Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:21])[CH:2]=[CH2:3]>CCOC(C)=O.[Pd]>[OH:21][C:5]1[C:6]2[CH2:12][CH2:11][N:10]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:9][CH2:8][C:7]=2[CH:19]=[CH:20][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Dissolve 7-allyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.5 g, 5 mmol) in EtOAc (50 mL) containing 10% Pd/C (1.3 g). Stir at ambient temperature at 1 atm with H2 (balloon) for 30 min. Filter the catalyst and wash with water (100 mL). Extract the resulting filtrate three times with EtOAc, wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo to give the desired intermediate as a white solid (1.45 g, 97%). MS (ES+) m/z: 302 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH:11]1[C:12]([OH:58])([CH3:57])[CH2:13][CH2:14][CH:15]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[CH2:16][C:17]([O:19][CH:20](/[C:25](/[CH3:48])=[CH:26]/[CH:27]=[CH:28]/[CH:29]([CH3:47])[CH2:30][CH:31]2[O:46][CH:32]2[CH:33]([CH3:45])[CH:34]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:35][CH3:36])[CH:21]([CH3:24])[CH:22]=[CH:23]1)=[O:18])(=O)C.C(O)(=O)C>>[O:49]([CH:15]1[CH2:14][CH2:13][C:12]([OH:58])([CH3:57])[CH:11]([OH:10])[CH:23]=[CH:22][CH:21]([CH3:24])[CH:20](/[C:25](/[CH3:48])=[CH:26]/[CH:27]=[CH:28]/[CH:29]([CH3:47])[CH2:30][CH:31]2[O:46][CH:32]2[CH:33]([CH3:45])[CH:34]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:35][CH3:36])[O:19][C:17](=[O:18])[CH2:16]1)[Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]
Reactant: CCC(O[Si](C)(C)C(C)(C)C)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(OC(C)=O)C=CC1C
Agent: CCC(O[Si](C)(C)C(C)(C)C)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(O)/C=C/C1C
Agent: CCC(O[Si](C)(C)C(C)(C)C)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: CCC(O[Si](C)(C)C(C)(C)C)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(O)C=CC1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Potassium carbonate (48 mg, 0.35 mmol) was added to a solution of (8E,12E,14E)-7-acetoxy-3,21-bis(t-butyldimethylsiloxy)-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (220 mg, 0.29 mmol) obtained in Example B11 methanol (15 mL), followed by stirring at room temperature for 15 hours. After acetic acid (40 μL, 0.69 mmol) was added, the reaction solution was evaporated. The residue was dissolved in ethyl acetate, and the solution was washed with a saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure to obtain the title compound (0.2 g, 95%) as a colorless amorphous.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:13]CC(C1C=C(CC)C=CN=1)=O>>[Br:13][CH2:2][C:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CCc1ccnc(C(=O)CBr)c1
Reactant: CC(=O)c1cc(C(C)C)ccn1
Product: CC(C)c1ccnc(C(=O)CBr)c1

Procedure:
* 2-Bromoacetyl-4-isopropylpyridine was prepared from 2-acetyl-4-isopropylpyridine (K. Ishihama et al., J. Agric. Food Chem., 1992, 40, 1647) according to the procedure for preparing 2-bromoacetyl-4-ethylpyridine described in Example 57.
Reaction SMILES: [CH3:1][C:2]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](=[O:36])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)([CH3:10])[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O>>[O:36]=[C:20]([C:21]1[S:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)[CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:2]([CH3:10])([CH3:1])[C:3]([OH:5])=[O:4])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)C(=O)O

Procedure:
2-(4-(3-Oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-methyl-2-(4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)propanoate according to general procedure E using 10 equivalents of trifluoroacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:7](=[O:18])[N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:5]2=[O:30].[CH2:31]([O:38][CH:39]1[CH2:42][NH:41][CH2:40]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(C)([O-])C.[Na+].C(P(CCCC)CCCC)CCC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:31]([O:38][CH:39]1[CH2:40][N:41]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7](=[O:18])[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:5]3=[O:30])[CH2:42]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(Cn2c(=O)c3cc(Br)ccc3n(C3CCOCC3)c2=O)cc1OC
Reactant: c1ccc(COC2CNC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(N4CC(OCc5ccccc5)C4)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 17.5 %

Procedure:
A mixture of 0.2 g of 6-bromo-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione, 0.096 g of 3-benzyloxyazetidine, 0.006 g of palladium acetate, 0.055 g of sodium tert-butoxide and 0.01 ml of tributylphosphine in 4 ml of DMF is stirred for 4 days at room temperature. The reaction mixture is filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (20/80, v/v) to give 0.041 g of the expected product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[I-].[Na+].C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1.[CH3:47][C:48]([OH:52])([C:50]#[CH:51])[CH3:49]>[Zn].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.C1COCC1.CCOC(C)=O.O.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:51]#[C:50][C:48]([OH:52])([CH3:49])[CH3:47])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C#CC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(C#CC(C)(C)O)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 90 °C
Yield: 67 %

