Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH:7]=1)=[O:5].[F:28][C:29]1[CH:30]=[C:31]([Mg]Br)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>C1COCC1>[F:28][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH:7]=1)=[O:5]
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2nc(C)c(C)cc2c1=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3nc(C)c(C)cc3c2=O)cc1F
Yield: 49.8 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 were used with 100 mg (0.273 mmol) of 6,7-Dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl amide, 1.2 mL (0.60 mmol, 0.5 M in tetrahydrofuran) of 3-fluoro-4-methoxyphenylmagnesium bromide and 1.2 mL of THF. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 58.7 mg 3-(3-Fluoro-4-methoxy-benzoyl)-6,7-dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,8]naphthyridin-4-one. LC-MSD, m/z for C25H22FN3O3 [M+H]: 432.16 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.1 min
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]=[CH:19][C:20]([O:34][CH:35]([CH3:37])[CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:38][O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][CH:50]([N:53]5[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]5)[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)Oc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC(C)C)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 35.2 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]benzamide (Intermediate Example 7) (0.10 g, 0.19 mmol), 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 58, Step B) (0.071 g, 0.19 mmol) and para-toluenesulfonic acid (0.088 g, 0.46 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]-5-(3-{2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamide (0.057 g, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (s, 1H), 9.36 (br. s., 1H), 8.45 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.08 (d, J=1.9 Hz, 1H), 7.66-7.80 (m, 2H), 7.35-7.49 (m, 3H), 7.31 (d, J=8.8 Hz, 1H), 7.15-7.26 (m, 2H), 6.96 (t, J=6.6 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.57 (d, J=5.1 Hz, 1H), 6.49 (dd, J=8.8, 2.3 Hz, 1H), 4.83-4.95 (m, 1H), 3.81 (s, 3H), 3.71-3.78 (m, 2H), 3.04-3.14 (m, 4H), 2.87 (s, 3H), 2.64-2.72 (m, 2H), 2.58-2.63 (m, 4H), 2.38-2.47 (m, 1H), 1.77-1.90 (m, 2H), 1.47-1.63 (m, 2H), 1.41 (d, J=6.0 Hz, 6H). MS (M−H, ES−) 850.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH:8]1(Br)[CH2:12][CH2:11][CH2:10][CH2:9]1.O>CN(C)C=O.CO>[CH:8]1([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: c1c[nH]cn1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: c1cn(C2CCCC2)cn1
Reaction time: 0.25 h

Procedure:
Imidazole (6.8 g, 0.1 mole) was dissolved in 100 ml of dry dimethylformamide (DMF). Sodium hydride, 50% dispersion in oil, (4.8 g, 0.1 mole) was added in small portions and the mixture was allowed to stir for 15 minutes. Cyclopentyl bromide (14.9 g, 0.1 mole) dissolved in 100 ml dry DMF was then added dropwise to the mixture which was kept under nitrogen and at about room temperature. Allowed to stir for a further 1 hour. When t.l.c. showed no further reaction, the mixture was poured onto approximately equal volume of water and shaken well. The product was then extracted with chloroform (3×200 ml) and dried over anhydrou MgSO4. The dry extract was evaporated down under vacuum. The DMF was then distilled off at 15 mmHg pressure to leave a yellowish oil. T.l.c. showed that the mixture was mainly product and an imidazole impurity, about 10 g nn on silica gel column with MeOH/EtOAC 1:9. Product fractions were combined and evaporated. Residual oil obtained was distilled under vacuum. B.pt. 67°-68° C./0.2 mm. Yield 2.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19]Cl)[CH:18]=1)[CH2:6][CH2:5]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1.O>O1CCOCC1.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][C:32]3[C:28]([CH3:27])=[N:29][O:30][C:31]=3[CH3:36])[CH:18]=1)[CH2:6][CH2:5]2
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(CCl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1noc(C)c1Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 120 °C
Yield: 10.9 %

Procedure:
6-Chloro-2-(5-chloromethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (example 140 [A]) (75 mg, 0.25 mmol), Pd(PPh3)2Cl2 (18 mg, 0.025 mmol), Na2CO3 (80 mg, 0.75 mmol) and 3,5-dimethylisoxazole-4-boronic acid (45 mg, 0.32 mmol) were dissolved in dioxane (4.0 mL). The resulting reaction mixture was heated at 120° C. for 3 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×125 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (10 mg, 10.9%) as a light yellowish solid. MS: 368.2 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:8](Cl)=[O:9])[CH2:7][CH2:6]1.[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]>C(=S)=S>[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:8]([CH:5]2[CH2:7][CH2:6]2)=[O:9])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccccc1
