Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[Na].[C:29]([S-:31])#[N:30].[K+].C([O-])(O)=O.[Na+]>C(O)C.C(OCC)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:13]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[N:12][C:29](=[S:31])[N:30]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)ON=C(Cc2ccc(F)cc2)c2ccncc2)cc1
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Fc1ccc(C2=NC(=S)N=C2c2ccncc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, 2-(4-fluorophenyl)-1-(4-pyridinyl)ethanone-O-[(4-methylphenyl)sulfonyl]oxime (0.03 mol/10.0 g) was dissolved in 60 ml of absolute ethanol. In an ice bath, the mixture was cooled to 0° C., and a freshly prepared solution of sodium (0.03 M/0.75 g) in 30 ml of absolute ethanol was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h. After addition of 500 ml of diethyl ether, stirring was continued for 30 min. The resulting precipitate was filtered off and washed 4× with in each case 50 ml of diethyl ether. The combined ether phase was extracted 3× with in each case 90 ml of HCl 10%. The aqueous extract was concentrated to 40 ml, and KSCN (0.05 mol/5.0 g) was added. With stirring, the reaction mixture was then heated under reflux for 1 h. When the mixture was neutralized using 270 ml of 5% strength NaHCO3 solution, the title compound was obtained as a yellow precipitate. The precipitate was filtered off, washed with H2O and dried in a drying cabinet at 60° C. Yield: 5.6 g (79%)
Reaction SMILES: C[Si](C)([CH2:9][CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CN=1.[F-].[K+].C(=O)([O-])[OH:22].[K+].OO>CO.O>[C:11]1([CH:10]([OH:17])[CH2:9][OH:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(CC(O)c1ccccc1)c1ccccn1
Reactant: O=C([O-])O
Agent: OO
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCC(O)c1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 95.5 %

Procedure:
To 129 mg (0.5 mmol) of the (2-hydroxy-2-phenylethyl)(2-pyridyl)silane obtained in Example 6, a solution of 58 mg (1.0 mmol) of potassium fluoride and 100 mg(1.0 mmol) of potassium hydrogencarbonate in methanol(1 ml)tetrahydrofuran(1 ml) was added, followed by 1.71 g (15 mmol) of 30% aqueous hydrogen peroxide. The mixture was continued to be stirred at an inner temperature of 50° C. for 6 hours, and then cooled to room temperature. After addition of 10 ml of water, the mixture was extracted with four portions of 10 ml of diethyl ether. The separated organic layers were combined together and washed with 10 ml of a 15% aqueous sodium thiosulfate solution. After drying over magnesium sulfate, the residue after the evaporation of the solvent was purified with silica gel chromatograph to give 66 mg of phenyl-1,2-ethanediol. Yield: 96%
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=[O:4].[CH2:26]=O>C(O)(=O)C>[F:25][C:2]([F:1])([C:21]([F:23])([F:24])[F:22])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:11][C:12]2[N:17]3[C:18](=[CH:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH2:26]1)=[O:4]
Reactant: O=C(NCCCCNCc1cccc2nccn12)C(F)(F)C(F)(F)F
Reactant: C=O
Solvent: CC(=O)O
Product: O=C(NCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 2620 mg (7.19 mmol) of 5-[N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 10 ml of acetic acid was added 8.1 ml (107.88 mmol) of a 37% aqueous solution of formalin. The mixture was heated for 30 minutes at 100° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of purified water. To this solution was added 2N sodium hydroxide to adjust the pH to 8, and extracted with 100 ml of dichloromethane. The organic layer was washed with 100 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography to afford 2250 mg of the desired compound (83.2%, a pale yellow liquid).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2)[CH3:2].Cl[C:19]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=[C:21]([S:30][CH3:31])[N:20]=1.C(N(CC)CC)C>C(O)CCC>[CH2:28]([O:27][C:25]([C:24]1[C:19]([N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)=[N:20][C:21]([S:30][CH3:31])=[N:22][CH:23]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)CCNc1ccc2c(c1)CCC2
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(c1ccc2c(c1)CCC2)c1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.2 %

Procedure:
To a solution of 3-(indan-5-ylamino)-propionic acid ethyl ester (5 g, 21.4 mmol) and ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (5 g, 21.4 mmol) in 40 mL of n-butanol was added triethylamine (3 mL, 21.4 mmol). The solution was stirred at rt for 2 days. The solvent was removed under vacuum. The residue was extracted into EtOAc, washed with water, brine and then dried with Na2SO4. Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:10-1:6, v/v), gave 8.2 g (90%) of the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.22 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 6.87 (d, J=7.6 Hz, 1H), 4.35 (t, 2H), 3.55 (q, 2H), 2.82 (m, 4H), 2.69 (t, 2H), 2.58 (s, 3H), 2.06 (m, 2H), 1.20 (t, 3H), 1.02 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[CH:6]=[CH:5]2.C(OCC)(=O)C.[CH3:25][N:26](C)C=O>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>[C:25]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[CH:6]=[CH:5]2)#[N:26]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cn1c(=O)ccc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)ccc2cc(C#N)ccc21
Reaction time: 24 h
Yield: 38 %

