Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(C)=CC=CC=1C.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[N:18]1[C:22](=[O:23])[CH2:21][C:20]([NH:24][C:25]2[CH:30]=[C:29]([NH:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:28]=[CH:27][C:26]=2[Cl:47])=[N:19]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:52](Cl)(=[O:54])[CH3:53].Cl>ClCCl>[Cl:17][C:12]1[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[C:11]=1[N:18]1[C:22](=[O:23])[CH:21]=[C:20]([NH:24][C:25]2[CH:30]=[C:29]([NH:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:28]=[CH:27][C:26]=2[Cl:47])[N:19]1[C:52](=[O:54])[CH3:53]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)n2C(C)=O)c1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
1.07 g (0.01 mole) of lutidine is added to a solution of 30.7 g (0.05 mole) of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-myristoylaminoanilino)-2-pyrazolin-5-one and 8 g (0.06 mole) of anhydrous aluminium chloride in 100 ml of dichloromethane. The solution is cooled to 10° C and 5.90 g (0.075 mole) of acetylchloride are added. 8 g (0.075 mole) of lutidine divided into 4 portions of 2 g each (one portion every 15 min) are added in a total period of time of 1 h, the temperature being kept below 10° C. The reaction mixture is stirred for 2 h more and then poured out into 1 l of 1N aqueous hydrochloric acid. The dichloromethane layer is washed until free from acid, dried, and concentrated by evaporation. The product is agitated with methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:37])([C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH2:11][CH2:12][CH2:13][CH2:14]OC1(C)C=CC(S([O-])(=O)=O)=CC1>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([F:9])([F:37])[C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC1(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC(S(=O)(=O)[O-])=CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCOc1ccc(Br)cc1
Reaction time: 24 h

Procedure:
To a solution of commercially available 4-bromophenol (46) (1 equi.) and 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-osylate (10) (1 equi.) in DMF (3 mL/mmole), cesium carbonate (1.25 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) eafforded 1-bromo-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-benzene (47) a colorless oil (65%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CN(C=O)C.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]([CH2:47][C:48]([O:50]C)=[O:49])[CH:44]=[CH:45][CH:46]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:41]2[CH:42]=[C:43]([CH2:47][C:48]([OH:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1cccc(CC(=O)O)c1)nn2-c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (600 mg) obtained in Step C of Example 35 in a mixed solvent of DMF (5 mL)/water (0.5 mL) were added methyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (567 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (60 mg) and potassium carbonate (405 mg). The reaction mixture was stirred overnight at 90° C. The reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate. The aqueous layer was neutralized with 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (205 mg).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:3][N:4]=2)[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3c2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (8.36 g, 18 mmol), trimethylsilylacetylene (5.1 mL, 37 mmol), Et3N (7.66 mL, 55 mmol), PdCl2(PPh3)2 (64 mg, 0.5 mol %) and PPh3 (48 mg, 1 mol %) in THF (40 mL) was stirred for 10 min at 23° C. while being purged with Argon. Then CuI (10 mg, 0.3 mol %) was added.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][N:3]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:2]12.N1C=CC=CC=1.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>ClCCl>[C:27]1([CH3:28])[CH:29]=[CH:30][C:24]([S:21]([O:10][CH2:9][CH2:8][CH2:7][N:6]2[CH2:5][CH2:4][N:3]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:2]3[CH2:1]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCN1CCN2CCCCC2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2CCN3CCCCC3C2)cc1

Procedure:
A solution of 4.5 g of the compound obtained in Step B, 2.5 ml of pyridine, and 4.8 g of tosyl chloride in 100 ml of dichloromethane is stirred for 24 hours at room temperature, and then washed with 100 ml of water and finally purified over a silica gel chromatography column, eluted with a mixture of CH2Cl2/MeOH (95/5), enabling the expected product to be isolated.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 98.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (84.6 mg, 99%).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[CH3:44][O:45][CH2:46][CH2:47][NH:48][C:49](=[O:54])[CH2:50][CH2:51][NH:52][CH3:53].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:44][O:45][CH2:46][CH2:47][NH:48][C:49](=[O:54])[CH2:50][CH2:51][N:52]([CH2:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[C:28]([NH:27][C:16]1[CH:17]=[CH:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:20][C:15]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=1)=[O:38])=[O:37])[CH3:53]
Reactant: CNCCC(=O)NCCOC
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCNC(=O)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 28.1 %