Reactant: O=C(Cl)C1CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOc1ccc(C(=O)C2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere a stirred suspension of 36.7 grams (0.275 mole) of aluminum chloride in 225 mL of carbon disulfide was cooled to 0° C., and 22.7 mL (0.25 mole) of cyclopropanecarboxylic acid chloride was added dropwise during a 15 minute period. During the addition and for 30 minutes after its completion the reaction mixture temperature was maintained at 0°-15° C. Then 34.8 mL of ethoxybenzene was added dropwise during a one hour period. The reaction mixture temperature was maintained at 5°-10° C. during this addition. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for one hour. Petroleum ether, 250 mL, was added to the reaction mixture, and the suspension was stirred for ten minutes. The solid was collected by filtration and washed with petroleum ether. The solid was returned to the reaction vessel and, with stirring, was cooled to 0°-10° C. while 50 mL of water was added dropwise during a 30 minute period. Upon completion of addition, the mixture was stirred until the evolution of hydrogen chloride ceased. An additional 250 mL of water was then added, and the mixture was stirred at ambient temperature for 30 minutes. It was then warmed to 80° C. where it stirred for an additional 30 minutes. The mixture was cooled, and a solid was collected by filtration. The solid was dissolved in methylene chloride, and the solution was dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual solid. The solid was recrystallized from heptane, yielding, in two crops, 44.0 grams of cyclopropyl (4-ethoxyphenyl) ketone, m.p. 67°-70° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[N:16][CH:17]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].COCCOCCO.[H-].[Na+].Br[CH2:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1)=[O:37]>CN(C=O)C.COCCO>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:35][C:36](=[O:37])[NH:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=3)[C:15]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[N:16][CH:17]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: COCCOCc1ncc(C(=O)NC2CCN(C(C)C)CC2)[nH]1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCO
Solvent: CN(C)C=O
Solvent: COCCOCCO
Product: COCCOCc1ncc(C(=O)NC2CCN(C(C)C)CC2)n1CC(=O)Nc1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 49 mg of 2-(2-Methoxy-ethoxymethyl)-3H-imidazole-4-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide [prepared by following the procedure from example 66 replacing 2-(2-methoxy-ethoxy)-ethanol by 2-methoxy-ethanol in step (i)] in DMF (3 mL) was added 17 mg of sodium hydride (60% in mineral oil). The mixture was stirred at 50° C. for 1 h and cooled to 30° C. 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide (41 mg) was added and stirring was continued for 1.5 h. Another portion of 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide (10 mg) was added. The mixture was stirred for 30 min at 30° C., carefully quenched by dropwise addition of water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][S:12]([C:15]2[CH:16]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[C:18]([OH:23])=[C:19]([CH:21]=O)[CH:20]=2)(=[O:14])=[O:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[NH2:42])[C:36]([NH2:38])=[NH:37].C1(=O)C=CC(=O)C=C1>C(O)C>[OH:23][C:18]1[C:19]([C:21]2[NH:42][C:41]3[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][C:33]=3[N:32]=2)=[CH:20][C:15]([S:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]
Reactant: O=Cc1cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc(-c2ccccc2O)c1O
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: CCO
Product: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCc4ccccc4)cc(-c4ccccc4O)c3O)nc2c1
Yield: 39.6 %

Procedure:
N-(3-Phenylpropionyl)-5-formyl-6,2′-dihydroxy-biphenyl-3-sulfonamide (0.065 g, 0.15 mmol), prepared as in Reference 22, 3,4-diaminobenzamidine hydrochloride (0.043 g 0.23 mmol) and benzoquinone (0.018 g, 0.16 mmol) were combined in ethanol (15 mL) and the mixture was heated under reflux for 1 hour. The solvent was evaporated in vacuum and the product was purified from the residue by reverse phase HPLC (acetonitrile/0.02N HCl gradient) to give 2-[2,2′-dihydroxy-5-(3-phenylpropionylaminosulfonyl)biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.033 g). 1H NMR (DMSO-d6): δ 2.50 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 6.82-7.22 (m, 9H), 7.72 (dd, J=9.2 Hz, J2=1.7 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.84 (d, J=9.2 Hz, 1H), 8.18 (s, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.99 (s, 2H), 9.34 (s, 2H), 12.06 (s, 1H). MS: found (M+H+) 556.4, (M−H+) 554.4, calc 555.16.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:57][C:58]1[NH:59][C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=1>C(Cl)Cl>[NH:59]1[C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=[C:58]1[NH:57][C:14](=[O:15])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1C#N
Yield: 95 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 26, 100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzimidazole (62 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25° C. for 3 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) to afford N-(1H-benzimidazol-2-yl)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (129 mg, 95%) as a yellow solid: mp 148-152° C.; EI-HRMS m/e calcd for C23H24N4O3S (M+) 436.1569, found 436.1573.
