Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 90 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and benzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 90%. Melting point: 218-220° C. (Ethyl acetate-hexane)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12]C)=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[CH3:14][NH:15][CH2:16][CH2:17][NH2:18]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:10]([NH:18][CH2:17][CH2:16][NH:15][CH3:14])=[O:12])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Reactant: CNCCN
Solvent: C1CCOC1
Product: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Yield: 61.8 %

Procedure:
A mixture of 20 g (99.0 mmol) of methyl 3,5-diamino-6-chloropyrazine-2-carboxylate (see U.S. Pat. No. 4,029,816 for an example of how to obtain this material) and 17 g (230.0 mmol) of N-methylethylenediamine was heated at reflux under an inert atmosphere for 30 hours. The rection mixture was cooled to ambient temperature and the solid was dissolved in 100 ml of tetrahydrofuran. The solution was filtered and evaporated. The residue was crystallized from 2-propanol. There was obtained 15.0 g (61.2 mmol, 61%) of 3,5-diamino-6-chloro-N-(2-methylaminoethyl)pyrazine-2-carboxamide; mp 142.5°-143° C.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([CH2:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:17]([C:16]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Cc1cccnc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1cc2cccnc2[nH]1
Yield: 115.9 %

Procedure:
A solution of 1-[2-(t-butoxycarbonylamino)pyridin-3-yl]hexan-2-one (Y) (4.2 g) (prepared, e.g, as described in Preparation 18), in dichloromethane (25 ml) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The solution was concentrated under vacuum and the residue was partitioned between aqueous ammonium hydroxide and ether. The ether layer was washed with brine, dried, and the solvent was evaporated. The residue was further purified by silica gel chromatography, eluting with 30% ethyl acetate-hexane, to give 2-(n-butyl)-7-azaindole (2.9 g), a compound of Formula (AB), as an oil, which crystallized on standing to a solid, m.p. 46°-47° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17](Br)[CH:18]=1)[C:13]([OH:15])=[O:14].Cl>CS(C)=O.O>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([S:8][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: SC1CCCC1
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Br)cc(SC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of sodium hydride (60% in mineral oil, 0.82 g, 20.5 mmol) and DMSO (15 mL) in a sealable flask at 0° C. was slowly added cyclopentanethiol (1.23 mL, 11.9 mmol). The mixture was stirred at room temperature for 30 min and then a solution of 3,5-dibromobenzoic acid (2.5 g, 8.9 mmol) in DMSO (10 mL) was added. The reaction was sealed and stirred at 80° C. overnight. After cooling, the reaction mixture was poured into water and adjusted to pH 5-6 with 15% HCl (aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to afford the crude product which was used for the next step reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([O:8]C)=[O:7].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(-c2ccc(C)cn2)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a flask were charged methyl 3-methoxy-5-(5-methylpyridin-2-yl)benzoate (80 mg, 0.2 mmol), barium hydroxide octahydrate (300 mg, 0.95 mmol), and methanol (10 mL). The mixture was stirred at room temperature overnight. 2N HCl (ethyl ether solution, 30 mL) was added and the volatiles were removed under reduced pressure. LC-MS: 244.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16]Br>>[N:1]1([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][NH:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc2c(c1)C(=O)NC2
Reactant: BrCCCCBr
Product: O=C1NCc2ccc(N3CCCC3)cc21

Procedure:
The starting material 6-pyrrolidin-1-yl-2,3-dihydro-isoindol-1-one was prepared from 6-amino-2,3-dihydro-isoindol-1-one (CAS 675109-45-2) and 1,4-dibromobutane in analogy to the precedure described in example 56.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCOCC2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCOCC2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.1 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(4-morpholinylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 21) (269 mg, 0.62 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (219 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C3CCCCO3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N(Cc1ccc(O)cc1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
To a solution of (4-iodo-phenyl)-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (3.43 g, 8.38 mmol) in 10 mL methylene chloride was added triethylamine (2.0 mL, 14.35 mmol) and benzenesulfonyl chloride (1.2 mL, 9.40 mmol). The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with water, was acidified with 1N HCl, and the aqueous solution was washed three times with methylene chloride. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated. The residue was dissolved in methanol and the solution was treated with a catalytic amount of 1N HCl. The reaction mixture was stirred at room temperature for 20 hr. The reaction mixture was made basic with saturated aqueous sodium bicarbonate and the aqueous solution was washed two times with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 3.21 g (82%) of the title compound of Step B.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[C:16](Cl)=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CCN(CC)CC>C(Cl)Cl.[Cu]I>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[C:19]([C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cl)nc1Cl
Reactant: C#CCCCCCC
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC#Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 78 %

