Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH2:20][CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[N:9][N:10]([CH2:21][CH2:20][C:19]#[C:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nn[nH]n2)cc1
Reactant: OCCC#Cc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C(#Cc1ccccn1)CCn1nnc(-c2ccccc2)n1
Temperature: 0 °C
Yield: 50.9 %

Procedure:
A mixture of 5-phenyl-2H-tetrazole (330 mg, 2.2 mmol), 4-(pyridin-2-yl)but-3-yn-1-ol (220 mg, 1.49 mmol) and triphenylphosphine polymer supported (750 mg, 2.2 mmol, loading 3 mmol/g) were dissolved DCM (3 mL) and stirred at 0° C. Diisoprpylazodicarboxylate (452 mg, 2.2 mmol) was added dropwise, at 0° C. over a period of 30 min. The reaction mixture was then warmed to room temperature and stirred over night. The reaction mixture was filtered through celite and the cake was washed with DCM. The combined organic layers were washed with aqueous ammoniac, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 209 mg of 2-(4-(5-phenyl-2H-tetrazol-2-yl)but-1-ynyl)pyridine (Yield: 51%) as a pink powder (M.P.=71-73° C.).
Reaction SMILES: C(OC([N:11]([CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48]CC2C=CC=CC=2)=[CH:44][CH:43]=1)[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27][CH3:28])[CH:21]=2)[NH:16][C:15]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>O1CCCC1.CO.[Pd].O>[CH3:36][C:34]1[CH:35]=[C:30]([C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][CH2:12][NH:11][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=2)=[CH:21][C:20]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=3)[CH:31]=[C:32]([CH3:37])[CH:33]=1
Reactant: [H][H]
Reactant: CCCNC(=O)Oc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(OCc4ccccc4)cc3)C(=O)OCc3ccccc3)c2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCNC(=O)Oc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(O)cc3)c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of propylcarbamic acid 3-(2-[benzyloxycarbonyl-[4-(4-benzyloxyphenyl)butyl]amino]-ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl ester (17 mg in a mixture of 1.5 mL tetrahydrofuran and 0.5 mL methanol) was added 16 mg of 10% palladium on carbon catalyst followed by acetic acid (0.010 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:6:1) gave the title compound (11 mg). m/e=514 (M+H)
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:25]=[C:26]1[N:30]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]([OH:40])=O)[CH2:33][CH2:32]2)[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[NH:27]1.C(N(CC)C(C)C)(C)C.[ClH:54].Cl.[CH3:56][O:57][C:58]1[CH:59]=[C:60]2[C:65](=[CH:66][CH:67]=1)[CH:64]([CH2:68][C:69]1[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=1)[CH:63]([NH2:75])[CH2:62][CH2:61]2.C(=O)(O)[O-].[Na+]>CN(C)C=O>[ClH:54].[ClH:54].[O:25]=[C:26]1[N:30]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]([NH:75][C@H:63]3[CH2:62][CH2:61][C:60]4[C:65](=[CH:66][CH:67]=[C:58]([O:57][CH3:56])[CH:59]=4)[C@H:64]3[CH2:68][C:69]3[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=3)=[O:40])[CH2:33][CH2:32]2)[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[NH:27]1
Reactant: O=C(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: COc1ccc2c(c1)CCC(N)C2Cc1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[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: COc1ccc2c(c1)CC[C@H](NC(=O)CN1CCC(n3c(=O)[nH]c4ccccc43)CC1)[C@@H]2Cc1cccnc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A solution of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (0.974 g, 2.57 mmol), 4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidineacetic acid (1.20 g, 2.57 mmol), and N,N-diisopropylethylamine (1.8 mL, 10.3 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 5 min. To this mixture, 1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenamine bis-hydrochloride 4 (0.80 g, 2.34 mmol) was added and stirring was continued for 18 h. The solution was heated to 100° C. for 1 h. The solution was cooled and poured into a saturated solution of aqueous sodium bicarbonate. A fine green precipitate was collected by filtration, and the solid was purified by reverse phase C18 HPLC eluted with a gradient of water/acetonitrile/trifluoroacetic acid 10/90/0.1 to 90/10/0.1. The cis product 19 was isolated as a colorless solid (0.386 g, 22%): 1H NMR (DMSO-d6) δ 1.76 (m, 4 H), 2.72–3.02 (m, 4 H), 3.16 (d, 2 H), 3.29–3.46 (m, 3 