Procedure:
Into a 8-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)-isonicotinamide 42a (250 mg, 0.31 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (6 mL), N-(2-methoxyethyl)-3-(methylamino)propanamide (185 mg, 1.04 mmol, 3.00 equiv, 90%), potassium carbonate (106 mg, 0.77 mmol, 2.00 equiv), and potassium iodide (32 mg, 0.19 mmol, 0.50 equiv). The resulting solution was stirred for 5 h at 60° C. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 1×20 mL of 10% sodium bicarbonate. The resulting mixture was washed with 1×20 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with water:methanol (0.05% TFA) (10:90). The product was obtained as 63.7 mg (23%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.87 (d, J=6 Hz, 1H), 8.29 (m, 2H), 8.06 (m, 2H), 7.70 (m, 8H), 7.31 (d, J=9 Hz, 1H), 4.70 (s, 2H), 4.50 (m, 2H), 3.43 (m, 2H), 3.39 (m, 6H), 2.89 (s, 3H), 2.76 (m, 2H), 1.86 (m, 4H), 1.73 (m, 2H). MS (ES, m/z): 731 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([Li])CCC.[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[C:30]1([Se:36]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:30]1([Se:36][C:22]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:20][CH2:21]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Br[Se]c1ccccc1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1([Se]c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of diisopropylethyl amine (5.59 g, 55.30 mmol) in anhydrous tetrahydrofuran (150 mL) was added a solution of butyllithium (1.6 M in hexanes, 34.5 mL, 55.30 mmol) at 0° C. The reaction solution was stirred at the same temperature for 1 hour, then added a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10.80 g, 50.00 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. The reaction mixture was stirred at the same temperature for 1 h then added phenylselenium bromide (11.90 g, 50.70 mmol). The mixture was continued to stir at −78° C. for 5 hour, then at ambient temperature for 16 hour. The reaction was quenched with saturated sodium hydrogencarbonate (200 mL), diluted with ethyl acetate (200 mL), saturated ammonium chloride (3×150 mL), brine (3×100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10%) to afford the title compound as a viscous liquid (14.10 g, 76%): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=7.6 Hz, 1H), 7.37-7.32 (m, 1H), 7.26 (dd, J=7.0, 7.0 Hz, 2H), 4.05 (dd, J=7.1 Hz, 2H), 3.90 (d, J=3.4 Hz, 4H), 2.20-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.82-1.70 (m, 2H), 1.57-1.46 (m, 2H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:1][C:2]2[CH:12]=[CH:11][C:5]([C:6](=[O:7])[N:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN(C)C(=O)c1ccc(N)cc1
Product: CN(C)C(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 100 %

Procedure:
Using general procedure A, 4-amino-N,N-dimethyl-benzamide (Schiemenz, G. P.; Stein, G., Tetrahedron, 26, 1970, 2007-2026) (619 mg, 3.77 mmol) and 1-Boc-4-piperidone (901 mg, 4.52 mmol) gave 4-(4-dimethylcarbamoyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.31 g).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[N:21]\[S:18]([N:13]2[C:14]3([CH2:16][CH2:15]3)[CH2:17][N:10]([C:4]3[C:5]4[CH:9]=[CH:8][NH:7][C:6]=4[N:1]=[CH:2][N:3]=3)[CH2:11][CH2:12]2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N\S(=O)(=O)N2CCN(c3ncnc4[nH]ccc34)CC23CC3)cc1

Procedure:
7-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diaza-spiro[2.5]octane-4-sulfonic acid amide (intermediate 1) (0.46 mmol) was suspended en dry toluene (5 ml), added 4-methoxybenzaldehyde (0.46 mmol) and stirred at reflux for 48 h. The obtained reaction mixture was concentrated in vacuo on silica. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5](=[CH2:9])[C:6]([O-])=[O:7].CN(C)CCCN=C=NCC.[CH2:22]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:23]=[CH2:24]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([C:6](=[O:7])[N:25]([CH2:22][CH:23]=[CH2:24])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH2:9]
Reactant: C=CCNCc1ccccc1
Reactant: C=C(CC(=O)OC)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCN(Cc1ccccc1)C(=O)C(=C)CC(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 48.8 %

Procedure:
587 mg of 2-methylene-succinate 4-methyl ester (4.07 mmol), 781 mg of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (4.07 mmol) and 75 mg of 4-(dimethylamino)pyridine (0.61 mmol) were added to the reaction solution containing 300 mg of allylbenzylamine (2.04 mmol) dissolved in methylene chloride solution (0.5 M) with stirring for 10 hrs at room temperature. After the resulting mixture was washed with 5% HCl solution (10 ml), the mixture was diluted with ethyl acetate, washed with 10 ml of solution mixture mixed with saturated NaHCO3 solution and saturated NaCl solution to separate into an organic layer and water layer. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (1:1) as an eluant to give 272 mg of 3-(allyl-benzyl-carbamoyl)-but-3-enoic acid methyl ester (o) (yield: 49%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:17]([OH:19])=O)=[CH:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:32][CH2:33][C@@H:34]([OH:51])[CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([O:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=2)[CH2:38][CH2:37]1.O>CN(C)C=O>[Cl:50][C:45]1[CH:44]=[C:43]([CH:48]=[CH:47][C:46]=1[Cl:49])[O:42][CH:39]1[CH2:38][CH2:37][N:36]([CH2:35][C@H:34]([OH:51])[CH2:33][NH:32][C:17]([C:10]2[C:9]3[C:14](=[CH:15][C:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])=[CH:7][CH:8]=3)[C:13](=[O:16])[NH:12][CH:11]=2)=[O:19])[CH2:41][CH2:40]1
Reactant: CNS(=O)(=O)c1ccc2c(C(=O)O)c[nH]c(=O)c2c1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc2c(C(=O)NC[C@@H](O)CN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)c[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.9 %