Procedure:
A mixture of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-chloro-6-chloropyridine from Example 69a (400 mg, 1.02 mmol), 1-octyne (0.23 mL, 1.54 mmol), Pd(PPh)3Cl2 (36 mg), CuI (catalytic amount) and NEt3 (2.5 mL) in CH2Cl2 (8 mL) was heated at reflux for 16 h. Heating was continued until no starting material remained. The solvent was removed, and the residue was washed with 10% NaOH then extracted with CH2Cl2. The organic extract was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; hexane:EtOAc, 3:1) to afford the title compound (335 mg, 72% yield): 1H NMR (CDCl3, 300 MHz) δ 0.91 (t, J=7.5 Hz, 3H), 1.23-1.40 (m, 4H), 1.48 (s, 9H), 1.56-1.69 (m, 2H), 1.81-2.06 (m, 5H), 2.46 (t, J=7.5 Hz, 2H), 3.27-3.47 (m, 2H), 3.98-4.21 (m, 4H), 7.29 (br, s, 1H), 7.98 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 421 (M+H)+.
Reaction SMILES: S([O-])([O:4][CH2:5][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:7])(=O)=O.[Na+].[OH2:24]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:7])[C:5]([O:24][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O
Reactant: CCCCCCOC(C)(COS(=O)(=O)[O-])OCCCCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Yield: 84 %