H), 3.54–3.75 (m, 2 H) superimposed on 3.72 (s, 3H), 3.92–4.07 (m, 3 H), 4.53–4.65 (m, 1 H), 6.63 (d, 1 H), 6.70–6.77 (m, 2 H), 7.04 (br s, 3 H), 7.59 (br s, 1 H), 7.99 (t, 1 H), 8.37 (d, 1 H), 8.74 (m, 2 H), 8.96 (d, 1 H), 10.5–10.71 (br s, 1 H), and 11.03 (s, 1 H); MS m/e 512 (MH+). A mixture of cis/trans isomers ˜8/2 0.490 g (28%) was also obtained as well as the purified trans isomer 20 as a colorless solid (0.136 g, 8%): 1HNMR (DMSO-d6) δ 1.70 (m, 6 H), 2.63–3.81 (m, 9 H) superimposed on 3.72 (s, 3 H), 3.83–4.00 (m, 3 H), 4.47–4.60 m, 1 H), 6.67–6.82 (m, 3 H), 7.02 (br s, 3 H), 7.21 (d, 1 H), 7.70 (t, 1 H), 8.14 (d, 1 H), 8.50–8.73 (m, 3 H), 9.70–10.10 (br s, 1 H), and 11.0 (s, 1 H);); MS m/e 512 (MH+) (FIG. 6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:17])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.C([Li])(CC)C.CON(C)[C:26]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[O:27].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:17][C:26](=[O:27])[C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:8]=1
Reactant: COc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Reactant: CON(C)C(=O)c1ccsc1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)c2ccsc2)c(NC(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl (5-methoxy-2-methylphenyl)carbamate (2.00 g) in tetrahydrofuran (38 mL) was added dropwise sec-butyllithium (1.00 mol/L hexane-cyclohexane solution, 18.5 mL) at −45° C., and this mixture was stirred for 30 minutes. Then, a solution of N-methoxy-N-methylthiophene-3-carboxamide (1.59 g) in tetrahydrofuran (4.1 mL) was added dropwise thereto, and this mixture was stirred at −45° C. for 30 minutes and at room temperature for additional 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.87 g). 1H-NMR (CDCl3) δ ppm: 1.53 (9H, s), 3.79 (3H, s), 4.08 (2H, s), 6.59 (1H, dd, J=2.8, 8.5 Hz), 7.08 (1H, d, J=8.5 Hz), 7.35 (1H, dd, J=2.8, 5.1 Hz), 7.43-7.56 (1H, br), 7.60 (1H, dd, J=1.3, 5.1 Hz), 7.80-8.10 (1H, br), 8.23 (1H, dd, J=1.3, 2.8 Hz).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][N:25]1[C:29]([C:30](=O)[C:31]([O:33][CH3:34])=[O:32])=[C:28]([O:36][CH2:37][C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[C:27]([CH3:44])=[N:26]1.O>C1COCC1.CCCCCC>[CH3:24][N:25]1[C:29](/[C:30](=[CH:2]\[O:3][CH3:4])/[C:31]([O:33][CH3:34])=[O:32])=[C:28]([O:36][CH2:37][C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[C:27]([CH3:44])=[N:26]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1c(OCc2csc(C)n2)c(C)nn1C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C(/C(=O)OC)c1c(OCc2csc(C)n2)c(C)nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a suspension of methoxymethyltriphenylphosphonium chloride (2 g, 5.84 mmol) in anhyrous THF was added 3.5 ml solution of lithium n-butylate (1.6 mol) in hexane. After stirring at room temperature for 30 minutes, methyl {1,3-dimethyl-4-[1-(2-methylthiazol-4-yl)methyloxy]pyrazol-5-yl}glyoxalate (0.6 g, 1.95 mmol) in anhydrous THF (6 ml) was added thereto and the mixture was allowed to stand for two hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel to obtain (E)-methyl 2-{1,3-dimethyl-4-[1-(2-methylthiazol-4-yl)methyloxy]pyrazol-5-yl}-3-methoxyacrylate (compound No. 9 in Table 1) as an oil (0.25 g, 38.1%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH:9]=[C:8]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25](OCC3C=CC=CC=3)=[O:26])[CH2:20]2)[C:3]=1C(OC)=O>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[C:3]2[C:25](=[O:26])[N:21]3[CH2:20][CH:19]([CH2:24][CH2:23][CH2:22]3)[C:8]=2[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:11]=1
Reactant: COC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)cc(-c2ccccc2O)nc1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(-c2ccccc2O)cc2c1C(=O)N1CCCC2C1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 41.7 %

Procedure:
To a solution of methyl 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-(2-hydroxyphenyl)nicotinate (60 mg, 0.130 mmol) in methanol (2.0 mL) and THF (1.0 mL) was added 10% Pd—C (200 mg). The mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 6.5 hrs. The mixture was filtrated on Celite®, and washed with MeOH and THF successively. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate, 2:1) to give 6-amino-4-(2-hydroxy-phenyl)-5,9-diaza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-8-one as a yellow solid (16 mg, yield; 40%).
