Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:6]([OH:8])=[O:7])(=O)C.C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.[F:50][CH:51]([F:55])[C:52](O)=[O:53].CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:10]1[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:12][CH:13]=[CH:14][C:9]=1[CH:5]([NH:4][C:52](=[O:53])[CH:51]([F:55])[F:50])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl)C(F)F
Reaction time: 16 h
Yield: 64 %

Procedure:
To a stirred solution of Example 13 Part A compound (222 mg, 0.45 mmol) under argon at room temperature in CH2Cl2 (2.5 mL) was added triethylamine (85 μL, 0.6 mmol), HOAt (69 mg, 0.5 mmol) and difluoroacetic acid (48 mg, 0.5 mmol) was added EDAC (96 mg, 0.5 mmol). After 16 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 156 mg (64% yield). LC/MS gave the correct molecular ion [(M+H)+=538] for the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22](Cl)[CH:23]=[CH2:24].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH2:24]([N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:14]1=[O:21])[CH:23]=[CH2:22]
Reactant: C=CCCl
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: C=CCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CCCC[C@@H]2C1=O

Procedure:
Prepared from compound 1 and allylchloride as described for compound 8. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60-95° C.). M.p. 99-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:14]1[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:13].OC1C2C(=CC=CC=2)[NH:26]C1=O.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=1[S:44](Cl)(=[O:46])=[O:45].S(Cl)(Cl)(=O)=O>>[NH2:26][C:5]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:4]2[C:8](=[CH:9][C:10]([F:11])=[C:2]([Cl:1])[CH:3]=2)[N:7]([S:44]([C:37]2[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:36]=2[O:35][CH3:34])(=[O:46])=[O:45])[C:6]1=[O:12].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:14]1[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:13]
Reactant: O=C1Nc2ccccc2C1O
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(Cl)cc21
Solvent: O=S(=O)(Cl)Cl
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(Cl)cc21

Procedure:
3-Amino-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-1,3-dihydroindol-2-one was prepared in analogy to example 1.1 to 1.3 using 5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one as 3-hydroxy-1,3-dihydroindol-2-one IV and 2,4-dimethoxyphenylsulfonyl chloride as sulfonyl chloride VII. 5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one was prepared in analogy to example a.1.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([CH2:10][CH:11]=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:13][N:14]1[CH:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH:15]1[CH3:21].Cl>O.CO>[CH3:21][CH:15]1[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[N:14]1[NH:13][CH:11]([CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]#[N:2]
Reactant: O=CCc1ccccc1
Reactant: CC1CCCC(C)N1N
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CCCC(C)N1NC(C#N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 126.5 %

