Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[CH2:1]([CH:8]([CH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)Cn1cccn1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C(Cc1ccccc1)Cn1cccn1
Reaction time: 1 h
Yield: 101.9 %

Procedure:
The resultant compound from Example 46 (100.0 mg, 0.409 mmol) in dioxane (2 ml) at 0° C. was treated with LiOH.H2O (22.0 mg, 0.524 mmol) in water (1 ml). After 1 h at 0° C. and 30 min at room temperature the solvent was evaporated and the residue was taken up in water, the pH was adjusted to pH 3-4, and the mixture was extracted with CHCl3 which was dried over Na2SO4 and evaporated to afford 96 mg (100%) of a solid. 1H NMR (CDCl3) δ7.56 (d,1H), 7.10-7.35 (m,6H), 6.26 (dd,1H), 4.30 (m,2H), 3.34 (m,1H), 3.12 (dd,1H), 2.72 (dd,1H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.ClCCl.CN(C=O)C.[CH3:19][S:20]([C:23]1[S:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21].[CH3:31][C:32]([CH3:53])([CH3:52])[CH2:33][CH2:34][NH:35][C:36](=[O:51])[C@H:37]([CH3:50])[CH2:38][C@H:39]([OH:49])[C@@H:40]([NH2:48])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.ClCCl>[CH2:41]([C@H:40]([NH:48][C:28]([C:26]1[S:27][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:24][CH:25]=1)=[O:30])[C@@H:39]([OH:49])[CH2:38][C@H:37]([C:36](=[O:51])[NH:35][CH2:34][CH2:33][C:32]([CH3:31])([CH3:52])[CH3:53])[CH3:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(S(C)(=O)=O)s1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
N-Cyclohexylcarbodiimide-N′-methyl polystyrene (138 mg @ 1.70 mmol/g; ex. Novabiochem) was treated with dichloromethane (0.5 ml) followed by a solution of 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in 4:1 dichloromethane/DMF (0.5 ml). 5-Methanesulfonyl thiophene-2-carboxylic acid (50 mg, 0.23 mmol) in DMF (0.5 ml) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenyl-hexanoic acid (3,3-dimethylbutyl)-amide (D2) (50 mg, 0.16 mmol) in dichloromethane (0.5 ml) were then added and the mixture was stirred gently overnight at room temperature. It was then diluted with dichloromethane (1 ml) and treated with methylisocyanate polystyrene (150 mg @ 1.80 mmol/g; ex. Novabiochem) and tris-(2-aminoethyl)-amine polystyrene (150 mg @ 3.20 mmol/g; ex. Novabiochem), and the mixture was stirred gently for a further 2 h. It was then filtered and the spent resins were washed with DMF (1 ml) and dichloromethane (1 ml). The combined filtrates were evaporated to dryness and the residue was triturated with diethyl ether to afford the title compound as a white solid (57 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[C:33]([C:40]([F:43])([F:42])[F:41])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C[N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.N>O.CN(C=O)C>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:44])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:32][C:33]=1[C:40]([F:43])([F:42])[F:41])(=[O:37])[NH2:46]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)c(C(F)(F)F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(N)=O)c(C(F)(F)F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.08 h
Yield: 28.6 %

Procedure:
In a 25 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-(trifluoromethyl)benzoic acid (42 mg, 64.2 μmol, Eq: 1.00) was combined with DMF (2.50 ml) to give a colorless solution. HATU (36.6 mg, 96.3 μmol, Eq: 1.5) and DIPEA (41.5 mg, 56.0 μl, 321 μmol, Eq: 5) were added. The reaction was stirred for 5 minutes and ammonia hydrochloride (34.3 mg, 642 μmol, Eq: 10) was added. The reaction mixture was stirred for overnight. The reaction mixture was poured into 10 mL of H2O and extracted with EtOAc (3×10 mL). The organic layers were combined, washed with H2O (1×10 mL), saturated NaCl (1×10 mL), dried over Na2SO4 and concentrated in vacuum. The crude material was purified by preparative HPLC (65-100% ACETONITRILE/water). The fractions were combined and freeze dried and triturated with CH2Cl2/hexanes to give a white foam (12 mg, 26% yield). (ES+) m/z Calcd: [(M+H)+]: 653. found: 653.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)=[CH:13][C:12]=1[NH:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=1>>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:20]=2)=[CH:13][C:12]=1[NH:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH:8]2[CH2:2][CH2:3][CH2:4][N:5]([CH3:9])[CH2:6][CH2:7]2)[CH:35]=1