Reaction SMILES: C([O:9][CH2:10][CH:11]1[CH2:16][O:15][C:14]2=[CH:17][S:18][CH:19]=[C:13]2[O:12]1)(=O)C1C=CC=CC=1.[OH-].[K+].Cl>C(O)C.O>[O:15]1[CH2:16][CH:11]([CH2:10][OH:9])[O:12][C:13]2=[CH:19][S:18][CH:17]=[C:14]12
Reactant: O=C(OCC1COc2cscc2O1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCC1COc2cscc2O1
Temperature: 25 °C
Yield: 85 %

Procedure:
In a 100 mL round bottom flask, 7.5 g (0.027 mol) (2,3-dihydrothieno[3,4-b][1,4]dioxin-3-yl)methyl benzoate was dissolved in a minimal amount of warm ethanol and dropwise added to a refluxing solution of 4.58 g (0.081 mol) potassium hydroxide in 50 mL water. After heating overnight, the reaction was cooled to room temperature and acidified to pH 7 by dropwise addition of concentrated hydrochloric acid. The reaction mixture was extracted with methylene chloride. The organic fractions were combined and the solvent removed under reduced pressure. Purification by column chromatography provided 3.95 g (85% yield) of (2,3-dihydrothieno[3,4-b][1,4]dioxin-3-yl)methanol. Structure was confirmed by 1H/13C NMR and LC-MS.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]4[CH2:20][CH2:19][CH2:18][O:17][CH2:16]4)[C:5]=3[C:4]=2[CH:3]=1.[F:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[F:23][C:24]1[N:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C@H:15]5[CH2:20][CH2:19][CH2:18][O:17][CH2:16]5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:26][CH:25]=1
Reactant: Cn1c(=O)n([C@H]2CCCOC2)c2c3cc(Br)ccc3ncc21
Reactant: OB(O)c1ccc(F)nc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)n([C@H]2CCCOC2)c2c3cc(-c4ccc(F)nc4)ccc3ncc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
Pd(Ph3P)4 (0.160 g, 0.14 mmol) was added to 8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one (1 g, 2.76 mmol), (6-fluoropyridin-3-yl)boronic acid (0.506 g, 3.59 mmol) and Cs2CO3 (1.799 g, 5.52 mmol) in 1,4-dioxane (23 mL) and water (3 mL) under nitrogen. The resulting mixture was stirred at 100° C. for 3 h then allowed to cool and the solvent removed under reduced pressure. The crude product was purified by FCC, elution gradient 0 to 7% MeOH in DCM to give the desired material (0.905 g, 87%) as a yellow solid. NMR Spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.83-1.86 (2H, m), 2.15-2.19 (1H, m), 2.49-2.64 (1H, m), 3.38-3.41 (1H, m), 3.49 (3H, s), 3.93 (1H, d), 4.15-4.26 (2H, m), 4.91-5.10 (1H, m), 7.42 (1H, dd), 7.96 (1H, dd), 8.13 (1H, d), 8.38 (1H, s), 8.44 (1H, td), 8.72 (1H, d), 8.96 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=379.1.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)[C@@H](NC(=O)C=Cc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, cinnamoyl chloride, and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white solid after removal of the solvent: m.p. 126°-140° C.
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[C-:18]#[N:19].[Na+]>CN(C=O)C>[C:18]([C@H:6]1[CH2:9][C@H:8]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1)#[N:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](C#N)C1
Temperature: 140 °C

Procedure:
cis-3-[(tert-Butoxycarbonyl)amino]cyclobutyl methanesulfonate (0.200 g, 0.754 mmol) in DMF (3 mL) was treated with NaCN (55 mg, 1.13 mmol, Aldrich) and the reaction was heated in the microwave to 140° C. for 10 minutes, followed by stirring overnight at 125° C. with an additional 55 mg (1.13 mmol) of NaCN having been added. The reaction mixture was partitioned between saturated NaHCO3 solution and EtOAc. The aqueous layer was extracted three additional times with EtOAc. The combined extracts were dried over sodium sulfate, decanted, and the solvent was removed in vacuo. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes, afforded tert-butyl (trans-3-cyanocyclobutyl)carbamate. Yield: (61 mg, 41%).
