Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CO>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)#[CH:10]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(F)cn1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
To a mixture of 5-fluoro-2-formylpyridine (1.10 g, 9.0 mmol) in MeOH (38 mL) was added potassium carbonate (2.44 g, 0.018 mol) followed by a solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (2.03 g, 11 mmol) in MeOH (12 mL). The mixture was stirred at room temperature for 90 min, then extracted with diethylether. The organic layers were then washed with sodium hydrogen carbonate solution (1 M) and brine, dried over sodium sulfate, filtered and evaporated at to give the title compound (1.01 g, 78%) as a light brown liquid. MS: m/e=121.0 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:17]OC(=O)C1C=CC=C(Br)C=1C>CO>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: COC(=O)c1cccc(Br)c1C
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(Br)ccc1C

Procedure:
The crude 5-bromo-2-methylbenzoic acid (1) (60.8 g; 283 mmol) was stirred in methanol (400 mL) and concentrated sulfuric acid (6 mL) was added. The mixture was heated at gentle boiling for 20 hours. The solvent was evaporated and the residue was taken up into toluene and water. The solution was shaken and the phases were separated. The organic layer was washed with dilute aqueous NaHCO3, water, and brine. The solution was dried with MgSO4, filtered, and evaporated to get an orange oil. Fractional distillation at reduced pressure yields a mixture of the title compound and 3-bromo-2-methylbenzoic acid methyl ester (47.9 g; 74%).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([NH:46][C:47](=[O:49])[CH3:48])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=[C:38]([NH:46][C:47](=[O:49])[CH3:48])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1cc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)cc(C(F)(F)F)c1
Yield: 50.5 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-[4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-5-(trifluoromethyl)[1,1′-biphenyl]-3-yl]acetamide (1.85 g) and pyridine hydrochloride (551 mg), the colorless amorphous title compound (591 mg) was obtained.
Reaction SMILES: [OH:1]CCN1CCNCC1.C(O)(=O)/C=C/C(O)=O.[Cl:18][C:19]1[S:20][CH:21]=[C:22]2[C:28](N3CCN(CCO)CC3)=[N:27][C:26]3[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=3[O:24][C:23]=12>C1(C)C=CC=CC=1>[Cl:18][C:19]1[S:20][CH:21]=[C:22]2[C:28](=[O:1])[NH:27][C:26]3[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=3[O:24][C:23]=12
Reactant: OCCN1CCN(C2=Nc3ccccc3Oc3c2csc3Cl)CC1
Reactant: OCCN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2Oc2c1csc2Cl

Procedure:
A 4.0 g. portion of the above product is reacted with 4.0 g. of phosphorus pentachloride in 103 ml. of dry toluene as described in Example 1, giving 3,10-dichloro-thieno[3,4-b][1,5]benzoxazepine which is further reacted with 25 ml. of N-hydroxyethylpiperazine and 25 ml. of dry toluene giving the base compound as a foam which is converted to 4-(3-chlorothieno[3,4-b][1,5]benzoxazepin-10-yl)-1-piperazine-ethanol fumarate, m.p. 144°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:19](Cl)(Cl)=[O:20]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([N:17]=[C:19]=[O:20])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: O=C(Cl)Cl
Solvent: CC#N
Product: Cc1nc(N=C=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 85 °C

Procedure:
5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) (1.74 mmol, 0.5 g) is added to acetonitrile (15 ml) and treated with phosgene (20% solution in toluene, 6.99 mmol, 3.7 ml). The reaction mixture is heated to reflux (85° C.) for 30 minutes. After cooling to room temperature the solvent is removed in vacuo to leave 5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole as an orange solid.
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](OC)=[O:13])Br.COC(=O)C(C1C=CC(Cl)=CC=1C(OC)=O)Br.[SH:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[C:37]#[N:38].OC1C=CC=CC=1C#N>>[OH:13][C:12]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2[S:34][C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[C:37]=2[N:38]=1
Reactant: N#Cc1ccccc1S
Reactant: COC(=O)c1ccccc1C(Br)C(=O)OC
Agent: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Agent: N#Cc1ccccc1O
Product: Oc1nc2c3ccccc3sc2c2ccccc12

Procedure:
The procedure was similar to step S19B, while the starting material was 23A in stead of 19A, and used 2-mercapto-benzonitrile in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC(Cl)(Cl)Cl>[CH2:13]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:10]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: O=C1CCCc2cccc(Cl)c21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC=CCC1CCc2cccc(Cl)c2C1=O
Yield: 35 %

