Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:35])[N:26]([C@H:28]([CH:33]=O)[CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:27])([CH3:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[C:20]([O:24][C:25](=[O:35])[N:26]([C@H:28]([CH2:33][NH:12][CH2:11][CH2:10][CH2:9][CH:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:29][CH:30]([CH3:31])[CH3:32])[CH3:27])([CH3:23])([CH3:22])[CH3:21]
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](CNCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
4,4-bis-(4-fluorophenyl)-butylamine (200 mg, 0.77 mmol) was dissolved in CH,2Cl2 (5 mL), treated with (S)-(1-formyl-3-methyl-butyl)-methyl-carbamic acid tert-butyl ester (229 mg, 1.0 mmol), stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3 (245 mg, 1.16 mmol), and stirred overnight at room temperature. The reaction was diluted with EtOAc (100 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 257 mg (70%) of the desired product as an oil. MS: 475.4 (M+1 for C28H40N2O2F2); an oil; TLC (SiO2), Rf 0.26 (4% MeOH/CH2Cl2); HPLC (1:1 CH3CN/H2O with 0.1% TFA, C-18 column) 100%, RT=15.013 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[N:6][C:5]2=[C:14]([C:16]([OH:18])=O)[CH:15]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:13]=[CH:12][S:11][CH:10]=4)=[N:6][C:5]=13)=[O:18])[CH2:23]2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccsc3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4ccsc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.9 %

Procedure:
A mixture of 6-chloro-2-(thiophen-3-yl)benzo[d]oxazole-4-carboxylic acid (70 mg, 0.25 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (57 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.13 mL, 1.0 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) followed by recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide (30 mg, 29%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=7.5 Hz, 1H), 8.25 (dd, J=3.0, 1.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.75 (dd, J=5.0, 1.5 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.52 (dd, J=5.5, 3.0 Hz, 1H), 4.60-4.53 (m, 1H), 3.12 (d, J=10.5 Hz, 2H), 2.65-2.58 (m, 2H), 2.53 (s, 3H), 2.12-1.95 (m, 3H), 1.60-1.52 (m, 1H), 1.49-1.43 (m, 2H), 1.14 (d, J=12.5 Hz, 2H); MS (ESI+) m/z 416 (M+H); HPLC 98.2% (AUC), tR=12.82 min.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:36])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]#[CH:27])[N:24]=3)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].[N:37]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)=[N+:38]=[N-:39].CC(O)(C)C>S([O-])([O-])(=O)=O.[Cu+2].[Cu].O>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:36])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[N:39]=[N:38][N:37]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[CH:27]=4)[N:24]=3)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: C#Cc1cnc2c(n1)c(C(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C1CC1)cn2COCC[Si](C)(C)C
Reactant: [N-]=[N+]=NC1CCCC1
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-c3cn(C4CCCC4)nn3)cnc21
Temperature: 125 °C
Yield: 68.8 %

Procedure:
A microwave vial was charged with 2-ethynyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol), azidocyclopentane (32.9 mg, 0.3 mmol), t-BuOH (0.6 mL), and H2O (0.6 mL). To this sticky mixture was added 1.0 M aqueous copper (II) sulfate (39.5 μL, 0.04 mmol) and copper powder (10.0 mg, 0.16 mmol). The vial was sealed and the heterogeneous reaction mixture was heated in a microwave reactor at 125° C. for 5 min. The reaction mixture was cooled to room temperature and filtered, rinsing with EtOAc. The filtrate was washed with water, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/hexanes) to afford 85 mg (70%) of 2-(1-cyclopentyl-1H-[1,2,3]triazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as an off-white foamy solid.
Reaction SMILES: [OH-].[Li+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][C:11]([O:13]C)=[O:12].Cl>O1CCCC1>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)CCC1CCCCO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCC1CCCCO1
Yield: 108.9 %