Reactant: CN1CCCC1CCCl
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(O)c1
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCCN(C)CC2)c1

Procedure:
As described hereinbefore in Example 7, 2-(2-chloroethyl)-N-methylpyrrolidine was reacted with N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-hydroxybenzamide and the reaction product was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-[2-(N-methylpyrrolidin-2-yl)ethoxy]benzamide (Example 7, Compound No. 32). On further elution an isomeric by-product was obtained. There was thus obtained the title compound NMR Spectrum: (DMSOd6) 1.6 (m, 1H), 1.79 (m, 3H), 2.04 (m, 2H), 2.17 (s, 3H), 2.24 (s, 3H), 2.52 (m, 4H), 3.18 (t, 4H), 3.76 (t, 4H), 4.66 (m, 1H), 7.1 (m, 2H), 7.21 (d, 1H), 7.4 (m, 4H), 7.5 (d, 1H), 7.56 (m, 1H), 7.78 (d, 1H), 9.83 (s, 1H), 10.11 (s, 1H); Mass Spectrum: M+H+543.
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=2)[N:18]=1.[K][S:37][C:38](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[S:39][K]>>[C:28]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[S:37][C:38](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[S:39][C:26]1=[N:25]2)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#CC(C#N)=C(S[K])S[K]
Reactant: O=C(c1ccccc1)c1ccc2nc(Cl)c(Cl)nc2c1
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: N#CC(C#N)=C1Sc2nc3ccc(C(=O)c4ccccc4)cc3nc2S1
Yield: 54 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 1.5 g of 2,3-dichloro-6-benzoylquinoxaline and 1.2 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a reddish brown powder weighing 1.0 g with a calculated overall yield of 54 percent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:16]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Product: CC(CNS(C)(=O)=O)c1ccc(C2CCCC2)cc1
Yield: 13 %

Procedure:
Condition 1: The product of Example 1, 0.50 g (1.71 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) under an atmosphere of nitrogen. To this was added tetrakis-(triphenylphosphine)palladium(0) (0.099 g, 0.086 mmol) followed by cyclopentyl magnesium bromide (2 M in diethyl ether, 2.14 ml, 4.28 mmol). The solution was heated to reflux for 16 hours. Upon cooling the reaction was partitioned between water and diethyl ether. The aqueous layer was back extracted with diethyl ether twice and the organic fractions combined. The organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. Chromatography (SiO2, 30% ethyl acetate/hexanes) gave the title compound 0.06 g (13%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH2:28][N:29]1[C:37]([NH2:38])=[C:36]2[C:31]([CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35]2)=[N:30]1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]2=[C:8]([C:33]3[CH:34]=[CH:35][C:36]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:28][C:27]3[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=3[F:25])[C:37]=4[NH2:38])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3c(N)n(Cc4ccccc4F)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5F)nc4c3)c3c(N)ncnn23)CC1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (0.5 g, 1.26 mmol) in DMF (15 mL) was added 2-(2-fluorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-3-amine (0.695 g, 1.89 mmol), solid Na2CO3 (0.4 g, 3.79 mmol) and water (1.9 mL). The solution was degassed for 10 min and tetrakis(triphenylphosphine)palladium(0) (0.146 g, 0.126 mmol) was added and the mixture was degassed for another 10 min. The mixture was heated at 110° C. for 1 h 15 min and then cooled to rt. The mixture was filtered through a plug of Celite® and the filtrate was concentrated. The crude purified using an ISCO® instrument using 40-100% ethyl acetate in hexanes. LC-MS [M+H]+=557.2, RT=2.65 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]Cl)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1.