Procedure:
8.85 g of 8-chloro-1-tetralone were dissolved in 90 ml of tetrachloromethane under argon and added to 21.0 ml of 3-buten-2-ol and 190 mg of p-toluenesulfonic acid. The reaction solution was heated to reflux on a water separator for 9 days. The solvent was removed in a vacuum and the residue was chromatographed on 200 g of silica gel firstly with hexane/ethyl acetate 9:1 and then with hexane/ethyl acetate 4:1. In addition to large amounts of unreacted educt (8.3 g), there were obtained 4.1 g (35%) of 2-(2-buten-1-yl)-8-chloro-1-tetralone as a yellow oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([O:22]C)=[O:21])[C:3]=1[CH3:29].[C:30]([Cu])#[N:31].CN1C(=O)CCC1>CCO>[C:25]([O:24][CH:19]([C:4]1[C:3]([CH3:29])=[C:2]([C:30]#[N:31])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: N#C[Cu]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1C#N
Temperature: 200 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A suspension of methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (10.5 mg, 22.1 μmol), CuCN (9.8 mg, 0.11 mmol), and NMP (500 μL) was heated to 200° C. in a microwave. The reaction was cooled to 23° C., treated with EtOH (2.5 mL), filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and treated with LiOH monohydrate until the pH was distinctly basic. The mixture was concentrated with warming to remove most of the water and all of the CH3CN. The solution was treated with EtOH (absolute, 500 μL) and THF (1.0 mL). The suspension was stirred at 23° C. for 1 h. It was filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) (5.2 mg, 55% over 2 steps).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[C@@H:16]([CH2:17][CH2:18][CH3:19])[O:15][C:14]([CH3:21])([CH3:20])[O:13]2)(=O)=O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:20][C:14]1([CH3:21])[O:15][C@H:16]([CH2:17][CH2:18][CH3:19])[C@@H:12]([CH3:11])[O:13]1
Reactant: CCC[C@H]1OC(C)(C)O[C@@H]1COS(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC[C@H]1OC(C)(C)O[C@@H]1C
Temperature: 20 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of (4R,5R)-(2,2-dimethyl-5-propyl-1,3-dioxolan-4- yl)methanol p-toluenesulfonate (3.04 g, 9.25 mmol) in 30 ml of diethyl ether was added dropwise at 0° C. and under argon to a stirred suspension of lithium aluminum hydride (0.380 g, 10 mmol) in 50 ml of diethyl ether. The mixture was additionally stirred at 20° C. for 24 hours. The excess of lithium aluminum hydride was destroyed by addition of 0.2 ml of water. After stirring for 5 minutes, the mixture was treated with 1.8 ml of 10% strength by weight sodium hydroxide solution. The resulting mixture was additionally stirred vigorously for a further 10 minutes. The precipitate was then filtered off and the filter residue was extracted three times with 50 ml of tetrahydrofuran in each case. The combined organic phases were dried over anhydrous sodium sulfate. After chromatography on 100 g of silica gel using n-pentane containing 10-20% by volume of diethyl ether as eluent, the residue yielded 92% of (4R,5R)-2,2,5-trimethyl-4-propyl-1,3-dioxolane as a colorless oil ([α]D20=+6.28° (c=2.5 in trichloromethane)).
Reaction SMILES: [N:1]1C=CC=N[CH:2]=1.Cl[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1>CN(C=O)C.CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[CH3:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:2]#[N:1])[N:13]=1
Reactant: c1cncnc1
Reactant: Cc1ccnc(Cl)n1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccnc(C#N)n1
Temperature: 110 °C
Yield: 67 %

Procedure:
2-chloro-4-methylpyrimidine pyrimidine (725 mg, 5.62 mmol) was combined with zinc cyanide (396 mg, 3.37 mmol) and tetrakis (triphenylphosphne)palladium (0) (716 mg, 0.562 mmol) in DMF (10 mL) and the slurry was heated at 110° C. under nitrogen for 0.5 h. The mixture was cooled to rt, diluted with EtOAc (70 mL) and washed twice with 2N ammonium hydroxide (50 mL). The EtOAc solution was washed with brine (20 mL) and concentrated in vacuo to provide the crude mixture. The crude was then purified by column chromatography (30% EtOAc in hexanes) to afford 4-methylpyrimidine-2-carbonitrile in 67% yield.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])[CH3:2]
Reactant: CCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCNc1ccccc1N
Reaction time: 2 h
Yield: 100 %

Procedure:
N-Ethyl-2-nitroaniline (0.97 g, 5.8 mmol) was dissolved in EtOAc (60 mL) and placed in a closed vessel. 10% Pd/C (0.4 g, 7 mol %) was added and the mixture was hydrogenated under 50 psi H2 for 2 h. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield the title product (0.79 g, 99%) as a brown liquid, which was used without further purification. 1H-NMR (CDCl3): δ 6.83 (1H, m), 6.64–6.74 (3H, m), 3.29 (3H, br s), 3.15 (2H, q), 1.30 (3H, t); TLC (2:98 MeOH/DCM Rf 0.24).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32](OC)=[O:33])(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:42]([OH:45])([CH3:44])[CH3:43]>C1COCC1>[C:1]([NH:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32]([O:45][CH:42]([CH3:44])[CH3:43])=[O:33])(=[O:3])[CH3:2]
Reactant: CC(C)O
Reactant: COC(=O)c1c(NC(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C(=O)OC(C)C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 50 °C
Reaction time: 14 h

