Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@@H:4]([NH:6][C:7]2[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)[C:3]1([CH3:20])[CH3:19].[NH2:21][CH2:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][C:33]([F:36])([F:35])[F:34])[CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([CH2:23][CH2:22][NH:21][C:9]2[N:8]=[C:7]([NH:6][C@@H:4]3[CH2:5][C@H:2]([OH:1])[C:3]3([CH3:20])[CH3:19])[C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:25][C:26]=1[O:32][C:33]([F:34])([F:35])[F:36])#[N:29]
Reactant: CC1(C)[C@@H](O)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C#N
Reactant: N#Cc1ccc(CCN)cc1OC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)[C@@H](O)C[C@H]1Nc1nc(NCCc2ccc(C#N)c(OC(F)(F)F)c2)ncc1C#N
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 29.5 %

Procedure:
A mixture of 4-(((1R,3S)-3-hydroxy-2,2-dimethylcyclobutyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (80 mg, 0.27 mmol), 4-(2-aminoethyl)-2-(trifluoromethoxy)benzonitrile (60 mg, crude)) and DIEA (105 mg, 0.81 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by standard methods to afford the title compound (34.4 mg, 0.077 mmol, 40% yield, over two steps). 1H NMR (400 MHz, CD3OD) δ8.14-8.07 (m, 1H), 7.82-7.80 (m, 1H), 7.45-7.43 (m, 2H), 3.97-3.93 (m, 1H), 3.83-3.70 (m, 2H), 3.68-3.59 (m, 1H), 3.10-2.01 (m, 2H), 2.58-2.54 (m, 1H), 2.15-2.06 (m, 1H), 1.21 (s, 3H), 0.95 (s, 3H). MS (ESI) m/z 447.2 [M+1]+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].S(=O)(=O)(O)O.[CH2:11]=[C:12]1[CH:19]2[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:12]1([CH3:11])[CH:13]2[CH2:21][CH:17]3[CH2:16][CH:15]([CH2:20][CH:19]1[CH2:18]3)[CH2:14]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: C=C1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 20 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 36.0 g (0.50 mol) of acrylic acid, 0.5g (5mmol) of sulfuric acid and 100 g of toluene. Separately 88.8 g (0.60 mol) of 2-methyleneadamantane, prepared by the same procedures as described in Reference Example 1, was dissolved in 100 g of toluene. The obtained solution of 2-methyleneadamantane in toluene was dropwise added to the content in the flask over a period of about 3 hours, while the content was maintained at a reaction temperature of about 20° C. Then the content was stirred for 5 hours at the same temperature. After completion of the reaction, the residual catalyst was neutralized by adding 40.0 g (50 mmol) of a 5% aqueous sodium hydroxide solution, and the neutralized liquid was washed with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 100.7 g (yield: 91.5%) of the object 2-methyl-2-adamantyl acrylate was obtained.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C1COCC1>[C:1]([NH:5][S:15]([C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)(=[O:16])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 94.8 %

Procedure:
To a solution of tert-butylamine (0.47 L, 6.4 mol) in THF (0.55 L) is slowly added, at 0° C., a solution of 4-nitrobenzenesulfonyl chloride (50 g, 0.23 mol) in THF (0.55 L) and the resulting mixture is stirred for 24 h at room temperature. The solvent is removed and the residue is taken up in a CHCl3/0.5 N HCl mixture, the layers are separated and the aqueous phase is extracted with CHCl3. The combined organic extracts are washed with H2O and brine and dried over MgSO4. The solvent is removed, yielding 56.3 g of a yellowish solid which is directly used in the next reaction (yield: 97%).
Reaction SMILES: O=C1N(C[C:9]([OH:11])=[O:10])C(C2C=CC(F)=CC=2)=NC=C1.[ClH:19].[CH3:20][C:21]([C:29]1[O:30][C:31]([CH:34]([OH:40])[C@@H:35]([NH2:39])[CH:36]([CH3:38])[CH3:37])=[N:32][N:33]=1)([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[ClH:19].[CH3:20][C:21]([C:29]1[O:30][C:31]([CH:34]([OH:40])[C@@H:35]([NH2:39])[CH:36]([CH3:37])[CH3:38])=[N:32][N:33]=1)([CH3:28])[C:22]1[CH:23]=[CH:24][C:25]2[O:10][CH2:9][O:11][C:26]=2[CH:27]=1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nccc1=O
Reactant: CC(C)[C@H](N)C(O)c1nnc(C(C)(C)c2ccccc2)o1
Agent: Cl
Product: CC(C)[C@H](N)C(O)c1nnc(C(C)(C)c2ccc3c(c2)OCO3)o1