Reaction SMILES: C(N(CC)CC)C.[C:8](=[S:10])=S.[CH:11]([C:14]1[C:19]([NH2:20])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:15]=1)([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH:11]([C:14]1[C:19]([N:20]=[C:8]=[S:10])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:15]=1)([CH3:12])[CH3:13]
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N=C=S
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 5.0 g of triethylamine in 10 ml of pyridine is cooled to from -5° C. to -10° C., and 20 ml of carbon disulfide are added dropwise. At -10° C., a solution of 15.0 g of 2,4-diisopropyl-6-(4-chlorophenoxy)-3-aminopyridine in 27 ml of pyridine is slowly added dropwise. The mixture is further stirred at -10° C. for 1 hour. A solution of 10.0 g of N,N'-dicyclohexylcarbodiimide in 10 ml of pyridine is then added. After a further 3 hours at -10° C., the mixture is stirred for 18 hours at room temperature. The reaction mixture is concentrated by evaporation and hexane is added to the residue. Thehhexane solution is filtered off and concentrated by evaporation. 2,4-Diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl isothiocyanate is obtained in the form of a yellow oil, which is used for the next reaction without being further purified; IR (CCl 4): 2090, 1490, 1220 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Cl:27])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)[C:6]1=[O:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CC(C)=O>[Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Cl:27])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]2)[C:6]1=[O:20]
Reactant: COc1cc(Cl)c(CC2CCN(C3CCC4(CC3)OCCO4)C2=O)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(Cl)c(CC2CCN(C3CCC(=O)CC3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxy-benzyl)-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (6.5 g, 15.7 mmol) in acetone (100 mL), add p-toluenesulfonic acid hydrate (3 g, 15.7 mmol) and stir for 24 hr at room temp. Add 5N hydrochloric acid (10 mL) heat to 45° C. for 1 hr. Reaction progress can be monitored by TLC. Concentrate the reaction mixture, dilute with saturated aqueous sodium hydrogen carbonate (500 mL) and extract with ethyl acetate (3×150 mL). Wash the combined extracts with water (100 mL) and brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate to about 50 mL volume, dilute with hexanes (50 mL) and filter to give 5.5 g, 95%, as a white solid. 1H NMR (CDCl3) δ 6.78 (s, 2H), 4.44-4.52 (m, 1H), 3.78 (s, 3H), 3.37-3.47 (m, 1H), 3.29-3.36 (m, 1H), 3.15-3.23 (m, 2H), 2.39-2.62 (m, 4H), 1.80-2.11 (m, 6H). LCMS (m+1) 370.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.CO>CN(C=O)C.O>[CH3:18][N:17]([CH3:19])[S:14]([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:3]1[CH2:2][O:1][C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)(=[O:15])=[O:16]
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CO
Reactant: Clc1cnc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1COc1cnc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
2-(Hydroxymethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (0.79 mmol) was dissolved in anhydrous DMF (5 mL) and cooled to 0° C. NaH (60% dispersion in mineral oil, 47 mg, 1.19 mmol) was added and the suspension was stirred for 2 min. 2-Chloroquinoxaline (195 mg, 1.19 mmol) in anhydrous DMF (3 mL) was added dropwise and the resulting suspension was allowed to warm to room temperature. After 2 h, MeOH (10 mL) was added slowly. The crude reaction mixture was poured into H2O (30 mL) and extracted with Et2O (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give crude N,N-dimethyl-4-phenyl-2-((quinoxalin-2-yloxy)methyl)-1H-imidazole-1-sulfonamide, which was used directly in the next reaction.