Procedure:
Ethyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate (2.37 g, 7.64 mmol)cuprous cyanide (8.87 g, 99.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (3.50 g, 3.03 mmol) in dimethylforamide (100 ml) was placed into a preheated oil bath at 140° C. After stirring for 24 h, the solution was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with 9:1, 4:1, 7:3, and 3:2 methylene chloride:ethyl acetate as the eluant to afford 0.74 g (38% yield) of ethyl 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetate. Method [7] retention time 2.87 min by HPLC (M+257).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].CC1(C)C(C)(C)OB(/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 120 h
Yield: 38.6 %

Procedure:
A mixture of 1 g of tert-butyl (2-bromobenzyl)carbamate, 1.12 g of ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate, 16 mg of palladium acetate, 72 mg of dicyclohexyl(2′,6′-dimethoxybiophenyl-2-yl)phosphine, 1.5 g of potassium phosphate, and 20 mL of toluene was stirred at 100° C. for 5 days. To the reaction mixture was added ether, followed by filtration through silica gel. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 412 mg of ethyl (2E)-3-(2-{[(tert-butoxycarbonyl)amino]methyl}phenyl)acrylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:35])=[N:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:35])=[N:29]3)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 300 mg (0.93 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 183 mg (1.03 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.58 ml (1.86 mmol) of titanium tert-butoxide is reacted to give 5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 460 mg of crude imine are cyclized in the same way as in Example 130 at −30° C. with 7.6 ml (7.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-65%) yields 135 mg of desired product.
Reaction SMILES: C(NC1SC=C(C(=NOC)C(N[CH:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([CH3:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O>[CH3:44][N:43]1[C:39]([S:38][CH2:37][C:34]2[CH2:35][S:36][C@@H:31]3[CH2:30][C:48](=[O:49])[N:32]3[C:33]=2[C:45]([OH:47])=[O:46])=[N:40][N:41]=[N:42]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A mixture of 1.4 g of the product of Example 3 and 5 ml of 50% aqueous formic acid was held on a water bath at 55° C. for 15 minutes and then 5 ml of water were added. The mixture was cooled and vacuum filtered and the filtrate was concentrated after the addition of 5 ml of ethanol. The residue was taken up in 5 ml of ethanol and the mixture was triturated and was vacuum filtered. The product was washed with ethanol and then ether, was vacuum filtered, dried and washed to obtain 0.557 g of pure 7-[{2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-3-[(1-methyl-tetrazol-5-yl)-thiomethyl]-ceph-3-eme-4-carboxylic acid in the syn configuration.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:48]3[C:44](=[O:54])[C:45]4[C:46](=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:47]3=[O:49])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 20 °C

Procedure:
135.0 g (417 mmol) 4-(1-diphenylmethylpiperidin-4-yl)-butan-1-ol, 109.5 g (417 mmol) triphenylphosphine and 61.3 g (417 mmol) phthalimide are suspended in THF and 72.6 g (417 mmol) azodicarboxylic acid diethyl ester are added dropwise within 2½ hours under protective atmosphere and light cooling (ca. 15-25° C.). After a further hour, the solvent is removed under vacuum and the residue is crystallized three times from acetic acid ester (1000 ml, 1200 ml and 1100 ml). Colorless crystals with a MP of 150-152 were recovered. Yield 103 g (54.5%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Si]([O:29][C@@H:30]([CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C.O.CCOC(C)=O>C1COCC1>[CH3:45][N:43]([CH3:44])[CH2:42][CH2:41][C@H:30]([OH:29])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)[C@H](CCN(C)C)O[Si](C)(C)C(C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@@H](O)CCN(C)C)nc1
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
Tetrabutylammoniumfluoride trihydrate (417 mg, 1.32 mmol) was added to a stirred solution of (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(dimethylamino)-N-(5-methylpyridin-2-yl)butanamide (Step 3) (310 mg, 0.88 mmol) in THF (5 mL). The reaction mixture was kept at ambient temperature for 30 minutes. Water and EtOAc were added and the two phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with EtOAc/MeOH:10/1) to give the title compound as a solid (110 mg), 1H NMR (300 MHz, CDCl3) δ 9.44 (br s, 1H), 8.15 (d, 1H), 8.12 (d, 1H), 7.51 (dd, 1H), 4.39 (dd, 1H), 2.63 (m, 2H), 2.28 (m, 9H), 2.09 (m, 1H), 1.92 (m, 1H).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=1[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=2[CH3:39])=[CH:16][CH:17]=1
Reactant: Cc1cc(C#N)ccc1Br
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(C#N)ccc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 4-bromo-3-methylbenzonitrile (0.20 g), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.02 g) in toluene (5 ml) and ethanol (2 ml). The reaction mixture was heated at 100° C. under nitrogen for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and the suspension stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue partitioned between diethyl ether and water. The aqueous layer was neutralised with a saturated solution of sodium bicarbonate in water and extracted with dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil (0.15 g)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1ccc2ccccc21
Temperature: 50 °C
Yield: 12.4 %