Procedure:
To a 10 mL microwave vial were sequentially added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.15 g, 0.401 mmol), sodium iodide (0.012 g, 0.080 mmol), zinc (5.25 mg, 0.080 mmol), DMSO(2.5 mL), triethylamine (0.112 mL, 0.802 mmol), and DBU (0.121 mL, 0.802 mmol). The suspension was stirred and degassed with nitrogen for 5 min, forming an emulsion. Next added 2-methyl-3-butyn-2-ol (0.194 mL, 2.006 mmol) and Pd(Ph3P)4 (0.046 g, 0.040 mmol). The stirring contents were heated at 90° C. for 3 hr, and then allowed to cool to room temperature. The reaction mixture was poured into a solution of water and 20% THF/EtOAc, and stirred. The layers were separated, and the organic layer washed with brine. The organic layer was dried over MgSO4, and then filtered through Celite, washing the filter pad with additional EtOAc. The filtrate was concentrated in vacuo and the crude residue dried overnight on a hi-vac pump. The crude product was purified by silica gel chromatography (eluent: gradient: 5-80% of DCM and Chloroform containing 10% 2M Ammonia (in methanol)). The collected product was dried in vacuum oven at 45° C. overnight, to afford the final product as 0.116 g (67% yield). LCMS E-S (M+H)=421.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.55 (m, 12 H), 2.13 (s, 3 H), 2.20 (s, 3 H), 4.35 (d, J=4.80 Hz, 2 H), 5.15-5.26 (m, 1 H), 5.70 (s, 1 H), 5.89 (s, 1 H), 7.65 (s, 1 H), 8.38 (s, 1 H), 8.93 (t, J=4.80 Hz, 1 H), 11.55 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Cl[C:34]1[C:39]([CH:40]=[O:41])=[C:38]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])[N:37]=[CH:36][CH:35]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH3:1][N:2]1[C:3](=[O:32])[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)=[CH:5][C:6]([C:34]2[C:39]([CH:40]=[O:41])=[C:38]([N:42]3[CH2:54][CH2:53][N:45]4[C:46]5[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=5[CH:52]=[C:44]4[C:43]3=[O:55])[N:37]=[CH:36][CH:35]=2)=[CH:7]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 100 °C
Yield: 91.4 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a condenser was charged with 111c (450 mg, 1.26 mmol), 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 103b (413 mg, 1.26 mmol), Pd(dppf)Cl2 (102 mg, 0.126 mmol), K3PO4.3H2O (85 mg, 0.352 mmol), and THF (10 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 7:1 petroleum ether/ethyl acetate to afford 111d as a yellow solid (700 mg, 63%). MS: [M+H]+ 608.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([N:10]2[CH2:17][CH2:16][C@@H:15]3[C@@H:12]([N:13]([C:18]4[N:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=4)[CH2:14]3)[CH2:11]2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[N:27]1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[CH3:25][C:20]1[CH:21]=[C:22]([CH3:24])[N:23]=[C:18]([N:13]2[C@@H:12]3[C@@H:15]([CH2:16][CH2:17][N:10]([C:8]([C:3]4[C:2]([N:26]5[CH:30]=[CH:29][N:28]=[N:27]5)=[CH:7][CH:6]=[CH:5][N:4]=4)=[O:9])[CH2:11]3)[CH2:14]2)[N:19]=1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4ncccc4Br)C[C@@H]32)n1
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4ncccc4-n4ccnn4)C[C@@H]32)n1
Temperature: 160 °C
Yield: 6.4 %