Procedure:
The intermediate 2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]hydroxymethyl)-2-(S)-methylpropyl]acetamide was prepared in an analoguous manner as described in Example 1 E using [6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]acetic acid. and 1-[2-(α,α-dimethylbenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride. The intermediate 1-[2-(α,α-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]-2-(S)-amino-3-methylbutan-1-ol hydrochloride was prepared using a similar procedure as described in Example 1 D. The heterocyclic intermediate 2-(α,α-dimethylbenzyl)-1,3,4-oxadiazole gave the following physical data.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[NH2:10][OH:11]>CCO>[OH:11][N:10]=[C:8]([NH2:9])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: NO
Reactant: Cc1cccc(C#N)n1
Solvent: CCO
Product: Cc1cccc(C(N)=NO)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-Methylpicolinonitrile (12 mg, 0.1 mmol) was dissolved in EtOH (0.5 mL) and treated with NH2OH (1.5 eq of a 50% aq solution). The mixture was stirred at room temperature for 12 hours then reduced to dryness to afford N′-hydroxy-6-methylpicolinimidamide (6) as a clear yellow oil, which was used without purification.
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@@H:17]([O:19]C(=O)C)[CH2:16][C@@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23][CH2:24][O-].[Na+].CCO>C(O)C>[CH2:23]([O:15][C:13](=[O:14])[C@H:12]1[CH2:16][C@H:17]([OH:19])[CH2:18][N:11]1[C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:24]
Reactant: CC[O-]
Reactant: CC(=O)O[C@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of N-CBZ-trans-4-acetoxy-D-proline (2.45 g, 7.31 mmol) in ethanol (50 mL) was added freshly prepared NaOEt/EtOH (0.017 g, 0.7 mmol of Na dissolved in 1 mL of EtOH). After stirring at room temperature for 20 minutes, the reaction was quenched with NH4Cl (0.1 g), and concentrated in vacuo to an oily solid. The desired alcohol was isolated (2.01 g, 94%) as a colorless oil by diluting the residue with ethyl ether (50 mL), filtering the solution through Celite, washing the filter cake with ethyl ether, and concentrating the combined filtrate and washings in vacuo. The alcohol was sufficiently pure to use directly in the next step: [α]25D +59° (c, 1.04 CHCl3); Spectra were identical in all respects to those of the enantiomer N-(benzyloxycarbonyl)-trans-4-hydroxy-L-proline ethyl ester; LRMS (CI, 70 eV, isobutane) m/e 294 (MH+, 100), 250 (98), 220 (24), 158 (25), 91 (89); HRMS (EI, 50 eV) m/e 293.1272 (293.1263 calcd for C15H19NO5).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.CC1(C)[O:33][C@H:32]([CH:34]=O)[CH2:31][O:30]1.Cl.CO>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:34][C@@H:32]([OH:33])[CH2:31][OH:30])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC1(C)OC[C@@H](C=O)O1
Agent: Br
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC[C@@H](O)CO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde. The protecting group is cleaved off by means of a 1.25 N HCl/methanol solution: The reaction mixture was stirred at room temperature for 5 h, evaporated to dryness and dried under a high vacuum. The product was converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5](OCC)=[O:6].[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[CH2:16][CH2:17][C:18]#[N:19])[CH3:13]>O1CCCC1>[CH2:21]([O:20][CH:15]([O:14][CH2:12][CH3:13])[CH2:16][CH:17]([C:5](=[O:6])[C:4]([F:11])([F:10])[F:3])[C:18]#[N:19])[CH3:22]
Reactant: CCOC(CCC#N)OCC
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(CC(C#N)C(=O)C(F)(F)F)OCC

Procedure:
Preparation of (trifluoromethyl)pyrrole carbonitriles and conversion thereof to dihalo (trifluoromethyl)pyrrole carbonitriles and dihalo- alkylated N-(trifluoromethyl)pyrrole carbonitriles can be achieved by the admixture of a dispersion of sodium hydride in tetrahydrofuran with a solution of ethyl trifluoroacetate and 3-cyano propionaldehyde diethyl acetal in tetrahydrofuran. The reaction that occurs yields 3-trifluoroacetyl-3-cyanopropionaldehyde diethyl acetal which is then heated with oxalic acid dihydrate in water to give the 3-trifluoroacetyl-3-cyanopropionaidehyde. The thus prepared aldehyde is then dissolved in glacial acetic acid and the resulting solution treated with ammonium acetate to provide the 2-(tri-fluoromethyl)pyrrole-3-carbonitrile. Halogenation of the above-said (trifluoromethyl)pyrrole carbonitrile may then be accomplished by reaction of said (trifluoromethyl)pyrrole carbonitrile with N-bromosuccinimide or N-chlorosuccinimide in the presence of tetrahydrofuran to yield the dihalo (trifluoromethyl)pyrrole carbonitrile. Alkylation or aoylation of this dihalo (trifluoromethyl)pyrrole carbonitrile with an alkyl halide or acylhalide in the presence of potassium t-butoxide and tetrahydrofuran yields the N-alkylated (or N-acylated) dihalo (trifluoromethyl)pyrrole carbonitrile.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=2)=O)=[CH:9][CH:8]=1)[CH3:4].Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[OH:35]/[N:34]=[C:15](/[C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=1)\[CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]([NH:5][C@H:3]([CH3:4])[CH2:2][OH:1])=[O:32])=[CH:12][CH:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](C)CO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](C)CO)cc1