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:17]2[CH:22]=[C:21]([I:23])[C:20]([O-:24])=[C:19]([I:25])[CH:18]=2)=[C:8]2[CH:14]=[C:13]([I:15])[C:11](=[O:12])[C:10]([I:16])=[CH:9]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+].[CH2:31]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42](=[O:53])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([NH2:52])[CH:47]=2)[NH2:44])[CH2:38][CH2:37]1)=[O:35])[CH3:32].C([O-])(=O)C.[Na+].[N:59]#[C:60]Br>C(O)C>[CH:1]1[CH:6]=[C:5]([C:7]([C:8]2[CH:9]=[C:10]([I:16])[C:11]([O-:12])=[C:13]([I:15])[CH:14]=2)=[C:17]2[CH:18]=[C:19]([I:25])[C:20](=[O:24])[C:21]([I:23])=[CH:22]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+:29].[CH2:31]([O:33][C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:42](=[O:53])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][C:60]#[N:59])[CH:47]=2)[NH2:44])[CH2:40][CH2:41]1)=[O:35])[CH3:32]
Reactant: N#CBr
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2cccc(N)c2)CC1
Agent: CC(=O)[O-]
Agent: O=C1C(I)=CC(=C(c2cc(I)c([O-])c(I)c2)c2ccccc2C(=O)[O-])C=C1I
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2cccc(NC#N)c2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
TIPPS-3-amino-(L)-phenylalanine-4-ethoxycarbonylpiperazide (14.6 g; 24.9 mmol), sodium acetate (anhydrous) (5.11 g; 62.2 mmol) and cyanogen bromide (2.9 g; 27.4 mmol) were dissolved in ethanol and the solution was stirred at RT for 10 h. After evaporating the solvent, the residue was taken up in ethyl acetate and the solution was extracted with 5% KHSO4, 5% NaHCO3 and distilled water. After evaporating the solvent, the crude product was purified chromatographically over silica gel.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9](OS(C)(=O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[C:25]([C:29]3[N:34]=[CH:33][C:32]([C:35]4[CH:36]=[N:37][NH:38][CH:39]=4)=[CH:31][N:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:37]2[CH:36]=[C:35]([C:32]3[CH:31]=[N:30][C:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([C:21]5[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=5)[CH:24]=4)=[N:34][CH:33]=3)[CH:39]=[N:38]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Temperature: 120 °C
Yield: 170.1 %

Procedure:
4-Methanesulfonyloxy-cyclohexanecarboxylic acid ethyl ester (AOKChem Co., Ltd; 689 mg; 2.75 mmol; 1.04 eq.) in DMF (5 mL) was added in one portion to a suspension of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 104 mg; 0.34 mmol; 1.0 eq.) and cesium carbonate (2.35 g; 7.21 mmol; 2.7 eq.) in DMF (10 mL). The reaction mixture was heated in MW at 120° C. for 35 min. It was then poured into water and filtered. The resulting solid was triturated with ACN to give the title compound as a yellow solid (264 mg, 17%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.57-8.46 (m, 2H), 8.26 (s, 1H), 8.24-8.18 (m, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.77-7.66 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.32-3.99 (m, 3H), 3.89 (s, 3H), 2.48-2.34 (m, 1H), 2.23-1.48 (m, 8H), 1.27-1.14 (m, 3H). MS (ESI+): 457.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.Br[CH2:16][CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O1CCOCC1.[I-].[K+]>[C:18]([CH2:17][CH2:16][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)#[N:19]
Reactant: N#CCCBr
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: COc1cc2c(cc1OC)CN(CCC#N)CC2
