Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:33])[C:21]([S:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][CH2:31][NH2:32])[N:29]=1)([CH3:23])[CH3:22])([CH3:18])([CH3:17])[CH3:16].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:15]([O:19][C:20](=[O:33])[C:21]([CH3:22])([S:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][CH2:31][NH:32][C:12]([C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)=[O:14])[N:29]=1)[CH3:23])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)c2cnn(-c3ccccc3)c2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
1-Phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (4.1 g) synthesized in Reference Example 16 was dissolved in methanol (40 mL) and tetrahydrofuran (40 mL), aqueous sodium hydroxide solution (1 mol/L, 40 mL) was added, and the mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under reduced pressure, aqueous hydrochloric acid solution (1 mol/L, 50 mL) was added, and the precipitated solid was filtrated. The solid was dissolved in ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1-phenyl-1H-pyrazole-4-carboxylic acid (2.5 g) as a white solid. This carboxylic acid (8.72 g) and 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (14 g) synthesized in Example 7 were dissolved in N,N-dimethylformamide (225 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (10.65 g) and 1-hydroxybenztriazole (HOBt) monohydrate (10.62 g) were successively added thereto, and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (16.2 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([CH3:13])[C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].Cl.[CH3:15][N:16]([C@@H:21]([CH:62]([CH3:64])[CH3:63])[C:22]([N:24]1[CH2:28][C@@H:27]([CH3:29])[CH2:26][C@H:25]1[C:30]1[NH:34][C:33]2[CH:35]=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([C:45]4[CH:50]=[CH:49][C:48]([C:51]5[NH:55][C:54]([C@@H:56]6[CH2:60][C@H:59]([CH3:61])[CH2:58][NH:57]6)=[N:53][CH:52]=5)=[CH:47][CH:46]=4)=[CH:41][CH:40]=3)[CH:37]=[CH:38][C:32]=2[N:31]=1)=[O:23])[C:17](=[O:20])[O:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:19][O:18][C:17]([N:16]([CH3:15])[C@@H:21]([CH:62]([CH3:64])[CH3:63])[C:22]([N:24]1[CH2:28][C@@H:27]([CH3:29])[CH2:26][C@H:25]1[C:30]1[NH:31][C:32]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([C:45]4[CH:50]=[CH:49][C:48]([C:51]5[N:55]=[C:54]([C@@H:56]6[CH2:60][C@H:59]([CH3:61])[CH2:58][N:57]6[C:7]([C@@H:6]([N:5]([CH3:13])[C:3](=[O:4])[O:2][CH3:1])[CH:10]([CH3:12])[CH3:11])=[O:8])[NH:53][CH:52]=5)=[CH:47][CH:46]=4)=[CH:43][CH:44]=3)=[CH:35][C:33]=2[N:34]=1)=[O:23])=[O:20]
Reactant: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](C)CN6)[nH]5)cc4)cc3)cc2[nH]1)C(C)C
Reactant: COC(=O)N(C)[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3ccc(-c4ccc5[nH]c([C@@H]6C[C@H](C)CN6C(=O)[C@H](C(C)C)N(C)C(=O)OC)nc5c4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 42.7 %