Procedure:
To a solution of methyl pyruvate 1 (10.0 g, 98.0 mmol) in toluene (100 mL) is added 1-hexanol 2 (40.1 g, 392 mmol) and p-Ts0H (186 mg, 0.98 mmol). The mixture is heated to reflux for 10 hours with azeotropic removal of water from the reaction mixture. The reaction is quenched with saturated NaHCO3 (100 mL), and the reaction mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give hexyl 2,2-bis(hexyloxy)propanoate 3 (29.5 g, 84%) as a colorless oil: Rf (15% EtOAc/hexane)=0.53; IR (thin film, cm−1) 2956, 2930, 2860, 1746 (C═O), 1467, 1280, 1137, 1062. 1H NMR (600 MHz, CDCl3) δ 4.14 (t, J=7.2 Hz, 2H), 3.48 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.35 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.65-1.63 (m, 2H), 1.59-1.54 (m, 4H), 1.49 (s, 3H), 1.35-1.24 (m, 18H), 0.86 (t, J=7.2 Hz, 9H); 13C NMR (150 MHz, CDCl3) δ 170.2, 99.5, 65.4, 62.6, 31.7, 31.3, 29.7, 28.5, 25.8, 25.5, 22.6, 22.5, 21.9, 14.0, 13.9.
Reaction SMILES: Cl.[CH2:2]([O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C(OC1CCNCC1)C1C=CC=CC=1.Br[CH2:33][C:34]1([CH3:47])[CH2:38][C:37]2[C:39]([CH3:46])=[C:40]([NH2:45])[C:41]([CH3:44])=[C:42]([CH3:43])[C:36]=2[O:35]1>C(OCC)(=O)C.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+].C(N(CC)CC)C>[CH2:2]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:33][C:34]2([CH3:47])[CH2:38][C:37]3[C:39]([CH3:46])=[C:40]([NH2:45])[C:41]([CH3:44])=[C:42]([CH3:43])[C:36]=3[O:35]2)[CH2:12][CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(COC2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(OCc3ccccc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
In ethyl acetate was suspended 2.0 g of 4-benzyloxypiperidine hydrochloride and the suspension was neutralized with aqueous 1N-auqeous sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. To a solution prepared by dissolving the resulting 4-benzyloxypiperidine in 0.5 mL of toluene were added 1.1 g of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 2.8 mL of triethylamine, and in an autoclave, the mixture was stirred under nitrogen gas at 180° C. for 15 hours. This reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with 3 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=1:1) and recrystallized from ethyl acetate/hexane to provide 1.1 g of the title compound. Yield 67%.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[N:20]([CH3:26])[C:19]([CH3:27])=[C:18]3[C:28]#[N:29])=[CH:14][CH:15]=2)[C:10]([CH3:30])=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:26][N:20]1[C:21]([CH3:25])=[C:22]([C:23]#[N:24])[CH:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[C:10]3[CH3:30])[C:18]([C:28]#[N:29])=[C:19]1[CH3:27]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1C
Agent: Cl
Solvent: C1COCCO1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C)N1C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
10.56 g (26.17 mmol) 5-(3,5-dicyano-1,2,6-trimethyl-1,4-dihydro-pyridin-4-yl)-3-methyl-indazole-1-carboxylic acid tert-butyl ester, from Synthetic Example 16, were dissolved in 70 mL dioxane. 350 mL of a 4 M solution of hydrochloric acid in dioxane was added. The mixture was stirred for 2 hours and then concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. Purification with column chromatography gave 1,4-dihydro-1,2,6-trimethyl-4-(3-methyl-1H-indazol-5-yl)-3,5-pyridinedicarbonitrile (5.46 g, 68.8%). (Cpd. No. 306, Table 7). 1H-NMR (DMSO-D6): δ=12.67 (br s, 1H), 7.50 (s, 1H), 7.48 (d, 1H), 7.26 (d, 1H), 4.44 (s, 1H), 3.21 (s, 3H), 2.48 (s, 3H), 2.24 (s, 6H) ppm. MS (ES+): 304.45 (M++1, 100%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11].CN(CCO)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CO.O.C(O)(C(F)(F)F)=O>[Cu]I.O>[CH3:11][CH:10]([CH3:12])[C@@H:9]([NH:8][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:13]([OH:15])=[O:14]
Reactant: Ic1cccnc1
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: [Cu]I
Agent: CN(C)CCO
Agent: O=P([O-])([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC(C)[C@@H](Nc1cccnc1)C(=O)O

