Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:29]1[C:34]([C:35]#[N:36])=[CH:33][CH:32]=[CH:31][N:30]=1.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:29]3[C:34]([C:35]#[N:36])=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(O)c2)CC1
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Oc3ncccc3C#N)c2)CC1
Temperature: 60 °C
Yield: 58.1 %

Procedure:
To a solution of 4-(3-hydroxy-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 1.0 mmol) in DMSO (5.0 mL) were added Cs2CO3 (660 mg, 2.0 mmol) and 2-chloro-3-pyridinecarbonitrile (172 mg, 1.2 mmol). The mixture was heated at 60° C. for 90 min. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc (3×). The organic layer was separated and dried (Na2SO4). The crude residue was purified (FCC) to give 4-[3-(3-cyano-pyridin-2-yloxy)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (229 mg, 56%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br-].[CH:12]1([Zn+])[CH2:14][CH2:13]1>C1COCC1.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>[CH:12]1([C:2]2[CH:3]=[C:4]([F:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:14][CH2:13]1
Reactant: [Zn+]C1CC1
Reactant: N#Cc1ncc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1ncc(C2CC2)cc1F
Temperature: 80 °C

Procedure:
To solution of 5-bromo-3-fluoropicolinonitrile (603 mg, 3.0 mmol) and Pd(PPh3)4 (173 mg, 0.15 mmol) in 10 mL of THF was added cyclopropyl zinc bromide (0.5 M, 10 mL) under N2. After being heated 80° C. for 4 h, the mixture was cooled to room temperature and quenched with sat. NH4Cl (aq). The mixture was extracted with EtOAc (3×) and the combined organic layers were washed with sat. NaHCO3 (aq.) and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography (elution with 0-8% EtOAc/Hex) to afford 5-cyclopropyl-3-fluoropicolinonitrile (406 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].B(F)(F)F.CCOCC.[CH:19]([O:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([N:29]2[CH2:34][CH2:33][C:32](=[CH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][C:24]=1[CH3:41])([CH3:21])[CH3:20]>ClCCl>[F:1][C:2]1[CH:9]=[C:6]([CH:7]([OH:8])[CH2:37][C:36](=[O:38])[CH:35]=[C:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[C:26]3[CH:39]=[CH:40][C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[C:24]([CH3:41])[CH:25]=3)[CH2:30][CH2:31]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)C=C1CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Reactant: O=Cc1cncc(F)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C(=O)N2CCC(=CC(=O)CC(O)c3cncc(F)c3)CC2)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-fluoronicotinaldehyde (51 mg, 0.41 mmol) in dichloromethane (1.7 mL) was cooled to −78° C. and boron trifluoride diethyl etherate (164 μL, 0.82 mmol) was added. The mixture was stirred at −78° C. for 5 min. The solution from step 1 was added. The mixture was stirred at −78° C. for 5 min, quenched with a buffer solution of pH=7. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to afford 4-(5-fluoro-3-pyridyl)-4-hydroxy-1-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butan-2-one (105 mg). 1H NMR (400 MHz, CDCl3) δ 8.46-8.31 (m, 2H), 7.53-7.49 (m, 1H), 7.24-7.22 (m, 2H), 6.83 (d, J=8.1 Hz, 1H), 6.09 (s, 1H), 5.26 (dd, J=8.9, 5.9 Hz, 1H), 4.62-4.53 (m, 1H), 4.13-4.12 (m, 1H), 3.69 (br d, 4H), 3.00 (br s, 2H), 2.88 (d, J=6.2 Hz, 2H), 2.37 (br s, 2H), 2.21 (s, 3H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 440.21, found 441.4 (M+1)+; Retention time: 1.65 minutes (3 min run).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[NH:22][CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4.Cl.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:22]([C:31](=[O:33])[CH3:32])[CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4
Reactant: CC(=O)Cl
Reactant: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 25 °C
Yield: 82 %