Procedure:
7.4 g of sodium cyanide, dissolved in 40 ml of water, and 18.0 g of phenyl acetaldehyde, dissolved in 30 ml of methanol, are added dropwise with ice-cooling to a mixture of 12.8 g of 1-amino-2,6-dimethylpiperidine, 60 ml of water and 8.6 ml of concentrated hydrochloric acid. The reaction mixture is stirred at room temperature for 3 days and extracted with dichloromethane. The combined organic phases are washed with water of pH 4-5 containing acetic acid, dried and concentrated in a rotary evaporator. 32.5 g of 2-((2,6-dimethylpiperidino)amino)-3-phenylpropionitrile are obtained, which are reacted further without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.[C:48](O)(=[O:50])[CH3:49].CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1.ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:48](=[O:50])[CH3:49])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: CC(=O)O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Temperature: 60 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
A mixture of 8a (0.20 g, 0.51 mmol), diphenyl-2-pyridylphosphine (0.20 g, 0.77 mmol) and acetic acid (0.12 mL, 2.05 mmol) was dissolved in anhydrous THF (15 mL) under an argon atmosphere. To this solution was added di-tert-butylazodicarboxylate (DBAD) (0.18 g, 0.77 mmol) in one portion and the mixture was stirred for 18 hours at 60° C. The solvent was under reduced pressure and the residue was dissolved in dichloromethane (25 mL). The CH2Cl2 portion was washed with 4 M HCl (2×25 mL) and saturated NaCl (25 mL), and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude residue. Flash column chromatography (eluent: n-hexanes/EtOAc, 7:3) gave 0.18 g (80%) of 34 as a white crystalline solid, mp 215-216° C.; 1H NMR (CDCl3): δ 1.10 (3H, s); 1.28 (1H, dd, J=6.0, 14.1); 1.45 (1H, m); 1.46 (3H, s); 1.64 (2H, m); 1.80 (1H, dd, J=3.0, 9.9); 2.10 (1H, m); 2.13 (3H, s); 2.18 (1H, ddd, J=3.3, 3.3, 15.0); 2.34 (1H, ddd, J=3.3, 13.0, 15.6); 2.45 (1H, dd, J=5.1, 13.5); 2.54 (1H, s); 2.90 (1H, dd, J=3.6, 13.2); 3.71 (3H, s); 4.85 (1H, dd, J=3.2, 3.2); 5.54 (1H, dd, J=5.1, 11.7); 6.38 (1H, dd, J=1.4, 1.7); 7.40 (2H, m); 13C NMR (CDCl3): δ 15.4, 16.3, 18.3, 21.2, 31.1, 35.2, 38.8, 43.2, 43.6, 51.1, 51.5, 52.1, 61.9, 72.3, 76.6, 108.5, 125.7, 139.4, 143.9, 169.6, 171.4, 172.4, 204.6; anal. C 63.63%, H 6.59%, O 29.70%, calcd for C25H28N2O7S, C 63.88%, H 6.53%, O 29.60%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)c2cc(N)ccc21

Procedure:
A solution of 230.0 mg (1.05 mmol) 3,4-dihydro-4,4-dimethyl-7-nitro-1(2H)-naphthalenone (Compound Y) in 5.0 ml of EtOAc was stirred at room temperature with a catalytic amount of 10% Pd-C under 1 atm of H2 for 24 hours. The catalyst was removed by filtration through a pad of Celite, and the filtrate concentrated under reduced pressure to give the title compound as a dark green oil. 1H NMR (CDCl3): δ 7.30 (1H, d, J=2.7 Hz), 7.22 (1H, d, J=8.4 Hz), 6.88 (1H, dd, J=2.7, 8.5 Hz), 2.70 (2H, t, J=6.6 Hz), 1.97 (2H, t, J=6.6 Hz), 1.34 (6H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>[OH-].[Na+]>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrCCCCCCBr
Reactant: CSc1ccc(CCCCO)cc1
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(CCCCOCCCCCCBr)cc1

Procedure:
From 4-(methylthio)benzenebutanol (5.6 g), 1,6-dibromohexane (18.3 g), TAB (0.5 g) and aqueous sodium hydroxide (50% w/v, 20 ml).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([Cl:29])C(=O)C1>CN(C=O)C>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([Cl:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Solvent: CN(C)C=O
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3Cl)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (20 mg, 0.07 mmol), NCS (35.6 mg, 0.27 mmol) in anhydrous DMF (0.4 mL) was stirred at room temperature for 2.5 h. Following solvent removal, the product (11 mg, 48.8%) was collected through silica gel column purification (CHC13:EtOAc at 9:1 to 5:5). 1H NMR (400 MHz, DMSO-d6) 7.40 (bs, 2H), 6.97 (s, 1H), 6.89 (s, 2H), 5.97 (s, 2H), 4.04 (s, 2H); MS m/z 322.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:7]=1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([S:15][C:9]1[N:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[C:12](=[O:13])[CH2:11][N:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(Cl)cc1NC(=S)NCC(N)=O
Solvent: CCO
Product: Cc1ccc(Cl)cc1N1C(=O)CN=C1SCc1ccccc1
Yield: 53.7 %