Procedure:
To a solution of (2S)-2-[methoxycarbonyl(methyl)amino]-3-methyl-butanoic acid (12.8 mg, 0.06765 mmol) and methyl methyl((S)-3-methyl-1-((2S,4S)-4-methyl-2-(6-(4′-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-yl)carbamate hydrochloride (48.1 mg, 0.0677 mmol) in DMF (2 mL) cooled in an ice bath is sequentially added HATU (28.3 mg, 0.0744 mmol) and DIPEA (0.035 mL, 0.203 mmol) under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 19 hours and diluted with saturated aqueous NaHCO3 (2 mL). The mixture is extracted with EtOAc (5×3 mL), and the combined organic layers are washed with H2O (3×3 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by reverse phase preparative HPLC to give methyl N-[(1S)-1-[(2S,4S)-2-[4-[4-[4-[2-[(2S,4S)-1-[(2S)-2-[methoxycarbonyl(methyl)amino]-3-methyl-butanoyl]-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]-N-methyl-carbamate (24.4 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1.[CH3:12][C:13]1[NH:14][C:15](=[O:25])[CH2:16][S:17][C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([O:10][CH:16]1[C:15](=[O:25])[NH:14][C:13]([CH3:12])=[C:18]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[S:17]1)=[O:9]
Reactant: CC1=C(c2ccncc2)SCC(=O)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
m-Chloroperbenzoic acid (8.97 g, 70% purity) was added to a solution of 5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (5.0 g) in dichloromethane (120 ml) under ice/water-cooling and the mixture was stirred for 10 minutes under ice/water-cooling. The mixture was washed with saturated sodium bicarbonate aqueous solution (2 times) and successively with water (1 time) and was dried over magnsium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ether-petrolem ether to give the titled compound (3.29 g, yield 37.6%) as pale yellow needles.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH3:20][O:21][CH2:22][CH2:23][NH:24][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: COCCN
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCOC)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (2-methoxy-ethyl)-amine to afford the title compound. MS: m/e=316 (M+H).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([S:20][CH3:21])[N:9]=2)[C:6]2[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=2[N:4]=1.ClC1C=CC=C(C(OO)=[O:35])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:26][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([S:20]([CH3:21])=[O:35])[N:9]=2)[C:6]2[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=2[N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of 2-(difluoromethyl)-1-[2-(methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (3 g) in dichloromethane (60 mL) was added m-chloroperbenzoic acid (75% wet) (1.9 g) under ice-cooling, and the mixture was stirred at 0° C. for 15 minutes. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (chloroform:methanol) to obtain 2-(difluoromethyl)-1-[2-(methylsulfinyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.8 g) as a white amorphous substance.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[CH2:18]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1)[CH3:19]>>[CH2:18]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:31][CH2:30]2)=[CH:26][CH:25]=1)[CH3:19]
Reactant: CCOCCOc1ccc(OC2CCNCC2)cc1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: CCOCCOc1ccc(OC2CCN(CC(=O)N[C@@H]3COc4nc([N+](=O)[O-])cn4C3)CC2)cc1
Yield: 30.6 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(2-ethoxyethoxy)phenoxy)piperidine (265 mg, 1.0 mmol) as crude materials, 75 mg title compound was generated and yield was 63%.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]2=[N:20][CH:21]=[N:22][C:23]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[C:18]2[CH:17]=[N:16]1.O>C(Cl)Cl.CO.C(O)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]2=[N:20][CH:21]=[N:22][C:23]([NH:24][CH2:25][C:26]([O:28][CH3:1])=[O:27])=[C:18]2[CH:17]=[N:16]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)CNc1ncnc2c1cnn2-c1ccccc1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CNc1ncnc2c1cnn2-c1ccccc1Cl

Procedure:
Trimethylsilyldiazomethane (2 M in diethyl ether) was added slowly to a stirred solution of N-[1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]glycine (Step 1) (0.80 g, 2.63 mmol) in DCM (4 mL) and MeOH (1 mL) until a yellow colour persisted. A few drops of acetic acid was added after 1 minute followed by the addition of DCM and water. The two phases were separated and the organic phase was concentrated in vacuo to give the title compound (795 mg), 1H NMR (300 MHz, CD3OD) δ 8.32 (s, 1H), 8.24 (s, 1H), 7.66 (m, 1H), 7.54 (m, 3H), 4.39 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([NH2:18])=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1.CN(C)C1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>C1COCC1>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([NH:18][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1(Oc2cc(N)c(F)cc2Cl)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Nc1cc(OC2(C(=O)OCC)CC2)c(Cl)cc1F

Procedure:
The obtained ethyl 1-(2-chloro-4-fluoro-5-amino-phenoxy)cyclopropanecarboxylate (1 equivalent) and dimethylaniline (1 equivalent) are added to THF and ethyl chloroformate (1 equivalent) is gradually added in drops thereto. After completion of addition, to the reaction solution is added aqueous diluted hydrochloric acid and the mixture is extracted with ethyl acetate. After concentrating the organic layer, the residue is subjected to chromatography to give ethyl 1-(2-chloro-4-fluoro-5-ethoxycarbonylaminophenoxy)cyclo-propanecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl.[CH3:13]O>>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: Cl
Product: COC(=O)c1ccc(O)c(O)c1
Yield: 86.5 %

Procedure:
A solution of 3,4-dihydroxy benzoic acid (2.8 g) in methanol (150 ml) was refluxed in presence of concentrated hydrochloric acid (0.5 ml) for 12 hrs. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate (150 ml) and washed with water (50 ml) 10% sodium bicarbonate solution (50 ml), brine solution (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 2.64 g of 3,4-dihydroxybenzoic acid methyl ester. (Yield 86.5%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:26][C@H:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH3:25])[N:3]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 47.3 %

Procedure:
2.4 g of 2,4,6-trichloropyrimidine was dissolved in 24 ml of tetrahydrofuran, and 2.0 ml of triethylamine was added at room temperature, and a solution of 2.0 g of (S)-(−)-1-(4-fluorophenyl)ethylamine in 12 mL of tetrahydrofuran was added dropwise, and then the mixture was stirred at room temperature for 9.5 hours. The reaction mixture was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 1.77 g of the objective compound.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Yield: 100 %