Procedure:
An aqueous solution of lithium hydroxide (4 mL of 2 M) was added to a solution of methyl 3-(tetrahydro-2H-pyran-2-yl)propionate (Preparation 5, 0.46 g, 2.67 mmol) in tetrahydrofuran (16 mL) and the reaction mixture was heated under reflux for 10 h. The cooled reaction mixture was acidified with aqueous 2N hydrochloric acid to pH 1, and then extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a colourless oil (460 mg, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15]O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH2:15][Br:36])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cc(Br)cc(-c2ccc(F)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2cc(Br)cc(CBr)c2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(5-Bromo-4′-fluorobiphenyl-3-yl)methanol (0.42 g, 1.5 mmol) and triphenylphosphine (0.78 g, 2.98 mmol) were combined in tetrahydrofuran (8 mL) and cooled to 0° C. N-Bromosuccinimide (0.59 g, 3.1 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 0.4 g (78%) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.60 (m, 1H), 7.50-7.54 (m, 3H), 7.47 (m, 1H), 7.12-7.15 (m, 2H), 4.47 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=O)[C:11]3[C:12]([CH3:15])=[CH:13][O:14][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17]/[C:16](=[N:23]\[NH:22][C:19]([NH2:21])=[NH:20])/[C:11]3[C:12]([CH3:15])=[CH:13][O:14][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1cccc(Br)c1)C2
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1cccc(Br)c1)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a mixture of 6-(3-bromophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g) and aminoguanidine hydrochloride (51 mg) were added ethanol (10 ml) and 6N hydrochloric acid (0.04 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(3-bromophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 32) (76 mg).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:11]1)C1C=CC=CC=1>[Pd].CCO>[OH:8][CH2:9][C@@H:10]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:23]([F:24])([F:25])[F:26])[C:27]([F:28])([F:29])[F:30])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](COCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CO)C1
Reaction time: 2 h
Yield: 100.2 %

Procedure:
A 150-mL round-bottomed flask was charged with tert-butyl (3R)-3-((benzyloxy)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.917 g, 1.67 mmol), palladium on activated carbon (10 wt %, wet, degussa type, 1.34 g, 0.632 mmol, Sigma-Aldrich, St. Louis, Mo.) and EtOH (15 mL). The reaction mixture was evacuated under vacuum and refilled with hydrogen (5 times). The mixture was hydrogenated under balloon pressure of hydrogen at 60° C. for 2 h. The catalyst was removed via filtration through a pad of filter agent. The filter cake was covered with sand and washed with EtOH. The filtrate was concentrated to give tert-butyl (3R)-3-(hydroxymethyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.767 g) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]3[C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19][N:18]3[CH3:25])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])=[N:33][CH:34]=[CH:35][C:36]=1B1OC(C)(C)C(C)(C)O1)(=[O:28])[CH3:27].CC([O-])=O.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])=[N:33][CH:34]=[CH:35][C:36]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]3[C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19][N:18]3[CH3:25])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCN(C)[C@H](c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc([C@@H]4C(=O)N(C)CCN4C)cc3)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 114a (228 mg, 0.56 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (215 mg, 0.56 mmol), Pd (dppf)Cl2 (47 mg, 0.056 mmol), 1.0 M NaOAc (93 mg, 1.12 mmol, 2.0 equiv), 1.0 M K3PO4 (240 mg, 1.12 mmol, 2.0 equiv), and acetonitrile (3 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1, V/V) to 114b (360 mg, 96%) as a brown solid. LCMS: [M+H]+ 665.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=3)[CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[CH2:14]2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>C(O)C>[Cl:39][C:34]1[CH:33]=[C:32]([C:13]2([CH2:12][CH2:11][N:8]3[CH2:9][CH2:10][C:5]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]3)[CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[CH2:14]2)[CH:37]=[CH:36][C:35]=1[Cl:38]
Reactant: COC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid methyl-ester (0.393 g, 0.60 mmol) and NaOH (6 mL, 1N, 6 mmol) were combined in ethanol (12 mL). The mixture was stirred for 48 h at ambient temperature. 1N HCl was added to adjust the pH to 1. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was chromatographed on silica gel eluting sequentially with 10% methanol in dichloromethane and then 20% methanol in dichloromethane. The fractions which contained the title compound were washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].[C:33](O)(=O)[CH3:34].C(=O)C>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH2:33][CH3:34])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCN(CCC)CCCCN(CC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (289 mg) obtained in Example 23-4 was dissolved in anhydrous methanol (6.0 ml) and added with sodium cyanoborohydride (92.8 mg), acetic acid (1.00 ml), and acetaldehyde (61.3 μl). The whole was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution, followed by stirring for a while. The resultant was subjected to extraction with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (311 mg) as a pale-yellow oily substance.
Reaction SMILES: [CH:1]1([CH:4]([OH:25])[C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[CH3:22])[C:12]3=[O:23])=[CH:7][C:6]=2[F:24])[CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[CH:1]1([C:4]([C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[CH3:22])[C:12]3=[O:23])=[CH:7][C:6]=2[F:24])=[O:25])[CH2:2][CH2:3]1
Reactant: Cc1ccncc1N1CCN(c2ccc(C(O)C3CC3)c(F)c2)C1=O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1ccncc1N1CCN(c2ccc(C(=O)C3CC3)c(F)c2)C1=O
Yield: 6 %

