98%).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[C:19]([F:30])[C:15]3[N:16]=[CH:17][O:18][C:14]=3[CH:13]=2)=[O:11])[CH2:4][O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:19]([F:30])[C:15]2[N:16]=[CH:17][O:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2cc3ocnc3c(F)c2Nc2ccc(I)cc2F)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOCC(O)CO)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide (488 mg, 0.89 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and washed with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) to afford the desired product (white solid, 310 mg, 48% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 8.96 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.53 (d, 1H), 7.28 (d, 1H), 6.40 (m, 1H), 4.84 (d, 1H), 4.60 (m, 1H), 3.87 (m, 1H), 3.72 (m, 2H), 3.36 (m, 2H). MS APCI (+) m/z: 527.8, [M+Na].
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:39]=O)=[C:22]2[C:26]=1[N:25]=[C:24]1[N:27]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[CH2:28][CH2:29][CH2:30][N:23]21.O>O1CCCC1>[Cl:17][C:18]1[C:26]2[N:25]=[C:24]3[N:27]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[CH2:28][CH2:29][CH2:30][N:23]3[C:22]=2[C:21](/[CH:39]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (0.78 mL, 3.93 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.157 g, 3.93 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (500 mg, 1.31 mmol) at 0° C. The mixture was stirred at room temperature for 4 hr and at 40° C. for 18 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound (489 mg, 1.08 mmol, 83%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:13][CH3:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.C(OCC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH:12]=[CH:11][N:10]=[C:9]3[CH2:13][CH3:14])=[CH:6][CH:7]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCc1nccn1-c1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCc1nccn1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Reaction time: 7 h
Yield: 75.6 %

Procedure:
1.9 g of 1-(4-aminophenyl)-2-ethylimidazole was added to a solution of 2.6 g of p-chlorobenzoyl chloride in 50 ml of toluene, and the mixture was refluxed with stirring for 7 hours. The reaction mixture was naturally cooled and diethyl ether was then added thereto. The precipitated crystal was recovered by filtration, washed sufficiently with ethyl ether and recrystallized from ethanol and then from water to obtain 2.5 g of the intended compound in the form of a hydrochloride. The melting point was 265° to 267° C. Elementary analysis values as C18H16ClN3O.HCl.1/2H2O were as follows.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([NH:15][OH:16])=[NH:14])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=O)=[CH:21][CH:20]=1>C(O)(=O)C>[Cl:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]2[O:16][N:15]=[C:13]([CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]3)[N:14]=2)=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CCC(CC)N1CCC(CC(=N)NO)CC1
Solvent: CC(=O)O
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc(CCl)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-((1-ethylpropyl)piperidin-4-yl)-N-hydroxyacetamidine (0.50 g, 2.2 mmol, prepared as described in Example 12), glacial acetic acid (15 mL) and 4-(chloromethyl)benzoyl chloride (0.46 g, 2.4 mmol) was stirred overnight at ambient temperature and then heated at reflux for 30 minutes. The mixture was concentrated in vacuo and the residue was dissolved in a mixture of 1 N hydrochloric acid (10 mL), water (50 mL) and diethyl ether (20 mL). The phases were separated and the aqueous phase was washed with diethyl ether (2×10 mL). The organic extracts were discarded and the aqueous phase was made alkaline (pH 10) with 4 N sodium hydroxide and then extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (MgSO4) and the solvent was evaporated. This afforded 0.70 g of 4-[5-(4-(chloromethyl)phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-1-(1-ethylpropyl)piperidine as an oil. 1H NMR (400 MHz, CDCl3) δ 0.87 (t, 6H), 1.22-1.49 (m, 4H), 1.40-1.52 (m, 2H), 1.67-1.74 (m, 2H), 1.78-1.88 (m, 1H), 2.13 (pent., 1H), 2.23-2.31 (m, 2H), 2.68-2.75 (m, 4H), 4.63 (s, 2H), 7.55 (d, 2H), 8.14 (d, 2H). HPLC: Rt=14.22 min.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:26][C:18]1[CH:17]=[C:16]([C:13]2[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=3)[O:15][N:14]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(CN=[N+]=[N-])cc3)n2)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CN)cc3)n2)cc1Cl
Temperature: 60 °C
Yield: 65.4 %

Procedure:
To a solution of 5-(4-(azidomethyl)phenyl)-3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole (0.066 g, 0.178 mmol) in THF (3.40 ml) and water (0.170 ml) was added polymer-supported triphenylphosphine (0.237 g, 0.711 mmol). After about 2 h the reaction mixture was heated to about 60° C. After about 1 h the reaction mixture was cooled to room temperature, filtered, concentrated in vacuo and purified by chromatography on silica gel (eluting with MeOH:DCM) to provide (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine (40 mg, 64%) as a colorless solid.