Procedure:
In analogy to example 151, step 3, N—((R)-1-hydroxypropan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid, MS (ESI+): m/z=448.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:12][CH:11]([CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:10]2)[N:4]=1.Cl>O1CCOCC1>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:12][CH:11]([CH2:13][CH2:14][NH2:15])[CH2:10]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)NCCC1CN(c2nccc(C(F)(F)F)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCCC1CN(c2nccc(C(F)(F)F)n2)C1

Procedure:
The process is performed according to the procedure described in Example 11 (step 11.2.). Starting with 3.67 g (10.60 mmol) of tert-butyl {2-[1- (4-trifluoromethylpyrimidin-2-yl)azetidin-3-yl]ethyl}carbamate and 10.60 mL (42.38 mmol) of a 4N solution of hydrogen chloride in dioxane, 1.75 g of product are obtained in the form of a yellow oil, after purification by chromatography on silica gel, eluting with a 100/0/0 to 90/10/1 mixture of dichloromethane, methanol and 28% aqueous ammonia.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[N:19]=[C:20]([CH3:23])[S:21][CH:22]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33]C)=[O:32])=[CH:4][CH:3]=1.CO.Cl>[Li+].[OH-].C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[N:19]=[C:20]([CH3:23])[S:21][CH:22]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([OH:33])=[O:32])=[CH:37][CH:38]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3csc(C)n3)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(COc2ccc3c(c2)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n3Cc2ccc(Cl)cc2)cs1

Procedure:
A solution of the ester from Step 1 (22.5 g) in 118 mL 1N LiOH, 120 mL THF, and 65 mL MeOH was heated at 60° C. for 2 hours. The mixture was cooled, poured onto 1N HCl, and extracted with EtOAc (3×). After washing the organic phase twice with brine, the solution was dried (MgSo4) and evaporated. The residue was swished with ether/hexane 1:2 to give the title compound as a solid; m.p. 196.5°-198° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[OH2:11]>[Cu]>[NH2:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([NH2:1])=[O:11])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: O
Agent: [Cu]
Product: NCc1ccc(C(N)=O)cc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
In a 100 ml autoclave (manufactured by Nitto Koatsu Co., Ltd., material: SUS-316), 43 g of water, 11.5 g of a water-containing p-aminomethylbenzonitrile (10 g as p-aminomethylbenzonitrile, purity: 86.7%.) and 2.0 g of sponge copper (R-300C, manufactured by NIKKO RICA CORPORATION) were charged and, after sealing the autoclave, the atmosphere in the autoclave was replaced by nitrogen and the reaction was conducted at 100° C. for 6 hours. After the completion of the reaction, the catalyst was collected by filtration and the filtrate was cooled to 5° C., and then the crystal was collected by filtration. 10.0 g of the resulting crystal (wet form, containing 8.05 g of p-aminomethylbenzamide) was suspended in 43 g of water and dissolved with heating to 70° C., followed by cooled again to 5° C., filtration and further drying to obtain 7.99 g of p-aminomethylbenzamide (yield based on p-aminomethylbenzonitrile: 71%). The purity of p-aminomethylbenzamide determined by analyzing using high-performance liquid chromatograph was 99% or higher.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[N:11]1[N:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:13]=[N:14][CH:15]=1.S(=O)(=O)(O)O.FC(F)(F)[C:30](O)=[O:31]>>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([N:12]2[N:13]=[N:14][CH:15]=[N:11]2)=[CH:21][C:20]=1[CH:30]=[O:31]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(-n2ncnn2)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Product: O=Cc1cc(-n2ncnn2)ccc1O

Procedure:
Hexamethylenetetramine (5.6 g) was added to 4-tetrazol-2-yl-phenol (1.6 g) in trifluoroacetic acid (40 ml) and the mixture heated at 60° for 24 h. On cooling, the solution was poured into sulphuric acid (2N, 100 ml), extracted with ether (3×100 ml), dried (Na2SO4) and evaporated. The residue was purified by FCC (dichloromethane) to give the title compound as a yellow solid (930 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][NH:4][C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1.C(N(C(C)C)CC)(C)C.Cl[C:37](=[O:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CC(N(C)C)=O>[CH2:41]([O:40][C:38](=[O:39])[C:37]([N:4]([CH2:3][CH:2]([CH3:26])[CH3:1])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:6]1)=[O:43])[CH3:42]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (9.24 g) and diisopropylethylamine (10.5 ml) in DMA (100 ml) was added dropwise ethyl chloroglyoxylate (3.4 ml) at 0° C. The reaction mixture was stirred at room temperature for 15 hr, and the reaction mixture was concentrated. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (10.3 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[N+:23]([O-])=O)[CH2:19][CH2:18][CH2:17]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>C(O)(=O)C.O>[NH2:23][C:22]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH2:19]2)=[CH:15][C:14]=1[O:13][CH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1ccc(COc2cc3c(cc2[N+](=O)[O-])CCC3)cc1F
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(COc2cc3c(cc2N)CCC3)cc1F
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 60.3 %