Procedure:
To a stirred solution of 3-(3-chloropropyloxy)morphinan.HCl 54 (3 mg, 0.008 mmol) and triethylamine (7 μL, 0.050 mmol) in dry dichloromethane (0.3 mL) was added acetyl chloride (1.8 μL, 0.025 mmol) and the mixture was stirred at room temperature. After starting material disappeared on TLC, solvent was concentrated and column chromatography gave 2.5 mg (82%) of the title compound: 1H NMR (300 MHz, CDCl3) δ6.96 (1H, t); 6.83 (1H, d); 6.75 (1H, d. d.); 4.92 (1H, m); 4.15 (2H, t); 3.81 (2H, t); 3.75 (1H, m); 3.12 (1H, m); 2.95 (1H, m); 2.62 (1H, m); 2.30 (1H, m); 2.18 (2H, m); 2.05 (3H, s); 1.00˜1.80 (10H, m).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:59]=[N:60][N:61]([CH3:64])[C:62]=5[CH3:63])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:79]>CO.O>[ClH:79].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:59]=[N:60][N:61]([CH3:64])[C:62]=5[CH3:63])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: Cc1c(-c2cccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc23)cnn1C
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: Cc1c(-c2cccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc23)cnn1C
Yield: 65 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[8-(1,5-dimethyl-1H-pyrazol-4-yl)-4-oxo-2-phenyl-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 5 g C18 cartridge {gradient 10 to 50% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (23 mg, 65%). 1H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 3H), 8.01 (dd, J=7.9 and 1.7 Hz, 1H), 7.71 (dd, J=7.3 and 1.6 Hz, 1H), 7.67 (s, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.37-7.22 (m, 7H), 3.74 (s, 3H), 2.57-2.43 (m, 4H), 2.22 (s, 3H), 2.19-2.05 (m, 1H), 1.81-1.69 (m, 1H). LCMS (Method E): RT=3.29 min, [M+H]+=462.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21].[H][H]>CO.[C].[Pd]>[CH:1]([N:14]1[CH2:17][CH:16]([N:20]([CH3:21])[CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CNC
Agent: [Pd]
Solvent: CO
Product: CN(C)C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 92 %

Procedure:
5% Palladium-carbon (1.5 g) was added to 1-benzhydrylazetidin-3-one (1.50 g) obtained from Referential Example 100 and 40% aqueous dimethylamine (4 mL) in methanol (30 mL). The resultant mixture was subjected to catalytic reduction in a hydrogen atmosphere overnight. The catalyst was filtered off, and then the solvent of the filtrate was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (1.55 g, 92%).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([O:10]CC)=O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[N:1]12[CH2:7][C:4]([C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:10])([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)C12CCN(CC1)C2
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Temperature: -30 °C
Reaction time: 16 h
Yield: 55.9 %