Procedure:
A mixture of N-acetyl-4-(4-nitrophenoxy)piperidine (1.6 g. 6.05 mmol) and 2N HCl (25 mL) was heated under reflux for 3 hours. The mixture was cooled and concentrated to give 1.5 g (100%) of 4-(4-nitrophenoxy)piperidine hydrochloride as an off-white solid; mp 216°-219° C.; 1H NMR (DMSO-d6): δ 9.05 (br s, 2H), 8.10 (d, 2H), 7.10 (d, 2H), 4.82 (m, 1H), 3.08 (m, 2H), 3.00 (m, 2H), 2.05 (m, 2H), 1.85 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O.C(OCC)(=O)C>[C:6]([C:5]1[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:10][C:2]([N:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27]2)=[N:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: NC(=O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cc(Nc3ccc(C(=O)N4CCOCC4)cc3)c(C(N)=O)cn2)C1
Temperature: 120 °C
Yield: 41.9 %

Procedure:
A solution of 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (230 mg, 0.637 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (166 mg, 0.829 mmol) in N-methyl-2-pyrrolidinone (2 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (107 mg, 0.829 mmol) in a vial, sealed and heated in a heating block at 120° C. for 2 days. The mixture was diluted with ethyl acetate and washed with water. Concentrated and the dark residue was chromatographed (ISCO Companion 12 g silica gel column and eluted with ethyl acetate) to give 140 mg of (R)-tert-butyl 1-(5-carbamoyl-4-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate as a white solid. LCMS: (M+H)+=525.21. 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9H) 1.50-1.65 (m, 2H) 1.68-1.81 (m, 1H) 1.91 (d, J=10.77 Hz, 1H) 3.16-3.36 (m, 2H) 3.55-3.80 (m, 10H) 3.88 (dd, J=12.85, 3.41 Hz, 1H) 4.68 (d, J=6.81 Hz, 1H) 5.75 (s, 2H) 6.41 (s, 1H) 7.30 (d, J=8.57 Hz, 2H) 7.44 (d, J=8.57 Hz, 2H) 8.32 (s, 1H) 10.33 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]([OH:19])=O)=[O:11])=[O:7])=[CH:4][C:3]=1[Cl:23].[O:24]=[C:25]1[O:29][CH:28]([O:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=CC=2)[CH:27]([NH:39]C(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)[CH2:26]1>>[CH:31]1([O:30][CH:28]2[CH:27]([NH:39][C:17]([CH:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:2]([NH2:1])=[C:3]([Cl:23])[CH:4]=3)[CH3:20])=[O:19])[CH2:26][C:25](=[O:24])[O:29]2)[CH2:32][CH2:33][CH2:38][CH2:37][CH2:36]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OC1CCCCC1
Yield: 47 %

Procedure:
Prepared from syn-(2-cyclohexyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a to give the title compound (153 mg, 47% yield). 1H-NMR (500 MHz, CD3OD) δ 1.06-2.38 (m, 14H), 1.42 (d, 3H), 2.50-2.66 (m, 1H), 2.69-2.82 (dd, 1H), 3.06-3.75 (m, 2H), 3.80-3.94 (m, 1H), 4.40-4.52 (m, 1H), 4.57-4.65 (m, 1H), 4.70-4.80 (m, 1H), 5.72 (d, 1H), 6.71 (m, 1H), 7.50-7.63 (m, 1H), 7.78 (d, 0.6H), 8.42 (d, 0.4H). Analytical HPLC 10.30 min. LC-MS (ES+) m/e=521.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[CH:9][C:10]=1Cl)[C:5](O)=[O:6].O1CCCC1.B(F)(F)F.O1CCCC1.O.C(Cl)[Cl:29]>>[NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[C:9]([Cl:29])[CH:10]=1)[CH2:5][OH:6]
Reactant: ClCCl
Reactant: Nc1c(Cl)ccc(C(=O)O)c1Cl
Agent: FB(F)F
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Cl)cc(CO)c1Cl
Temperature: 8 °C
Reaction time: 1 h