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A suspension of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9.20 g, 40.1 mmol, 1.00 equiv, Aldrich), 3-bromopropionitrile (3.66 mL, 44.1 mmol, 1.10 equiv, Aldrich), potassium carbonate (33.25 g, 240.6 mmol, 6.00 equiv), and potassium iodide (266 mg, 1.60 mmol, 0.04 equiv) in n-butanol (70 mL) and 1,4-dioxane (70 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, MeOH-EtOAc 0:1 to 1:19) to afford 8.39 g of white solid (59%), which was characterized spectroscopically.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]1>C(Cl)Cl.C1COCC1.[Cl-].[Na+].O.CN(C=O)C>[Cl:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: OCC1CCCNC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1c(Cl)cncc1Cl)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3,5-dichloroisonicotinic acid (250 mg, 1.30 mmol) in CH2Cl2 (6.5 mL) was added DMF (cat.) and oxalyl chloride (0.45 mL, 5.2 mmol), and the mixture was stirred at room temperature for 2 h then concentrated in vacuo. To the residue was added THF (2 mL), Et3N (0.27 mL, 1.9 mmol), and a solution of 3-piperidinemethanol (150 mg, 1.30 mmol) in THF (4.5 mL), and the mixture was stirred at room temperature for 21 h. The mixture was diluted with CH2Cl2 (50 mL) and brine (30 mL) and the phases were separated. The organic layer was washed with brine (2×50 mL) and saturated NaHCO3 (2×50 mL). The organic layer was dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a crude oil. Purification of the crude material by column chromatography on silica gel (100:5:1 CH2Cl2/MeOH/NH4OH) gave a yellow oil (mixture of isomers) (147 mg, 39%). 1H NMR (CDCl3) δ 1.28-1.96 (m, 4H), 2.89-3.26 (m, 3H), 3.35-3.45 (m, 1H), 3.50-3.72 (m, 2H), 4.29-4.56 (m, 1H), 8.54 (m, 2H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@@H:20]([C:21]2[NH:22][CH:23]=[C:24]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[CH:32]=[C:31]([C:36]3[CH:37]=[C:38]([C:42]5[N:43]=[C:44]([C@@H:47]6[CH2:52][C@@H:51]7[C@@H:49]([CH2:50]7)[N:48]6C(OC(C)(C)C)=O)[NH:45][CH:46]=5)[CH:39]=[CH:40][CH:41]=3)[CH:30]=[CH:29]4)[N:25]=2)[CH2:19][C@H:18]2[C@@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@H:16]12[CH2:17][C@H:18]1[CH2:19][C@H:20]([C:21]1[NH:22][CH:23]=[C:24]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[CH:32]=[C:31]([C:36]3[CH:37]=[C:38]([C:42]5[N:43]=[C:44]([C@@H:47]6[CH2:52][C@@H:51]7[C@@H:49]([CH2:50]7)[NH:48]6)[NH:45][CH:46]=5)[CH:39]=[CH:40][CH:41]=3)[CH:30]=[CH:29]4)[N:25]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2cccc(-c3ccc4cc(-c5c[nH]c([C@H]6C[C@@H]7C[C@@H]7N6C(=O)OC(C)(C)C)n5)ccc4c3)c2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2ccc3cc(-c4c[nH]c([C@H]5C[C@@H]6C[C@@H]6N5)n4)ccc3c2)cc(-c2c[nH]c([C@@H]3C[C@H]4C[C@H]4N3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a solution of tert-butyl(1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (130 mg, 0.20 mmol) in DCM (2 mL) and the mixture was stirred for 2 h at RT. The volatiles were removed under vacuum and the crude product was purified by prep HPLC (methanol/water, 0.1% TFA) to yield a TFA salt of (1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (103 mg) as a tan solid. LC-MS retention time 1.303 min; m/z 499.13 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm 5 μM column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.33 (s, 1H), 8.22 (d, J=12.5 Hz, 2H), 8.02 (dd, J=8.6, 5.8 Hz, 2H), 7.90-7.97 (m, 2H), 7.75-7.82 (m, 4H), 7.58 (t, J=7.8 Hz, 1H), 4.74-4.78 (m, 2H), 3.46-3.53 (m, 2H), 2.64-2.74 (m, 4H), 2.04-2.12 (m, 2H), 1.19-1.26 (m, 2H), 1.02 (ddd, J=14.2, 7.3, 7.2 Hz, 2H).