Procedure:
A mixture of 2-[3-(5-chloro-2-methylphenyl)-thioureido]-acetamide (20.6 g), benzyl chloride (25.0 g), and ethanol (350 mL) was heated at reflux for 2.5 hours. The insolubles were removed by filtration and discarded. The filtrate was concentrated to one-half volume. Diethyl ether (300 mL) was added. The precipitated solid was separated by filtration and discarded. The filtrate was evaporated to dryness. The residue was dissolved in chloroform (300 mL) and washed with water. The organic phase was dried over anhydrous MgSO4, decolorized on carbon then evaporated to dryness. The residue was triturated with diethyl ether to give the title compound (14.2 g) as an off-white solid, m.p. 140°-142° C. Anal. Calcd. for. C17H15Cl N2O S: C, 61.72; H, 4.57; N, 8.47. Found: C, 61.62; H, 4.39; N, 8.37. Mass spectrum (EI, M.+) m/z 330/332. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.46 (m, 1H), 7.42 (m, 2H), 7.38 (d, 2H), 7.22-7.32 (m, 3H), 4.31-4.48 (m, 4H), and 2.06 ppm (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]([C:19]2[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=3[Cl:31])[CH:21]=[CH:22][N:23]=2)[C:15](Cl)=[N:16][CH:17]=1>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:15]2[C:14]([C:19]3[N:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=4[Cl:31])[CH:21]=[CH:22][N:23]=3)=[CH:13][C:12]([Br:11])=[CH:17][N:16]=2)=[CH:5][CH:4]=1
Reactant: Clc1cccc(-n2ccnc2-c2cc(Br)cnc2Cl)c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CNc2ncc(Br)cc2-c2nccn2-c2cccc(Cl)c2Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of excess (4-methoxyphenyl)methanamine (0.2 mL) in dioxane (2 mL)was added 5-bromo-2-chloro-3-(1-(2,3-dichlorophenyl)-1H-imidazol-2-yl)pyridine (0.089 g, 0.222 mmol). The mixture was heated at 100° C. for 16 hours in a sealed reaction vessel. The mixture was then cooled, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and the combined organics dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography (20% hexanes/methylene chloride to 25% ethyl acetate/methylene chloride to provide 0.065 g of N-(4-methoxybenzyl)-5-bromo-3-(1-(2,3-dichlorophenyl)-1H-imidazol-2-yl)pyridin-2-amine [LC-MS m/e=505.0 (M+H)]. Using the same procedure, N-(4-methoxybenzyl)-5-bromo-3-(1-(2,3-difluorophenyl)-1H-imidazol-2-yl)pyridin-2-amine and N-(4-methoxybenzyl)-5-bromo-3-(1-(3-chloro-2-fluorophenyl)-1H-imidazol-2-yl)pyridin-2-amine can be produced from 5-bromo-2-chloro-3-(1-(2,3-difluorophenyl)-1H-imidazol-2-yl)pyridine and 5-bromo-2-chloro-3-(1-(3-chloro-2-fluorophenyl)-1H-imidazol-2-yl)pyridine, respectively
Reaction SMILES: [CH:1]([N:14]1[CH2:19][C@@H:18]2[CH2:20][C@H:15]1[CH2:16][N:17]2[C:21]1[N:26]=[CH:25][C:24]([C:27](OCC)=[O:28])=[CH:23][N:22]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:32].[K+].[NH2:34]O.CO>C1COCC1>[CH:1]([N:14]1[CH2:19][C@@H:18]2[CH2:20][C@H:15]1[CH2:16][N:17]2[C:21]1[N:26]=[CH:25][C:24]([C:27]([NH:34][OH:32])=[O:28])=[CH:23][N:22]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3C(c2ccccc2)c2ccccc2)nc1
Reactant: [OH-]
Reactant: NO
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1cnc(N2C[C@@H]3C[C@H]2CN3C(c2ccccc2)c2ccccc2)nc1
Reaction time: 1 h
Yield: 79 %