Procedure:
11.0 g of methyl 2-fluoro-4-{[(6-nitro-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate was dissolved in 120 mL of acetic acid and 12.0 mL of water, and 8.89 g of reduced iron was added thereto at 60° C., followed by stirring at 60° C. for 4.5 hours. The reaction liquid was cooled to room temperature, and then filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended in water and ethyl acetate, neutralized by the addition of sodium hydrogen carbonate, and then filtered through Celite. After the filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (toluene:ethyl acetate=95:5 to 90:10) to obtain 6.06 g of methyl 4-{[(6-amino-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-2-fluorobenzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[NH2:17].CCCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH3:23])=[C:14]([Br:13])[CH:15]=1)=[O:12])([O-:3])=[O:2]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: CCOc1ccc(N)cc1Br
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOc1ccc(NC(=O)Nc2ccccc2[N+](=O)[O-])cc1Br
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-Nitrophenyl isocyanate (3.34 g) in 100 mL of toluene was added 3-Bromo-4-ethoxyaniline (3.1 g). The mixture was stirred at 20° C. for 30 min. Hexane (300 mL) was added and the resulting solid was filtered and dried to yield N-(2-Nitrophenyl)-N'-(3-bromo-4-ethoxyphenyl)-urea as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].[NH2:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][SH:13].O>C(O)C>[CH3:2][C:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][S:13]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(=O)c1cccnc1
Solvent: CCO
Solvent: O
Product: CC1(c2cccnc2)NC(C(=O)O)CS1
Yield: 37.8 %

Procedure:
A mixture of 3.63 g of 3-acetylpyridine, 3.63 g of L-cysteine, 25 ml of water and 25 ml of ethanol was refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure, isopropanol was added to the residue, and the resultant powder was collected by filtration. Ethanol was added to the powder, the insoluble matter was filtered off, and the filtrate was concentrated to dryness. The residue was dissolved in water and adjusted to pH 6 by addition of diluted hydrochloric acid under ice cooling and stirring, and the resultant powder was collected by filtration, washed with ethanol and dried to give 2.54 g of 2-methyl-2-(3-pyridyl)thiazolidine-4- carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCOCC.CC(C)=O.CCOCC>[N:17]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[O:9])[CH:4]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: O=C(c1ccc(F)cc1)c1cc(CBr)on1
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(c1ccc(F)cc1)c1cc(CN2CCOCC2)on1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4.5 g of (5-bromomethylisoxazol-3-yl-4-fluorophenylmethanone in 100 ml of Et2O was added dropwise to a solution of 7 ml of morpholine in 300 ml of 50% acetone/Et2O. The resulting mixture was stirred at room temperature for 20 hours. This mixture was filtered and the volatiles evaporated to give a residue which was dissolved in 600 ml of Et2O. The organic solution was washed with water until it became neutral and then with saturated NaCl, and dried over Na2SO4 and concentrated in vacuo to give 4.3 g of a crystalline solid. A 3.6 g sample of the amine was recrystallized from 65 ml of 8% toluene/hexane to yield 2.4 g (64%) of crystals, m.p. 72°-74°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:16][C:15]([S:17]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:16][C:15]([S:17]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)(=[O:18])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1

Procedure:
N-[5-(4-Methylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 13C using 4-methyl-phenylboronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 2% ethyl acetate/hexanes gave N-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole as a pale yellow solid in 77% yield.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17](=[O:18])[CH2:16][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1]
Reactant: COC(=O)CCl
Reactant: Nc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CNc1ccc(F)cc1F
Reaction time: 16 h

Procedure:
A suspension of 2,4-difluoroaniline (15.0 g) and sodium bicarbonate (19.5 g) in methyl chloroacetate (15.2 ml) was stirred at 90°-100° under nitrogen for 16 h. Work up according to the method of Intermediate 11 gave an oil (14.1 g) which was purified by FCC on triethylamine deactivated silica eluting with chloroform:petroleum ether (1:8) to give the title compound (8.75 g) as an oil, t.l.c. on triethylamine deactivated silica (chloroform:petroleum ether, 1:8) Rf 0.21.