Procedure:
To the product of EXAMPLE 91 (10 mg) in isopropanol (4 mL) and THF (1 mL) was added Cs2CO3 (10 mg). The reaction stirred for about 14 hours at 50° C. LC/MS indicated incomplete reaction and the solution was then heated to 90° C. in a pressure tube for three hours. The reaction was concentrated and then diluted with EtOAc. After washing with saturated aqueous NaHCO3 the solution was dried (Na2SO4). The concentrated residue was purified by preparative TLC on silica gel eluted with 5% methanol in CH2Cl2 affording the title compound. HPLC/MS: 558.0 (M+1), 560.0 (M+3); Rt=4.93 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[C:10]([N:17]1[CH2:22][CH2:21][NH:20][C@H:19]([CH3:23])[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[CH3:9])[C@H:19]([CH3:23])[CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1ccc(Br)c(C)c1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)c(C)c1

Procedure:
To a mixture of 1-bromo-2,4-dimethylbenzene (3.8 mL), (R)-4-N-Boc-2-methylpiperazine (5.0 g), palladium (II) acetate (281 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (1.19 g) and sodium tert-butoxide (3.4 g) was added toluene (50 mL), and the mixture was refluxed for 3 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give (R)-4-(2,4-dimethylphenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. The compound was dissolved in chloroform (8.0 mL), 4N hydrogen chloride/ethyl acetate (8.0 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was alkalified, and extracted with chloroform. The organic layer was evaporated to give (R)-1-(2,4-dimethylphenyl)-2-methylpiperazine (1.2 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCO>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(N2CCN(CC(=O)OC(C)(C)C)CC2)cc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc(N2CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
A solution of the product of Step E (0.05 g; 0.129 mmol) in 60% TFA in CH2Cl2 (5 ml) was refluxed for 2 h, cooled to room temperature then diluted to 7 ml with EtOH. The resulting mixture was evaporated to dryness under reduced pressure kept in vacuo for 1 h. The residue was treated dissolved in EtOH (2 ml) and 3 drops of concentrated NH4OH was added. The resulting mixture was partially concentrated under reduced pressure and the precipitate, formed was filtered off, washed with Et2O and dried to give the titled compound (0.02 g; 47%) as colourless solid. 1H-NMR (CD3OD+CDCl3) 7.07 (d, 2H, J=8.6 Hz); 6.86 (d, 2H, J=8.6 Hz); 4.63 (s, CD3OH); 3.58 (s, 2H); 3.38 (m, 8H); 2.49 (t, 2H, J=7.8 Hz); 1.53 (m, 2H); 1.24 (m, 10H); 0.83 (m, 3H).
Reaction SMILES: OC1CCNCC1.BrC1SC(C=O)=CC=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:27][C:26]([CH:28]=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:28]/[C:26]2[S:27][C:23]([N:20]3[CH2:19][CH2:18][CH:17]([OH:16])[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: O=Cc1ccc(N2CCC(O)CC2)s1
Reactant: COc1ccc(CC#N)cc1OC
Agent: O=Cc1ccc(Br)s1
Agent: OC1CCNCC1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Yield: 49.2 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 4-hydroxypiperidine (3.03 g) was introduced into 5-bromothiophene-2-carboxaldehyde (1.91 g), to thereby yield 5-(4-hydroxypiperidin-1-yl)-thiophene-2-carbaldehyde (yield: 1.36 g, 64%). The produced 5-(4-hydroxypiperidin-1-yl)-thiophene-2-carbaldehyde (1.27 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.06 g) through Method A (production step 2), to thereby yield the target product (yield: 1.09 g, 50%).
Reaction SMILES: [Si]([CH2:17][CH2:18][NH2:19])(OCCOC)(OCCOC)OCCOC.[Si:20]([CH2:30][CH2:31][CH2:32][NH2:33])([O:27][CH2:28]C)([O:24][CH2:25]C)[O:21][CH2:22]C.[Si](CCCN)(OCCOC)(OCCOC)OCCOC.[Si](CCCOCCCN)(OCC)(OCC)OCC.[Si](COCCN)(OCC)(OCC)OCC.[Si](CCCOCCN)(OCC)(OCC)OCC>>[Si:20]([CH2:30][CH2:31][CH2:32][NH:33][CH2:17][CH2:18][NH2:19])([O:27][CH3:28])([O:24][CH3:25])[O:21][CH3:22]
Reactant: COCCO[Si](CCN)(OCCOC)OCCOC
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: CCO[Si](CCCOCCCN)(OCC)OCC
Agent: CCO[Si](CCCOCCN)(OCC)OCC
Agent: CCO[Si](COCCN)(OCC)OCC
Product: CO[Si](CCCNCCN)(OC)OC