Procedure:
A solution of ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate (4 g, 23 mmol) in THF (60 mL) was added dropwise to a solution of phenyllithium (1.5 M in 70% cyclohexane/30% diethyl ether, 63.1 mL, 94.6 mmol) pre-cooled to −30° C. under Ar. The reaction was warmed to RT and stirred for 16 h. The reaction was treated with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Trituration (diethyl ether) afforded the title compound (3.595 g, 54%). EI-MS m/z 280 (MH)+ Rt (1.56 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:25]2)[C:21](=[O:37])[NH:20][C:19]2([C:38]([OH:40])=O)[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:53]1([S:56]([NH2:59])(=[O:58])=[O:57])[CH2:55][CH2:54]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][Si:30]([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:31])[CH3:32])[CH2:25]2)[C:21](=[O:37])[NH:20][C:19]2([C:38]([NH:59][S:56]([CH:53]3[CH2:55][CH2:54]3)(=[O:58])=[O:57])=[O:40])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(O[Si](C)(C)C(C)(C)C)CN2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O[Si](C)(C)C(C)(C)C)CN2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
14-tert-Butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (500 mg, 0.86 mmol.) was dissolved in 25 mL of THF and treated with CDI (180 mg, 1.12 mmol.). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere). After refluxing the reaction mixture for 2 h, it was cooled to rt and treated sequentially with cyclopropylsulfonamide (135 mg, 1.12 mmol.) and DBU (170 mg, 1.12 mmol.). The reaction mixture was stirred for 4 h at rt, and the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and pH 4 buffer. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. It was then purified by flash chromatography (eluting with 33% ethyl acetate in hexane) to give 300 mg (51%) of [18-(tert-butyl-dimethyl-silanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, CD3OD) δ 1H 0.07 (s, 3H), 0.08 (s, 3H), 0.85 (s, 9H), 0.87-1.49 (m, 21H), 1.73-1.95 (m, 3H), 2.08-2.16 (m, 1H), 2.25-2.36 (m, 2H), 2.42-2.56 (m, 1H), 2.85-2.93 (m, 1H), 3.65-3.74 (dd, J=10.61, 3.66 Hz, 1H), 3.89 (d, J=10.25 Hz, 1H), 4.34 (m, J=9.70, 9.70 Hz, 1H), 4.43 (t, J=7.87 Hz, 1H), 4.57 (s, 1H), 4.94-5.01 (m, 1H), 5.10 (d, J=8.78 Hz, 1H), 5.66-5.75 (m, 1H), 6.55 (s, 1H), 10.13 (s, 1H); MS m/z 683 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[C:29]([CH3:39])=[C:30]([O:34][CH2:35][CH2:36][NH:37][CH3:38])[CH:31]=[CH:32][CH:33]=1.[CH3:40]C(O)C>Cl.C(Cl)Cl>[CH3:38][N:37]([CH3:40])[CH2:36][CH2:35][O:34][C:30]1[C:29]([CH3:39])=[C:28]([NH:27][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:4][N:3]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CC(C)O
Reactant: CNCCOc1cccc(N)c1C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3C)n2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A microwave vial was charged with methyl 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoate (Intermediate Example 3) (1.75 g, 4.79 mmol), {2-[(3-amino-2-methylphenyl)oxy]ethyl}methylamine (863 mg, 4.79 mmol), iPrOH (10 mL) and 1 drop HCl, and the reaction mixture was stirred in a microwave reactor at 140° C. for 30 min. The mixture was diluted with DCM and quenched with saturated NaHCO3. The organics were separated, dried over MgSO4, and the solvent was removed. The crude material was purified via silica gel chromatography to give 1.70 g (68% yield) of the title compound. MS (APCI+) m/z 523 [M+H].
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:6][CH:5]=1.Cl.[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH2:38])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH:38][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([S:16](=[O:17])(=[O:18])[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:30])([F:1])[F:31])=[CH:29][CH:28]=2)=[CH:27][CH:26]=1)[CH3:34]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from 4-[2-(4-trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1.CCN(C(C)C)C(C)C>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([CH2:16][N:13]3[C:11]4=[N:12][C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[CH:8][N:9]=[C:10]4[N:15]=[N:14]3)[CH2:18]2)=[N:28][CH:29]=1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCNC4)c3n2)cn1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(Br)cn5)C4)c3n2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)-1-(piperidin-3-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (0.26 g, 0.89 mmol) was dissolved in EtOH (15 ml), and then 5-bromo-2-chloropyrimidine (0.33 g, 1.33 mmol) and DIPEA (0.77 ml, 4.43 mmol) were added, followed by stirring at 50° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give (1-((1-(5-bromopyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (0.28 g, 70%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][CH:14]([F:29])[C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH2:24][CH2:23][C@H:22]([OH:25])[C:21]2=[O:26])=[CH:17][CH:16]=1>ClCCl.O>[CH3:8][S:9]([O:25][CH:22]1[CH2:23][CH2:24][N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([CH:14]([F:13])[F:29])=[CH:28][CH:27]=2)[C:21]1=[O:26])(=[O:11])=[O:10]
Reactant: O=C1[C@@H](O)CCN1Cc1ccc(C(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OC1CCN(Cc2ccc(C(F)F)cc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Triethylamine (0.319 mL, 2.29 mmol) and methansulfonyl chloride (0.131 mL, 1.68 mmol) was added to a stirred solution of (S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg, 1.53 mmol) in dichloromethane (7.63 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was diluted with water and the aqueous mixture was extracted with dichloromethane. The combined organic layers were washed with 10% sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel column chromatography (0-100% EtOAc). The pure fractions were combined and concentrated in vacuo to afford 1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl methanesulfonate (322 mg, 66% yield) as a white solid: LC-MS (M+H)+320.1; 1H NMR (500 MHz, chloroform-d) δ 7.53 (d, J=7.9 Hz, 2H), 7.38-7.33 (m, 2H), 6.67 (br. t, J=1.0 Hz, 1H), 5.27 (dd, J=8.2, 7.5 Hz, 1H), 4.60-4.49 (m, 2H), 3.41-3.35 (m, 1H), 3.33 (s, 3H), 3.27 (dt, J=9.9, 7.3 Hz, 1H), 2.64-2.55 (m, 1H), 2.27 (ddt, J=13.9, 8.9, 7.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Brc1cncnc1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2N)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cncnc2)n1