Procedure:
The title compound was prepared by treating (1R,6S)-3-[(3-bromopyridin-2-yl)carbonyl]-8-(4,6-dimethylpyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (30 mg, 0.08 mmol), with 1H-1,2,3-triazole (43 uL, 0.75 mmol), Cs2CO3 (49 mg, 0.15 mmol), CuI (3.5 mg, 0.02 mmol), and (R,R)-(−)-N,N′-dimethyl-1,2-cyclohexanediamine (12 uL, 0.05 mmol) in 1,4-dioxane containing 3% water. The mixture was heated to 160° C. in a sealed tube. The reaction was purified directly on 16 g SiO2 with 0-2% NH3 MeOH/CH2Cl2 to give partially purified material which was further purified to the individual two isomers, the title compound (2 mg, 4% yield) and Example 183 (10 mg, 10% yield) by reverse phase HPLC. MS (ESI) mass calcd. for C20H22N8O, 390.5; m/z found, 391.2 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[N:18]=[C:19]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)[CH2:37][CH2:36]3)=[C:31]([CH3:48])[CH:30]=2)[C:20]([C:25]([NH2:27])=[O:26])=[N:21][C:22]=1[CH2:23][CH3:24]>CN(C)C=O>[C:25]([C:20]1[N:21]=[C:22]([CH2:23][CH3:24])[C:17]([O:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:18][C:19]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][CH:38]([N:41]3[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]3)[CH2:37][CH2:36]2)=[C:31]([CH3:48])[CH:30]=1)(=[O:26])[NH2:27]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
To a mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (860 mg) and N,N-dimethylformamide (30 mL) was added 55% oily sodium hydride (200 mg) under ice-cooling. After stirring for 30 minutes under ice-cooling, 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (1 g) was added thereto, followed by further stirring for 1 hour under ice-cooling. 55% oily sodium hydride (100 mg) was added thereto, followed by stirring at room temperature for 4 hours, and then 55% oily sodium hydride (100 mg) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-ethyl-6-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (284 mg).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH:21]=[N:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[H][H].CCN(CC)CC>CCO.C1COCC1.[Pd]>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc3cccnc3nc2-c2ccc(C)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCCC3)cc1
Reaction time: 48 h

Procedure:
A solution of 2,3-dip-tolylpyrido[2,3-b]pyrazine (step 1)(181 g, 487 mmol) in EtOH/THF (1:2, 2100 ml) was treated with 10% palladium on carbon (30 g, 28.8 mmol) and the reaction mixture was placed under 0.1 bar of hydrogen at RT. After 2 days and 4 days respectively, additional batches of 10% palladium on carbon (10 g, 9.6 mmol, twice) were added along with Et3N (85 ml, 706 mmol, twice). After 7 days in total, the reaction mixture was filtered through Hyflo (filter material) and washed through with THF (2.5 L in portions). The filtrate was concentrated in vacuo to give a green/yellow solid. The solid was triturated with 1:1 TBME/heptane (500 ml) and filtered. The solid was washed with 1:1 TBME/heptane (200 ml) to give a pale yellow solid which was dried overnight to afford the title compound; HPLC (Agilent 1200), Rt 4.73 min, Method B.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([CH:26]=[C:27]([Cl:29])[CH:28]=2)[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:19]([CH3:22])=[N:20][N:21]=4)[C:13]=3[CH:12]=[C:11]2[C:23](O)=[O:24])[CH2:4][CH2:3][CH2:2]1.[CH:30]([N:33](CC)C(C)C)(C)C.Cl.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67]>CN1C(=O)CCC1.CC#N>[F:69][C:68]([F:71])([F:70])[C:66]([OH:72])=[O:67].[F:69][C:68]([F:71])([F:70])[C:66]([OH:72])=[O:67].[N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([CH:26]=[C:27]([Cl:29])[CH:28]=2)[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:19]([CH3:22])=[N:20][N:21]=4)[C:13]=3[CH:12]=[C:11]2[C:23]([NH:33][CH3:30])=[O:24])[CH2:2][CH2:3][CH2:4]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cc(Cl)cc(CN4CCC4)c3)n12
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1cc(Cl)cc(CN2CCC2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 6-[3-(azetidin-1-ylmethyl)-5-chlorobenzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.035 g, 0.085 mmol, from Step 9) in NMP (2 mL) was added N,N-diisopropylethylamine (0.059 mL, 0.34 mmol), methylamine hydrochloride (9.9 mg, 0.15 mmol, Alfa Aesar) and HATU (0.042 g, 0.11 mmol). After 30 minutes, the reaction was complete, and the reaction mixture was diluted with MeCN and a small amount of TFA. The product was purified by preparative HPLC-MS (Waters SunFire C18, Sum 30×100 mm, H2O (0.1% TFA) MeOH @ 60 mL/min). Yield: (0.01 g, 30%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.Cl.Cl[CH2:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>CN(C)C=O>[NH:19]1[CH:20]=[CH:21][N:22]=[C:18]1[CH2:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: ClCc1ncc[nH]1
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: c1ccc2cc3[nH]c(SCc4ncc[nH]4)nc3cc2c1
Yield: 10.7 %