Procedure:
MnO2 (357 mg, 41.055 mmol) was added to 1-[4-(cyclopropyl-hydroxy-methyl)-3-fluoro-phenyl]-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-161a: 200 mg, 8.586 mmol) in DCM (20 mL) under nitrogen atmosphere and worked up in a manner similar to what has been described previously for example 160 (Step 2) to afford 175 mg of the product (60.13% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:13][C:14]([OH:16])([CH3:17])[CH3:15])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1cnc(Cl)nc1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)CNc1nc(Cl)ncc1C(=O)O
Temperature: 3.5 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A suspension of 19.9 g (86.73 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid in 155 mL of THF is cooled on an ice bath to 2-5°C., and a solution of 8.5 g (95.40 mmol) of 1-amino-2-methyl-2-propanol and 36.3 mL (260.19 mmol) of triethylamine in 60 mL of THF is added dropwise. The mixture is stirred at room temperature overnight. Ethyl acetate and water are added. After separation of the phases by settling, the aqueous phase is acidified with aqueous 1N HCl solution to pH 2. The precipitate is isolated by filtration to give 12.6 g of the expected product in the form of a pale yellow solid, which is used as obtained in the following step. Yield=59%.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.[C-]#N.[Na+].Br[C:10]1[N:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=1>CN(C=O)C.CCOC(C)=O.O>[NH2:16][C:13]1[N:14]=[CH:15][C:10]([C:4]#[N:5])=[N:11][CH:12]=1
Reactant: Nc1cnc(Br)cn1
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cnc(N)cn1
Temperature: 135 °C
Yield: 49.9 %