[C:13]([O-:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[K+].O>C(O)C>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][S:20][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1
Reactant: C=Cc1cnc(C)c(O)c1CCl
Reactant: [O-]C(=S)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C=Cc1cnc(C)c(O)c1CSC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 65 g. of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine in 1 liter of ethanol under nitrogen there was added 96 g. of potassium thiobenzoate in 200 ml. of water over 30 minutes. After 1 hour, the ethanol was evaporated at 40° C. and the aqueous solution was extracted with 4 × 300 ml. of ethyl acetate. The extract was washed with 1 × 75 ml. of water, dried over magnesium sulfate and concentrated to dryness to give 2-methyl-3-hydroxy-4-benzoylthiomethyl-5-vinylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14]O)[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[I:8].[N-:16]=[N+]=[N-].[Na+].O.CCOC(C)=O>CC#N.O=S(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH2:16])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: OCc1cn(-c2ccc(I)c(F)c2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: NCc1cn(-c2ccc(I)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a suspension of (1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanol (0.39 g, 1.23 mmol) in CH3CN (7 mL), SOCl2 (2.5 mL) was added. Upon the addition, the suspension became clear. It was then concentrated in vacuo. The residue was dissolved in DMF (7 mL), NaN3 (0.32 g, 4.92 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in MeOH (6 mL), Ra—Ni (50% slurry in H2O, ˜200 mg) was added. The mixture was hydrogenated under balloon H2 for 2 h. It was then filtered through celite. The filtrate was concentrated in vacuo to give (1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanamine as a solid (0.268 g).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)([CH3:5])[CH3:4].C1COCC1.Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]2[N:32]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][C:36]=3[F:45])[N:33]=[CH:34][C:27]=12>C(Cl)Cl>[F:45][C:36]1[CH:37]=[C:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH:39]=[CH:40][C:35]=1[N:32]1[C:28]2=[N:29][CH:30]=[N:31][C:26]([O:19][CH:16]3[CH2:15][CH2:14][N:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH:3]([CH3:5])[CH3:4])=[CH:12][N:11]=4)[CH2:18][CH2:17]3)=[C:27]2[CH:34]=[N:33]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Reactant: CC(C)Oc1ccc(N2CCC(O)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL round-bottomed flask equipped with a N2 inlet septum was placed a stir bar, NaH (60% in mineral oil, 364 mg, 0.91 mmol) and 5′-isopropoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol (215 mg, 0.91 mmol). THF (anhydrous, 3 mL) was added to the mixture. The resulting suspension was stirred about 30 min at room temperature. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (297 mg, 0.91 mmol) was then added in one portion. The mixture was stirred overnight under N2 at room temperature and the resulting slurry turned slightly yellowish. The slurry was added CH2Cl2 and filtered. The filtrate was concentrated under vacuum to give the crude product. Purification by preparative HPLC gave the desired product as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 1.36 (d, 6H), 2.17 (m, 2H), 2.30 (m, 2H), 3.13 (s, 3H), 3.74 (m, 2H), 3.97 (m, 2H), 4.50 (m, 1H), 5.76 (m, 1H), 7.04 (d, 1H), 7.60 (m, 1H), 7.87 (m, 1H), 7.94 (m, 3H), 8.34 (s, 1H), 8.64 (s, 1H). Exact mass calculated for C26H28FN5O4S 525.18, found 526.2 (MH+)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[N:18]=2)=[CH:5][C:4]=1[CH3:19])#[N:2].[BH4-].[Na+].[ClH:22]>CO.O1CCCC1.O.O.O.O.O.O.[Co](Cl)Cl>[ClH:22].[ClH:22].[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[N:18]=2)=[CH:5][C:4]=1[CH3:19]
Reactant: Cc1cc(-c2nc3c(s2)NCCCC3)ccc1C#N
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3c(s2)NCCCC3)ccc1CN
Reaction time: 20 h
Yield: 20.1 %

Procedure:
A solution of 2-(4-cyano-3-methylphenyl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (20 g) and cobalt chloride hexahydrate (35.3 g) in a mixture of methanol (90 ml) and tetrahydrofuran (60 ml) was ice-cooled, followed by addition of a powder of sodium borohydride (33.1 g) gradually, and further stirred for 20 hrs. at room temperature. After acidifying with an aqueous 4N-hydrochloric acid, the reaction mixture was extracted with diethyl ether. The aqueous layer was alkalified with an aqueous ammonia and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was purified by a column chromatography on silica gel, and neutralized with hydrogen chloride to give the title compound (yield 20.1%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH2:6]([S:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17])[C@H:7]([NH2:11])[C:8]([OH:10])=[O:9].B([O-])([O-])[O-]>>[C:1]([CH2:2][N:11]([CH2:2][C:1]([OH:5])=[O:4])[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][S:12][S:13][CH2:14][C@H:15]([N:19]([CH2:15][C:16]([OH:18])=[O:17])[CH2:7][C:8]([OH:10])=[O:9])[C:16]([OH:18])=[O:17])([OH:5])=[O:4]
Reactant: N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Reactant: O=CC(=O)O
Agent: [O-]B([O-])[O-]
Product: O=C(O)CN(CC(=O)O)[C@@H](CSSC[C@@H](C(=O)O)N(CC(=O)O)CC(=O)O)C(=O)O

Procedure:
The alternative route, relying on in solution phase synthesis of an intermediate product starts with addition of a large excess (40 times) of glyoxylic acid to L-cystine in an alkaline borate buffer. The intermediate product was thereafter, after pH manipulations and conductivity adjustment of the reaction mixture, purified with ion exchange chromatography to give N,N,N′,N′-tetrakis (carboxymethyl)-L-cystine.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.Cl.C(OC(C(C)(C)CN1CCC(CN)CC1)=O)C1C=CC=CC=1.[CH2:57]([O:64][C:65]([C:67]([CH3:85])([CH3:84])[CH2:68][N:69]1[CH2:74][CH2:73][CH:72]([CH2:75][NH:76][C:77](=O)[O:78]C(C)(C)C)[CH2:71][CH2:70]1)=[O:66])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.Cl.[OH-].[Na+]>ClCCl.CO>[CH2:57]([O:64][C:65]([C:67]([CH3:85])([CH3:84])[CH2:68][N:69]1[CH2:74][CH2:73][CH:72]([CH2:75][NH:76][C:77]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2=[O:13])=[O:78])[CH2:71][CH2:70]1)=[O:66])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC(C)(C)C(=O)OCc2ccccc2)CC1
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Agent: CC(C)(CN1CCC(CN)CC1)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC(C)(C)C(=O)OCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a stirred mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (J. Med. Chem. 1999, 42, 2870-2880) (411 mg, 2.33 mmol) and triethylamine (1.00 mL, 7.17 mmol) in dichloromethane (20.0 mL) was added 4-nitrophenyl chloroformate (470 mg, 2.33 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. To the mixture was added a suspension of 1-(2-benzyloxycarbonyl-2-methylpropyl)-4-aminomethylpiperidine hydrochloride [prepared from concentration of a mixture of tert-butyl [{1-(2-benzyloxycarbonyl-2-methylpropyl)piperidin-4-yl}methyl]carbamate (step 1 of Example 