Procedure:
7-[(Methylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.1 g) in dimethyl formamide (7 ml) was treated with N,N-carbonyldiimidazole (0.06 g) and the mixture was heated at 55° C. for 45 min. (2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.11 g) in dimethyl formamide (1 ml) was added and the mixture was stirred at ambient temperature for 18 h. 1 Drop of water was added and the solvent was evaporated. Purification using revere phase HPLC (Symmetry C8 column) and acetonitrile/aqueous ammonium acetate as eluent yielded the title compound as a white solid (0.03 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][NH:56][CH2:55]1>CN(C=O)C>[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][N:56]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:55]1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Reactant: Clc1ccccc1OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(Oc2ccccc2Cl)C1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 26.7 %

Procedure:
DIPEA (141 mg, 1.09 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (67 mg, 0.27 mmol) in DMF (3 mL) followed by HOBt (39 mg, 0.28 mmol) and EDCI (56 mg, 0.28 mmol). After 2 minutes of stirring, 3-(2-chloro-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (60 mg, 0.27 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Partitioning with cold water and ethyl acetate and concentration of the organic layer after drying over sodium sulfate afforded a residue which was purified by column chromatography (using silica gel 60-120 and 100% EtOAc as eluent) to afford 30 mg (26.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[3-(2-chloro-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 411, 98.45%. 1H NMR (300 MHz, DMSO-d6): δ 8.34 (d, 1H), 8.28 (d, 1H), 8.12 (t, 1H), 7.72 (d, 1H), 7.44 (m, 3H), 7.38 (m, 1H), 7.26 (m, 1H), 6.8 (m, 1H), 6.7 (d, 1H), 5.1 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.8 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.[CH3:17][C:18]1[C:19]([Sn](CCCC)(CCCC)CCCC)=[N:20][CH:21]=[CH:22][CH:23]=1>CN(C=O)C.[Cu](I)I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:19]4[C:18]([CH3:17])=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Cc1cccnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C
Yield: 74 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.512 mmol), 3-methyl-2-tributylstannanylpyridine (235 mg, 0.614 mmol), Pd2(PPh3)2Cl2 (36 mg, 0.051 mmol) and copper iodide (29 mg, 0.153 mmol) in DMF (4 mL) was purged with nitrogen and then heated at 100° C. for 1 h using microwave irradiation. The reaction mixture was diluted with MeOH (30 mL) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-5% MeOH in EtOAc) affording the title compound as a white solid (135 mg, 74%). LCMS: RT 3.22 min [M+H]+ 355.9/357.9
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:5].[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:4](=[O:5])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: CON(C)C(=O)c1ccc2[nH]ncc2c1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Example 75B (900 mg, 4.39 mmol) in tetrahydrofuran (10 mL) was cooled under argon with an ice bath and treated with a 2M solution of benzyl magnesium chloride in tetrahydrofuran (6.6 mL, 13.16 mmol). The reaction was stirred overnight at room temperature followed by the addition of one more equivalent of benzyl magnesium chloride. The mixture was heated at 70° C. for 9 hours. One more equivalent of benzylmagnesium chloride was added, and the reaction was heated at 70° C. for another 90 minutes and was allowed to cool to room temperature. Aqueous saturated ammonium chloride was added, and the product was extracted with ethyl acetate and purified by silica gel column chromatography using 30% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 237.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[CH3:18])[CH2:6]1)=[O:4].[NH:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:13]1[C:12]([CH3:18])=[C:11]([N:7]2[C:8](=[O:10])[CH2:9][N:5]([C:3](=[O:4])[CH2:2][N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[CH:21]=[N:20]3)[CH2:6]2)[CH:16]=[CH:15][CH:14]=1
Reactant: c1cnc2[nH]ncc2c1
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1N1CN(C(=O)Cn2ncc3cccnc32)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-Chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (230 mg, 0.8 mmol, 1 eq), 1H-Pyrazolo[3,4-b]pyridine (96 mg, 0.8 mmol, 1 eq), Cesium carbonate (653 mg, 2.0 mmol, 2.5 eq) in DMF (6 ml) was stirred at room temperature overnight. It was diluted with ethyl acetate, washed with water and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 370.1
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([Br:1])=[C:3]([CH:6]=1)[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(Br)c(C=O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c(C=O)cc1OCc1ccccc1

Procedure:
B2 is benzylated with benzyl bromide and potassium carbonate in DMF to obtain 5-benzyloxy-2-bromo-4-methoxybenzaldehyde (B3).