Procedure:
Into a 1 liter three-neck flask was introduced 40 g (0.19 mole) of 3-amino-2,4-dichlorobenzoic acid and 150 ml of tetrahydrofuran. The solution was cooled to 8°-10° C. in an ice bath. A borontrifluoride-tetrahydrofuran (1M) solution (280 ml) was added dropwise over a period of 1 hr. After being stirred at 8° C. for an additional 1 hr. the solution was allowed to warm up slowly to room temperature. The reaction flask was then cooled again in an ice bath and 50 ml of water was added through a dropping funnel. The mixture was taken into 1 liter of methylene chloride and washed once with NaHCO3 and twice with water, then dried over calcium sulfate. The methylene chloride solution afforded 19.2 g of crude solid product, mp 111-121. Five grams of the crude solid was recrystallized from acetonitrile to yield 4.2 g of 3-amino-2,5-dichlorobenzyl alcohol; mp 121-127; nmr (DMSO-d6) δ4.50 (D, 2H), 5.34 (t, 1H), 5.52 (S, 2H), 6.73 (S, 2H); ir (CHCl3) 3490, 3380, 3240, 1630 and 1598 Cm-1.
Reaction SMILES: [C:1]([N:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([NH:14][C:15]2[C:19]3[CH:20]=[C:21]([CH2:24][C:25](OC)=[O:26])[CH:22]=[CH:23][C:18]=3[O:17][C:16]=2[C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=2)=[O:30])=[O:13])[CH2:8][CH2:7]1)[CH3:5])(=[O:3])[CH3:2].[BH4-].[Li+].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([N:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([NH:14][C:15]2[C:19]3[CH:20]=[C:21]([CH2:24][CH2:25][OH:26])[CH:22]=[CH:23][C:18]=3[O:17][C:16]=2[C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=2)=[O:30])=[O:13])[CH2:8][CH2:7]1)[CH3:5])(=[O:3])[CH3:2]
Reactant: COC(=O)Cc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C(C)=O)CC3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(=O)N(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(CCO)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonylamino]-5-methoxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.95 g) obtained in Example 2 is suspended in tetrahydrofuran (65 ml), and thereto is added lithium borohydride (238 mg), and the mixture is stirred at room temperature for 12 hours. To the reaction solution is poured 10% hydrochloric acid under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. Subsequently, the reaction solution is neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate, then chloroform/methanol=40/1), and the resulting residue is suspended in diethyl ether. The precipitates are collected by filtration to give the title compound (2.24 g).
Reaction SMILES: COC(=O)C(N1C(=O)CCN(C(=O)/C=C/C2C=CC([Cl:26])=C(Cl)C=2)CC1)CC(O)=O.CCN(CC)CC.[CH2:37]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][C@H:40]2[OH:45])[CH2:38]1>>[ClH:26].[CH2:38]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][C@H:40]2[OH:45])[CH2:37]1
Reactant: COC(=O)C(CC(=O)O)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: O[C@@H]1CNCCC12CC2
Solvent: CCN(CC)CC
Product: Cl

Procedure:
In analogy to the procedure described in example 6A, 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-succinic acid 1-methyl ester (intermediate 7) with 1.5 eq. of Et3N (added before cooling) and 1.05 eq. of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave, after purification on a SiO2-column (dichloromethane/Isopropanol 97.5:2.5-9:1 gradient), the titled compound in 33% yield as white foam. MS: 552.0 (MH+, 2Cl).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[N:15]2[N:16]=[C:17]([NH2:19])[N:18]=[C:14]2[CH:13]=[C:12]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:11]=1>>[CH:3]1([N:2]([CH3:1])[C:10]2[N:15]3[N:16]=[C:17]([NH2:19])[N:18]=[C:14]3[CH:13]=[C:12]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Product: CN(c1cc(-c2cccnc2)cc2nc(N)nn12)C1CCCCC1

Procedure:
A mixture of N-methyl-cyclohexylamine (4 mL) and 5-chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine, which may be produced as in Example 1A, (300 mg, 1.22 mmol) was microwaved at 200° C. for 3 h. On cooling, the product was triturated with toluene/cyclohexane then taken up in CH2Cl2 and washed with aqueous Na2CO3. The organic layer was separated, dried (MgSO4), and concentrated to produce N5-cyclohexyl-N5-methyl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine. MS m/z 323 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CNOC.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].OS([O-])(=O)=O.[Na+]>ClCCl.C(OCC)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CNOC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=CCCCc1ccccc1

Procedure:
A solution of 4-phenylbutyric acid (1.64 g, 10.0 mmol), N,O-dimethyl hydroxylamine hydrochloride (1.58 g, 16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.06 g, 10.7 mmol), 1-hydroxybenzotriazole (1.56 g, 11.6 mmol), and N-methylmorpholine (2.8 mL, 26 mmol) in dichloromethane (40 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated. A mixture of the concentrate and lithium aluminum hydride (9.0 mmol, 1 equiv.) in diethyl ether (49 mL) at room temperature was stirred for 90 minutes, treated with 1M NaHSO4, diluted with diethyl ether, washed sequentially with 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 148 (M+H)+.