Procedure:
(CH3OCH2CH2O)3Si(CH2)2NH2 ; (C2H5O)3Si(CH2)3NH2 ; (CH3OCH2CH2O)3Si(CH2)3NH2 ; (C2H5O)3Si(CH2)3O(CH2)3NH2 ; (C2H5O)2C6H5Si(CH2)3O(CH2)3NH2 ; (C2H5O)3SiCH2O(CH2)2NH2 ; (C2H5O)3Si(CH2)3O(CH2)2NH2 ; (C2H5O)2CH3Si(CH2)3NH2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:18]1[CH2:19][CH2:20][CH2:21][C@@H:17]1[C:9]1[O:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nc2ccccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2oc([C@H]3CCCN3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 16 mL flask, trifluoroacetic acid (4 mL) was added to a mixture of tert-butyl (2R)-2-(1,3-benzoxazol-2-yl)pyrrolidine-1-carboxylate (88 mg, 0.31 mmol; which may be prepared as described in Step 2) dissolved in dichloromethane (4 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was concentrated to dryness and the residue used in the next step without further purification.
Reaction SMILES: [C:1]1([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.[CH2:10](I)[CH:11]=[CH2:12]>>[CH2:12]([O:4][C:3]1[CH:2]=[C:1]([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=1)[CH:11]=[CH2:10]
Reactant: C=CCI
Reactant: Cc1cc(O)cc(O)c1
Product: C=CCOc1cc(C)cc(O)c1

Procedure:
Orcinol and allyl iodide were processed as described in Example 88C to provide the title compound. MS (DCI) m/z 165 (M+H)+.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1([C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CO>[ClH:1].[ClH:1].[O:18]1[CH2:19][CH2:20][N:15]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N1CCOCC1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(morpholine-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (20.0 mg, 0.038 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 14.5 mg (99%) of the desired product. LC-MS: RT=1.49 min, [M+H]+=307.1.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N+:6]([O:9][CH2:10][CH2:11][CH2:12][OH:13])([O-:8])=[O:7].C(N(CC)CC)C>>[C:1]([O:13][CH2:12][CH2:11][CH2:10][O:9][N+:6]([O-:8])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: O=[N+]([O-])OCCCO
Solvent: CCN(CC)CC
Product: CCC(=O)OCCCO[N+](=O)[O-]
Temperature: 3 °C
Reaction time: 2 h

Procedure:
9.1 mmol Propionyl chloride were dissolved in 10 ml TMBE and cooled to 3° C. 8.25 mmol 3-Nitrooxypropanol and 9.1 mmol triethylamine in 5 ml TMBE were dropped over a period of 5 min at 3 to 6° C. After 2 hours and 30 minutes stirring without cooling the reaction mixture were extracted with 1N HCl, twice with water, washed with brine, dried over Na2SO4 and the solvent was removed in vacuo leaving 1.35 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[NH2:29].CN1CCOCC1.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:29][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][N:23]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnccn1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 97 mg, 0.28 mmol), pyrazin-2-ylamine (29 mg, 0.31 mmol) and 4-methylmorpholine (123 μL, 1.12 mmol) were combined in N,N-dimethylformamide (1.5 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (117 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 16 h, further portions of pyrazin-2-ylamine (10 mg, 0.11 mmol), 4-methylmorpholine (41 μL, 0.37 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) were added. After stirring an additional 3 h, the reaction mixture was treated with ethyl acetate (100 mL) and saturated aqueous brine solution (200 mL). The phases were separated and the organic phase was washed with a 0.2 M aqueous potassium bisulfate solution and saturated aqueous brine solution (50 mL) and a 1:1 mixture of saturated aqueous sodium bicarbonate solution and saturated aqueous brine solution (50 mL) then dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-pyrazin-2-yl-acetamide (62 mg, 52%) as a clear, colorless film which was then lyophilized from aqueous acetonitrile to afford a white solid: LC-MS (ESI) m/e calcd for C18H19ClN4O4S [M+] 422.08, found 423 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.91 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.98 (m, 1 H, OCH), 7.57 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.68 (d, Jm=1.5 Hz, 1 H, Ar), 8.22 (d, Jo=8.2 Hz, 1 H, Ar), 8.33 (m, 1 H, Ar), 8.41 (m, 1 H, Ar), 9.29 (brs, 1 H, Ar), 9.56 (s, 1 H, NH).