Procedure:
Title compound 202 (0.140 g, 0.338 mmol), potassium hydroxide (4M, 0.34 mL), hydroxylamine (50% in water, 0.34 mL), MeOH (2 mL) and THF (2 mL) were combined and the reaction mixture was stirred for 1 hour. HCL 3N was added to adjust the pH to 8. After 15 minutes stirring, the solid was filtered and well dried to afford the title compound 203 (0.107 g, 79%) as a white powder. 1H NMR (DMSO-d6) δ (ppm): 7.80 (dd, J=8.0, 2.0 Hz, 1H), 7.61 (ddd, J=8.4, 6.8, 1.2 Hz, 1H), 7.46-7.41 (m, 3H), 7.38-7.30 (m, 3H), 3.62 (t, J=7.2 Hz, 2H), 2.06 (t, J=7.2 Hz, 2H), 1.61-1.51 (m, 4H), 1.44-1.28 (m, 4H). LRMS: (calc) 390.12. (found) 391.3 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[S:34])[NH:20][C:21](=[O:33])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([OH:32])=O)[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].[NH2:35][C:36]1[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[NH:38][N:37]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[S:34])[NH:20][C:21](=[O:33])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([NH:35][C:36]5[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[NH:38][N:37]=5)=[O:32])[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)co2)c(=O)[nH]c1=S
Reactant: Nc1n[nH]c(C(F)(F)F)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)Nc3n[nH]c(C(F)(F)F)n3)co2)c(=O)[nH]c1=S

Procedure:
A solution of the product of example 2 step (iii) (0.34 g), 4-(dimethylamino)pyridine (0.34 g), 3-amino-5-trifluoromethyl-1,2,4-triazole (J. Gen. Chem. USSR (Engl. Transl.) 1983, vol53, part 7, p1514) (0.42 g) and N,N-diisopropylethylamine (1.46 ml) in N,N-dimethylformamide (6 ml) was treated with bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (1.3 g). After 2 hours the solution was quenched with aqueous tartaric acid. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 30% ethyl acetate in toluene. The product was triturated with ethyl acetate/isohexane and the solid collected.
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[CH2:17][CH:16]([OH:18])[C:13]3([CH2:15][CH2:14]3)[CH2:12]2)=[N:4][C:5]([CH3:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:19]1([CH2:24][C@@H:25]([C:26]([NH:9][NH:8][C:7]2[C:2]([F:1])=[C:3]([N:11]3[CH2:17][C@@H:16]([OH:18])[C:13]4([CH2:14][CH2:15]4)[CH2:12]3)[N:4]=[C:5]([CH3:10])[N:6]=2)=[O:27])[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: Cc1nc(NN)c(F)c(N2CC(O)C3(CC3)C2)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2C[C@@H](O)C3(CC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
5-(5-Fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-5-azaspiro[2.4]heptan-7-ol (82 mg, 0.324 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (115 mg, 0.27 mmol), and HOAt (44 mg, 0.324 mmol) were dissolved in 2 mL of DMF. NMM (0.089 mL, 0.81 mmol) was added, followed by EDC (62 mg, 0.324 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(7S)-7-hydroxy-5-azaspiro[2.4]hept-5-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (91 mg, 63%). LCMS: (M+H)+: 535.3.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11]CC1.[OH2:15]>>[C:3]([OH:5])(=[O:4])[CH2:2][CH2:11][CH2:12][CH2:13][C:8]([OH:14])=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: O
Reactant: O=C1CCCCC1
Product: O=C(O)CCCCC(=O)O