Procedure:
1.0 g of 1H-Naphth[2,3-d]imidazole-2-thiol and 0.8 g of 2-chloromethylimidazole-hydrochloride were heated for 11/2 hours at 90° in 20 ml of dimethylformamide. The precipitate formed was filtered off, washed with a small amount of acetonitrile, and dissolved in 2 N sodium bicarbonate solution. The aqueous phase was extracted three times with 30 ml of ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, and then concentrated by evaporation. The residue was recrystallised from 150 ml of acetonitrile. 150 mg of 2-[(Imidazole-2-ylmethyl)thio]-1H-naphth[2,3-d]imidazole having a melting point of 172° was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[C:9]1=[N:10][NH:11][C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[C:8]1[CH2:7]2.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(N(C(C)C)CC)(C)C>C1COCC1>[C:30]1([O:29][C:27]([N:10]2[C:9]3[C:21]4[C:6]([CH2:7][C:8]=3[C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:11]2)=[CH:5][C:4]([O:3][CH3:2])=[C:23]([O:24][CH3:25])[CH:22]=4)=[O:28])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc2c(cc1OC)-c1n[nH]c(Nc3cccc(F)c3)c1C2
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)Oc1ccccc1)C2

Procedure:
To a mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (1.5 g g, 4.2 mmol), phenyl chloroformate (Compound 55a) (0.76 mL, 6.3 mmole) and THF (10 mL) was added Diisopropylethylamine (DIPEA) (1.4 mL, 8.4 mmole) at room temperature with stirring. The reaction was stirred at room temperature over night. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The solvent was dried over sodium sulfate and removed via rotovap to give a crude material (Compound 433). MS m/z 446.1 (M+H)+.
Reaction SMILES: OC1C=C(C=CC=1)OCC[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[C:16]1(=[O:17])[NH:8][C:9](=[O:18])[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:15]12
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 70 °C

Procedure:
A mixture of 2-[2-(3-hydroxy-phenoxy)-ethyl]-isoindole-1,3-dione (24) (5 g, 17.6 mmol), 4-bromoethyl butyrate (3.0 mL, 21.28 mmol) and cesium carbonate (6.2 g, 35.38 mmol) in NMP (30 mL) was warmed at 70° C. for 12 h. The mixture was cooled to room temperature and poured into crushed ice. This mixture was extracted with EtOAc and the organic layer was washed with water, then brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (0 to 10% EtOAc-hexanes gradient) gave ether 5 as clear oil. Yield (3.33 g, 47%): 1H NMR (400 MHz, CDCl3) δ 7.85-7.87 (m, 2H), 7.71-7.74 (m, 2H), 7.10-7.14 (m, 1H), 6.42-6.47 (m, 3H), 4.08-4.22 (m, 6H), 3.95 (t, J=6.0 Hz, 2H), 2.49 (t, J=7.4 Hz, 2H), 2.04-2.11 (m, 2H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1]C1C2C(=CC=C(C=O)C=2)NC=1.C([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[C:38]3[C:33](=[C:34]([CH:39]=[O:40])[CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[CH2:22][CH2:21]1)=[O:19])(C)(C)C>>[Cl:1][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][C:34]=2[CH:39]=[O:40])[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][N:20]([C:18]([OH:17])=[O:19])[CH2:21][CH2:22]2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCn2ccc3c(C=O)cccc32)CC1
Reactant: O=Cc1ccc2[nH]cc(Cl)c2c1
Product: O=Cc1cccc2c1c(Cl)cn2CCCCC1CCN(C(=O)O)CC1

Procedure:
The title compound was prepared using methods analogous to those described for Intermediate 1 from 4-[4-(4-formyl-indol-1-yl)-butyl]-piperidine-1-carboxylic acid tert-butyl ester. MS: mass calcd. for C23H31ClN2O3, 418.20; m/z found, 441.3 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH:12]=[CH:11][CH2:10]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.B1C2CCCC1CCC2.[OH-:26].[Na+].OO>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:10][CH2:11][CH:12]([OH:26])[CH2:13]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1OC1CC=CC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1OC1CCC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A solution of Example 25A (1.18 g, 5 mmol) in THF (20 mL) was treated with a solution of 9-BBN (0.5M in THF, 10 mL, 5.0 mmol) via syringe. After stirring at room temperature overnight, the solution was cooled with an ice bath, treated with a solution of NaOH (0.2 g) in water (2 mL), treated dropwise with hydrogen peroxide (30% wt, 0.56 g, 5.0 mmol), and stirred for 3 hours. The mixture was treated with water (50 mL) and ethyl acetate (150 mL) and the organic phase was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 60% ethyl acetate/hexanes to provide 0.55 g (42.8%) of the desired product. MS (DCI/NH3) m/z 275 (M+NH4)+; 1H NMR indicated two isomers in ˜4:1 ratio. The spectrum of the major isomer (300 MHz, CDCl3) δ 7.79 (d, J=2.4 Hz, 1H), 7.46 (dd, J=8.8, 2.7 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.95–5.05 (m, 1H), 4.55–4.60 (m, 1H), 1.4–2.30 (m, 7H).