Procedure:
A mixture of indole (11.7 g), ethyl 4-bromobutyrate (58.5 g) and potassium carbonate (41.5 g) in N,N-dimethylformamide (500 ml) was heated at 50° C. for 10 hours. The mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and ice water. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (1 kg) eluting with a mixture of methanol, chloroform and hexane (1:50:50) to give ethyl 4-(1-indolyl)butyrate (2.86 g) as a blue oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Brc1cccnc1
Product: COc1ccc(-c2cccnc2)cc1C=O

Procedure:
The title compound was prepared by employing the method described in Example 111, Step A with (3-formyl-4-methoxyphenyl)-boronic acid and the commercially available 3-bromopyridine. NMR (400 MHz, CDCl3): δ 10.53 (s, 1H), 8.89 (d, 1H, J=2 Hz), 8.63 (dd, 1H, J=5,1 Hz), 8.10 (dt, 1H, J=8,2 Hz), 8.09 (d, 1H, J=2 Hz), 7.83 (dd, 1H, J=9,2 Hz), 7.56 (dd, 1H, J=8,5 Hz), 7.17 (d, 1H, J=9 Hz), 4.02 (s, 3H). Mass spectrum (NH3 /CI): 214 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH:3]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[C:27]([NH:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28].[OH-].[Na+].O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:27]([NH:31][C:32]([CH2:33][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]1=[O:1])=[O:35])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)NC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCCCC2)c2ccccc2NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.0 g) was suspended in toluene (25 ml), N-tert-butyl-2-bromoacetamide (1.14 g), 1N aqueous sodium hydroxide (15 ml) and tetra n-butylammonium bromide (90 mg) were added thereto, and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, separated. The aqueous layer was extracted with ethyl acetate, the ethyl acetate extract was combined with the former organic layer, and the combined extract was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, ether was added to the residue for trituration, collected by filtration, to thereby obtain 1.09 g of the title compound (Yield: 83.0%).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][N:23]=[CH:24]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH:24]1[C:25]2[C:20](=[C:19]([C:2]#[C:1][N:3]3[C:11]4[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=4[C:5]4[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]3=4)[CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1
Reactant: Brc1cccc2cnccc12
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2cccc3cnccc23)CCN(C)C1

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (194 mg, 0.866 mmol, 5-bromo-isoquinoline (150 mg, 0.721 mmol, TBAF.3H2O (680 mg, 2.15 mmol) and dichlorobis(triphenylphosphine) palladium(II) (25 mg, 0.035 mmol) was stirred at 85° C. for 5 min. The reaction mixture was diluted with water and extracted with EtOAc (3×40 mL). The organic layer was washed with water (5×30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography using silica (100:200) and 0.5% MeOH-DCM to yield 5-isoquinolin-5-ylethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 9.3 (s, 1H), 8.62 (d, 1H), 8.17 (d, 1H), 7.93 (dd, 2H), 7.6 (t, 1H), 7.57 (d, 1H), 7.23 (s, 1H), 7.17 (d, 1H), 3.65 (s, 2H), 3.07 (t, 2H), 2.93 (t, 2H), 2.6 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[CH3:51][N:52]1[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:55]3[CH2:56][CH2:57][CH2:58][N:52]([CH3:51])[CH2:53][CH2:54]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4CCCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (182 mg, 0.000272 mol) in DCM (4 mL) and 1-methylhexahydro-1H-1,4-diazepine (43.4 mg, 0.00038 mol) were mixed with sodium triacetoxyborohydride (115 mg, 0.00054 mol) and AcOH (19.5 mg, 19 μL). The solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a glassy foam (150 mg). Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a solid. Further purification of the material was needed and this was carried out on a Chomatotron utilizing silica gel [DCM-MeOH-conc. aq. NH3, (90:7:3)] to afford 42 mg of the title compound as a glassy solid. LC-MS m/z 768.7 (M+H)+.