Reaction SMILES: [CH3:1][C:2]([CH3:52])([CH2:6][C:7]([O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:12]([CH2:13][CH2:14][C@:15]3([CH3:49])[C@@H:24]2[CH2:23][CH2:22][C@H:21]2[C@@:16]3([CH3:48])[CH2:17][CH2:18][C@@:19]3([C@@H:36]([OH:47])[CH2:37][NH:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[CH2:31][C:30](=[O:32])[C:29]([CH:33]([CH3:35])[CH3:34])=[C:20]32)[C:11]1([CH3:51])[CH3:50])=[O:8])[C:3]([O-:5])=[O:4].[Na+].S([O-])(O)=O.[CH3:58][C:59]([CH3:63])(N)[CH:60]=O.[CH3:64][CH2:65][N:66]([CH2:69]C)[CH2:67]C.[BH3-]C#N.[Na+]>CO>[CH3:52][C:2]([CH3:1])([CH2:6][C:7]([O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:12]([CH2:13][CH2:14][C@:15]3([CH3:49])[C@@H:24]2[CH2:23][CH2:22][C@H:21]2[C@@:16]3([CH3:48])[CH2:17][CH2:18][C@@:19]3([C@@H:36]([OH:47])[CH2:37][N:38]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[CH2:64][CH2:65][N:66]([CH3:69])[CH3:67])[CH2:31][C:30](=[O:32])[C:29]([CH:33]([CH3:35])[CH3:34])=[C:20]32)[C:11]1([CH3:50])[CH3:51])=[O:8])[C:3]([O:5][C:59]([CH3:63])([CH3:60])[CH3:58])=[O:4]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)[O-])C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2([C@@H](O)CNCc2ccc(Cl)cc2)CC1=O
Reactant: CCN(CC)CC
Reactant: CC(C)(N)C=O
Agent: O=S([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2([C@@H](O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 71.7 %

Procedure:
Added a solution of 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (55 g, 69.3 mmol) dissolved in methanol (825 mL), dimethyl amino acetaldehyde hydrogen sulfite sodium salt (66.8 g, 0.35 mol) and Et3N (38.7 g, 0.38 mol) into a reactor. The reaction was stirred for 2-3 hrs at 30-40° C. under nitrogen protection. NaBH3CN (8.8 g, 0.14 mol) was added and stirred at 30-40° C. under nitrogen protection for 13-15 hrs. Next, the reaction temperature was adjusted to 50-60° C. and stirred for 3-5 hrs. The reaction mixture was then concentrated to 275 mL and then DCM (550 mL) was added, followed by water (440 mL). The two phases were separated and the water phase was extracted with DCM (twice with 385 mLs each time). The organic phase was washed with water (twice with 358 mLs each time). Next, the organic phase was concentrated to give 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate 43 g oil. Yield is 71%. 1HNMR (400 MHz, CDCl3) δ=7.27-7.29 (m, 4H), 4.46-4.50 (m, 1H), 4.08-4.13 (m, 2H), 4.00-4.02 (m, 1H), 3.59-3.60 (m, 1H), 3.09 (m, 1H), 2.03-2.67 (m, 14H), 0.62-1.42 (m, 57H);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22]([OH:24])=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.CNC.C1COCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22](=[O:24])[N:27]([CH3:28])[CH3:25])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccccc23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
The 2-t-butoxycarbonyl-9-carboxymethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.65 g, 5.0 mmol) obtained in the above step (1) was dissolved in methylene chloride (30 ml), and the solution was mixed with carbonyldiimidazole (0.81 g, 5.0 mmol), stirred at room temperature for 30 minutes, mixed with 2 M dimethylamine-THF solution (3 ml, 6.0 mmol) and further subjected to 1 hour of the reaction. The reaction solution was concentrated, the resulting residue was dissolved in ethyl acetate (50 ml), washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure. By adding diisopropyl ether (30 ml) to the resulting residue, 1.71 g of the thus precipitated title compound (4.8 mmol, 96% in yield) was obtained as crystals.