Procedure:
The title compound, light brown solid, MS (ISP): m/e=327.0 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-bromo-pyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]([NH:17][C:18](=[O:26])OC3C=CC=CC=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.[CH3:27][C:28]1[CH:29]=[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:31]=[C:32]([CH3:34])[CH:33]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]([NH:17][C:18]([N:38]3[CH2:39][CH2:40][N:35]([C:30]4[CH:31]=[C:32]([CH3:34])[CH:33]=[C:28]([CH3:27])[CH:29]=4)[CH2:36][CH2:37]3)=[O:26])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: O=C(Nc1cc(-c2cccnc2)nc2ccccc12)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(N2CCN(C(=O)Nc3cc(-c4cccnc4)nc4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Phenyl N-[2-(pyridin-3-yl)quinolin-4-yl]carbamate(171 mg, 0.5 mmol) and 1-(3,5-dimethylphenyl)piperazine(95 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove tetrahydrofuran, and purified by column chromatography(ethylacetate:hexane=1:1) to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:7]1=[CH:8][C:9]3[C:10](=O)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17](=O)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:26])[CH3:25].I.O.II>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:7]1=[CH:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:26])[CH3:25])[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1ccccc1C3=O
Agent: I
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)c2cc(Br)ccc2-c2cc3cc4ccccc4cc3cc21
Reaction time: 48 h
Yield: 60.5 %

Procedure:
2-bromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene-6,11-dione (20 g, 0.05 mol) was dissolved in acetic acid (200 ml), and added with 57% HI (50 ml), followed by reflux-stirring for 48 hours. After the reaction was completed, the resultant solution was added with distilled water (500 ml). The produced solid was filtered and dissolved in toluene (200 ml) and iodine (4.05 g, 0.016 mol) was added thereto, followed by reflux-stirring for 3 hours. After the reaction was completed, through extraction and column chromatography, 2-bromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene (11.3 g, yield 61%) was obtained.
Reaction SMILES: Cl.[CH:2]1([C:5]([NH:7][C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:6])[CH2:4][CH2:3]1.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:2]1([C:5]([NH:7][C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][N:11]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:12][CH2:13]2)=[O:6])[CH2:3][CH2:4]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(NC1(c2ccccc2)CCNCC1)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1(c2ccccc2)CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)C1CC1
Yield: 102.1 %

Procedure:
A mixture of 0.565 g of 4-(cyclopropylcarbonylamino)-4-phenylpiperidine hydrochloride in 50 ml of DCM is cooled to +5° C., 0.565 g of trityl chloride is added followed by 0.7 ml of triethylamine and the mixture is kept stirring while allowing the temperature to rise to RT. The reaction mixture is washed with water, the organic phase dried over MgSO4 and the solvent evaporated under vacuum. 1 g of the expected product is obtained after crystallization from ether.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:24]2[C:28]3[CH:29]=[C:30]([N:33]=[C:34]=[O:35])[CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)=[CH:19][CH:18]=1>CCOCC.CN(C)C=O>[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:24]2[C:28]3[CH:29]=[C:30]([N:33]4[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:34]4=[O:35])[CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COc1ccc(-c2nsc3ccc(N=C=O)cc23)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
A mixture of 60% sodium hydride in mineral oil (15.9 g, 0.397 mol) and N,N-dimethylformamide is cooled to -10° C., treated over one hour with a solution of ethyl 3-amino-4,4,4-trifluorocrotonate (72.7 g, 0.397 mol) in ether, warmed to and stirred at room temperature for 90 minutes, cooled to -70° C., treated over 80 minutes with a solution of 3-(6-methoxy-m-tolyl)-1,2-benzisothiazol-5-yl isocyanate (107 g, 0.361 mol) in N,N-dimethylformamide while maintaining the temperature below about -65° C., slowly warmed to and stirred at room temperature overnight, and poured onto ice. The resultant aqueous mixture is washed with ethyl acetate, acidified to pH 2 with concentrated hydrochloric acid, and extracted with diethyl ether. The organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an orange oil (110 g, 70.5%) which is identified by NMR spectral analyses.