Procedure:
An operation was conducted in the same manner as in Example 1 except that trifluoroacetic acid containing 0.1 mass % of water was replaced by an aqueous solution containing 93.1 mass % (90 volume %) of trifluoroacetic acid and that cyclohexanone was used as a raw material for reaction. As a result, no adipic acid (intended product) was obtained and cyclohexanone used as a raw material was recovered quantitatively.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([C@@H:8]1[CH2:13][C@@H:12]2[C@@H:10]([CH2:11]2)[N:9]1[C:14]([OH:16])=O)=[O:7])[CH:3]=[CH2:4].[C:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH2:29]C(O)=O)[N:21]=1)(=[O:19])[CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:5][C:6]([C@@H:8]1[CH2:13][C@@H:12]2[C@@H:10]([CH2:11]2)[N:9]1[C:14](=[O:16])[CH2:29][N:22]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]([C:17](=[O:19])[CH3:18])=[N:21]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)O
Reactant: CC(=O)c1nn(CC(=O)O)c2ncccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(C)=O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-allyl ester hydrochloride (1.03 g, 6.43 mmol), (3-acetyl-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid (prepared as described in Part A, 1.3 g, 5.93 mmol) and HBTU (2.70 g, 7.12 mmol) in DMF (19.7 mL) was added DIPEA (3.11 mL, 17.8 mmol). The reaction mixture was stirred for 16 h at RT. DMF was evaporated. The residue was poured into NH4Cl (sat. aq. solution) and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 0:10) to give the title compound. Rf, TLC (EtOAc)=0.6; MS (LCMS): 369.0 [M+H]+, 391.0 [MH+Na]+; tR (HPLC conditions d): 2.78 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](O)=[O:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH:8][NH:9][C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:12]2[CH3:11])=[O:18])=[N:6][CH:7]=1
Reactant: Cc1cc(F)cnc1NN
Reactant: CN1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(F)cnc1NNC(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
A solution of Intermediate 105b (76 mg, 0.537 mmol), (S)-1-methyl-pyrrolidine-2-carboxylic acid (55 mg, 0.72 mmol) and HOBT (8 mg, 0.72 mmol) in anhydrous DCM (5 mL) was treated with EDC (138 mg, 0.717 mmol) and stirred at RT under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM, to afford the title compound (76 mg, 56%). 1H NMR (400 MHz, CDCl3): 1.74-2.05 (3H, m), 2.15-2.33 (4H, m), 2.34-2.46 (1H, m), 2.52 (3H, s), 3.02-3.12 (1H, m), 3.15-3.25 (1H, m), 6.70 (1H, s), 7.08-7.18 (1H, m), 7.90 (1H, d, J=2.8 Hz), 9.52 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.O.[NH2:35][NH2:36].C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:35][NH:36]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 44.6 %

Procedure:
A mixture of crude N-({(2R,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)benzamide (0.23 mmol theoretical) and hydrazine monohydrate (0.25 mL, 5.14 mmol) in ethanol (3 mL) was stirred at 100° C. in a sealed tube for 15 hours. The mixture was cooled, poured into saturated aqueous NaHCO3 (15 mL), and extracted with EtOAc (2×10 mL). The extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were concentrated in vacuo, taken up in a small amount of CH3OH, and added to saturated aqueous NaHCO3 (25 mL). That mixture was extracted with 90/10 CH2Cl2/IPA (3×25 mL), and the extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (47 mg) as a pale yellow solid. LC-MS (ES) m/z=459 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.8 Hz, 3H), 2.73-2.91 (m, 1H), 3.39-3.55 (m, 2H), 3.57-3.71 (m, 2H), 3.73-3.83 (m, 1H), 4.08-4.74 (bs, 2H), 5.39 (s, 2H), 6.14 (s, 2H), 6.57 (s, 1H), 7.45-7.51 (m, 2H), 7.51-7.60 (m, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.95 (s, 1H), 8.68 (t, J=5.5 Hz, 1H), 11.53 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[ClH:33]>O1CCOCC1>[ClH:33].[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)Cc1ccc(CN2CCN(c3ccccc3)CC2)cc1

Procedure:
Using 2.3 g of methyl 4-bromomethylphenylacetate, 2.0 g of 1-phenylpiperazine, 2 ml of triethylamine, and 80 ml of dioxane, the reaction procedure of Example 2 was otherwise repeated and the reaction product was converted to the hydrochloride using 2N-hydrochloric acid and recrystallized from methanol-ether to provide 2.0 g of the title compound melting at 231° C.-234° C.