Procedure:
Heat a suspension of 1.85 g (20.7 mmol) of copper cyanide and 1 g (20.7 mmol) of sodium cyanide in 20 ml of DMF to 135° C., while stirring. Add 3.6 g (20.7 mmol) of 5-bromopyrazin-2-amine to the solution obtained, and maintain the temperature of 135° C. for 18 h. Then add 2 equivalents of sodium cyanide and of copper cyanide and continue heating for a further 24 h. After cooling, add 100 mL of 0.3N aqueous solution of sodium cyanide, stir the mixture for 1 h at 40° C., then distribute it in 300 mL of EtOAc/water 1:1 mixture. After washing with 2×100 mL of water, dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 100% of EtOAc. After concentration under reduced pressure, we obtain 1.24 g of 5-aminopyrazine-2-carbonitrile in the form of oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH2:10](Cl)[CH:11]=[CH2:12]>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)[CH:11]=[CH2:10]
Reactant: C=CCCl
Reactant: Cc1cc(O)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: C=CCOc1ccc(Br)c(C)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a dark yellow solution of 4-bromo-3-methyl-phenol (4.68 g, 25 mmol) in isopropanol (60 mL) and 3 N aq. NaOH (20 mL), allylchloride (8.18 g, 107 mmol) is added. The mixture is stirred at 70° C. for 3 h before it is cooled to rt, diluted with diethyl ether and washed with 1 N aq. NaOH solution (275 mL) and 1 M aq. HCl solution (70 mL) followed by brine (70 mL). The org. extract is dried over MgSO4, filtered, concentrated and dried to give crude 4-allyloxy-1-bromo-2-methyl-benzene (5.67 g) as a yellow oil; LC-MS: tR=0.59 min; [M+1]+=not detectable; 1H NMR (CDCl3): δ 2.38 (s, 3H), 4.52 (dt, J=5.3, 1.5 Hz, 2H), 5.29-5.34 (m, 1H), 5.39-5.46 (m, 1H), 6.00-6.11 (m, 1H), 6.65 (dd, J=8.8, 3.0 Hz, 1H), 6.83 (d, J=3.0 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:5])C.Cl.[NH:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].C(N(CC)CC)C.O>ClCCl.CO>[CH3:5][C:4]1[N:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:16]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[N:17]=1
Reactant: CCOC(C)=NC(=O)c1ccccc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reaction time: 8 h
Yield: 56 %

Procedure:
N-(1-ethoxy-ethylidene)-benzamide 400mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-(3-methyl-5-phenyl-[1,2,4]triazole-1-yl)-benzenesulfonamide (368 mg, yield: 56%) was obtained as a solid phase.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=2)[C:5]([Br:17])=[CH:4][CH:3]=1.[C:18]1(B(O)O)[C:31]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=2)[CH:27]=[CH:26][CH:25]=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O.C(O)CCC.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.C1(C)C=CC=CC=1>[Br:17][C:5]1[C:6]2[C:10](=[N:9][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:7]=2)[C:2]([C:18]2[CH:31]=[CH:30][C:29]([C:28]3[C:33]4[C:24]5=[C:23]6[C:22](=[CH:21][CH:32]=4)[CH:5]=[CH:4][CH:3]=[C:2]6[CH:10]=[CH:6][C:25]5=[CH:26][CH:27]=3)=[CH:20][CH:19]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
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: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: Brc1ccc(-c2ccc(-c3ccc4ccc5cccc6ccc3c4c56)cc2)c2nn(-c3ccncc3)nc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A mixture of Intermediate A (1.41 g, 4 mmol), pyrene-1-boronic acid (0.49 g, 2.0 mmol), tetrakis(triphenylphosphine)palladium (0) (0.50 g, 0.43 mmol), sodium carbonate (2.12 g, 20 mmol) in water (10 mL), n-butanol (30 mL), and toluene (30 mL) was heated under argon at 110° C. for 5 hours. The reaction mixture was poured into water (200 mL), treated with 5 N NaOH (20 mL), stirred for 1 hour, and extracted with dichloromethane (2×200 mL). The extract was dried over anhydrous sodium carbonate, and the volatiles were removed under reduced pressure. The residue was chromatographed (silica gel, dichloromethane/tetrahydrofuran 9:10) to give 4-bromo-7-(4-(pyren-1-yl)phenyl)-2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole (purity 90%, 650 mg, 53% yield) as yellow crystals. 1H NMR (400 MHz, CDCl3): δ 8.72 (m, 2H, pyridine), 8.31 (d, J=7.7 Hz, 1H, pyrene), 8.24 (dd, J=7.7 and 1.1 Hz, 1H, pyrene), 8.16-8.20 (m, 6H, pyrene and pyridine), 8.04 (t, J=7.7 Hz, 1H, pyrene), 8.00 (m, 2H, pyrene), 7.86 (d, J=7.7 Hz, 1H, benzotriazole), 7.86 (d, J=7.3 Hz, 1H, benzotriazole).