Procedure:
3-Iodopyridine (525 mg, 2.58 mmol), D-valine (250 mg, 2.13 mmol), copper(I) iodide (40.6 mg, 0.213 mmol), dimethylaminoethanol (400 mg, 4.49 mmol), potassium phosphate tribasic (1359 mg, 6.40 mmol), and water (2 mL) was stirred at 80° C. overnight. The reaction was washed with EtOAc, then the aqueous portion was concentrated. The residue was slurried with MeOH and the MeOH portion was concentrated. The product was isolated using preparative reverse phase HPLC (MeOH/water/TFA) and used in next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.N1(CO)C=[CH:26]N=N1.[BH4-].[Na+]>CO>[CH3:26][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:3][CH2:2]1
Reactant: C1CCCn2c(nnc2C2(C3CCNCC3)CCCC2)CC1
Reactant: OCn1ccnn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C2(c3nnc4n3CCCCCC4)CCCC2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
3-(1-Piperidin-4-ylcyclopentyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (263 mg) and 1H-triazole-1-methanol (86 mg) were diluted with methanol (4 ml), followed by stirring at 60° C. for 1 hour. After 1H-triazole-1-methanol (93 mg) was added thereto and the whole was stirred for 1 hour, 1H-triazole-1-methanol (107 mg) was further added and the whole was stirred for 1 hour. The reaction solution was cooled to room temperature and then sodium borohydride (91 mg) was added thereto, followed by stirring at room temperature for 16 hours. The reaction solution was subjected to evaporation under reduced pressure and the resulting residue was diluted with a 1M aqueous sodium hydroxide solution (30 ml), followed by extraction with chloroform (15 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:6) and then the resulting solid washed with hexane to obtain 105 mg of 3-[1-(1-methyl-4-piperidinyl)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (white solid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][CH:7]=1.Cl.N[C@@H]1CC[CH2:16][CH2:15][C@H:14]1[OH:19].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC1COC1>CC(O)C.[Ni](I)I>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:15]2[CH2:14][O:19][CH2:16]2)[CH:3]=1
Reactant: OB(O)c1cncc(Br)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: I[Ni]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: Brc1cncc(C2COC2)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a vial were added (5-bromopyridin-3-yl)boronic acid (110 mg, 0.544 mmol), nickel iodide (5.10 mg, 0.016 mmol), trans-2-aminocyclohexanol hydrochloride (2.473 mg, 0.016 mmol), sodium bis(trimethylsilyl)amide (100 mg, 0.544 mmol) and 2-propanol (0.5 mL). The reaction was stirred under nitrogen for 10 minutes prior to addition of a solution of 3-iodooxetane (50 mg, 0.27 mmol) in 2-propanol (0.2 mL). The vial was sealed and heated at 80° C. overnight. The reaction was then filtered through celite with the aid of ethanol. The solution was concentrated and purified by flash chromatography on silica gel (10-100% ethyl acetate in hexanes) to provide the title compound: LCMS m/z 215.90 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 8.56 (s, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 5.11-5.08 (m, 2H), 4.72-4.70 (m, 2H), 4.34-4.29 (m, 1H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:42][CH2:41][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:30][O:31][CH2:32]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:46]CO>>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:46][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:30][O:31][CH2:32]3)[CH2:41][CH2:42]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1ccccc1COC3
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCCCc1ccccc1COC3
Yield: 59.6 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (37 mg, 0.062 mmol) and NaOH (0.312 mL, 0.312 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then filtered and purified by preparative HPLC to obtain (2S)-2-(tert-butoxy)-2-{4,26-dimethyl-11,25-dioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl}acetic acid (21 mg, 0.037 mmol, 59.6% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.29 (d, J=7.7 Hz, 1H), 7.26-7.19 (m, 2H), 7.17-7.11 (m, 1H), 6.53 (s, 1H), 5.71 (s, 1H), 4.74-4.58 (m, 4H), 4.50-4.42 (m, 1H), 3.68-3.20 (m, 4H), 2.82-2.75 (m, 1H), 2.66 (d, J=8.4 Hz, 2H), 2.51 (s, 3H), 1.90-1.81 (m, 2H), 1.71-1.51 (m, 8H), 1.19 (s, 3H), 1.15 (s, 9H). LCMS (M+1)=565.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][C:15]([C:21]#[N:22])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([C:21]#[N:22])=[CH:14][N:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ncc(C#N)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCN(c2ncc(C#N)cc2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.5 %

Procedure:
To a solution of 0.045 g (0.14 mmol) of (5′-cyano-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in ethanol is added 0.015 g (0.0070 mmol) of 5% palladium on carbon. The mixture is placed under an atmosphere of hydrogen and stirred at room temperature overnight. The mixture is filtered through diatomaceous earth and concentrated under reduced pressure to give 0.043 g (95%) of (3′-amino-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester as a red oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:13]([Cl:12])(=[O:15])=[O:14])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Yield: 86 %

Procedure:
Chlorosulfonic acid (40 mL) is added slowly to 1-chloro-isoquinoline (9.92 g, 60.6 mmol) at 0° C. with stirring under nitrogen. The resultant mixture is heated at 155° C. for 24 hours. Then the mixture is cooled to ambient temperature before it is poured very slowly into ice (200 g). While cold, the mixture is extracted with dichloromethane (300 mL). The organic layer is dried over Na2SO4, filtered and concentrated in vacuo to give 13.6 g (51.9 mmol, yield 86%) of 1-chloro-isoquinoline-5-sulfonyl chloride as a white powder. 1H NMR (CDCl3): δ7.87(t, J=7.5 Hz, 1H), 8.52 (d, J=6.2 Hz, 1H), 8.59 (d, J=6.2 Hz, 1H), 8.62 (d, J=7.5 Hz, 1H), 8.82 (d, J=7.5 Hz, 1H).