1) (640 mg, 1.49 mmol) and 10% HCl in MeOH (20.0 mL)] and triethylamine (1.00 mL, 7.17 mmol) in dichloromethane (5.00 mL). The resulting mixture was stirred for 13 h at room temperature and 0.5 M NaOH aq. was added to the mixture. The mixture was extracted with dichloromethane. The extracts were washed with 0.5 M NaOH aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, eluting with dichloromethane /methanol (10:1)) to give 508 mg (63%) of the title compound as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[CH:11]1([CH2:14][N:15]2[C:23]([N:24]3[CH2:29][C@H:28]([CH3:30])[NH:27][C@H:26]([CH3:31])[CH2:25]3)=[N:22][C:21]3[C:16]2=[N:17][C:18]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)=[N:19][C:20]=3[N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:13][CH2:12]1.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(Cl)Cl.CO.CN(C)C=O>[C:45]([N:27]1[C@@H:28]([CH3:30])[CH2:29][N:24]([C:23]2[N:15]([CH2:14][CH:11]3[CH2:13][CH2:12]3)[C:16]3[C:21]([N:22]=2)=[C:20]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[N:19]=[C:18]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)[N:17]=3)[CH2:25][C@H:26]1[CH3:31])(=[O:47])[CH3:46]
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H](C)N1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1[C@H](C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
Triethylamine (73.7 μl, 0.53 mmol) was added to a methylene chloride (10 ml)-dimethylformamide (1.5 ml) mixture solution of 5-{9-(cyclopropylmethyl)-8-[cis-3,5-dimethylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (102.3 mg, 0.22 mmol) at room temperature followed by the addition of acetic anhydride (24.9 μl, 0.26 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 3 days followed by the addition of acetic anhydride (6.2 μl, 0.07 mmol) and the resulting mixture was further stirred for 3 days. The reaction mixture was poured into methylene chloride-methanol (10:1) and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to 0.10 give the title compound (107.7 mg, 97%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][OH:5])(=[O:3])[CH3:2].[C:6]1(=[O:13])[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1(=O)CCCCC1.C(OCC)(=O)C>[C:6]1(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1.[C:1]([O:4][OH:5])(=[O:3])[CH3:2].[C:1]([OH:4])(=[O:3])[CH2:2][CH2:9][CH2:8][CH2:7][C:6]([OH:13])=[O:12]
Reactant: O=C1CCCCCO1
Agent: CC(=O)OO
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CCCCC(=O)O

Procedure:
60 g/hour of cyclohexanone and 170.5 g/hour of a solution of ethyl acetate used as a solvent and containing 30% of peracetic acid (51.4 g/hour of pure peracetic acid which corresponds to 1.1 mole based on one mole of cyclohexanone) were introduced in a flowing-type reactor of 2 liters. The reaction was conducted under a reaction temperature of 50° C. The composition of the solution obtained was ε-caprolactone: 28.78%, unreacted cyclohexanone: 0.52%, unreacted peracetic acid: 1.31%, by-produced adipic acid: 0.59%, caprolactone polymers: 0.30%, acetic acid: 21.16% and ethyl acetate (which was the solvent): 47.34%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1ccc(C#CCCO)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(CCCCO)cc1
Reaction time: 6 h
Yield: 94.6 %

Procedure:
Methyl 4-(4-hydroxy-1-butynyl)phenylacetate (10.6 g, 0.0485 mol) was dissolved in methanol (200 mL), then 10% palladium on carbon (1.1 g) was added, and the mixture was stirred under hydrogen (50 psi). After 6 hours, additonal 10% palladium on carbon (1 g) was added, and the mixture was stirred overnight. The catalyst was filtered through celite, the filtrate was concentrated and dried in vacuo to give 10.20 g (94.5%) of methyl 4-(4-hydroxy-1-butyl)phenylacetate as a yellow liquid. FAB-MS m/z=223 (M+H); HRMS calcd for C13H19O3 (M+H) 223.1334, found 223.1328.