Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10](F)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25]Br)[CH3:22].O.C[S:32](C)=O>C(OCC)(=O)C>[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][S:32][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[C:11]=1[O:12][CH3:13])[CH3:22]
Reactant: CS(C)=O
Reactant: CCOC(CBr)OCC
Reactant: COC(=O)c1ccc(F)c(OC)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(CSc1ccc(C(=O)OC)c(F)c1OC)OCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In 59 mL of dimethyl sulfoxide is dissolved 11.8 g of methyl 2,4-difluoro-3-methoxybenzoate, to which are added 23.0 g of potassium carbonate and 9.33 g of sodium hydrogen sulfide n-hydrate (purity 70%). The mixture is stirred at 60° C. for 2 hours. Then, 25 mL of bromoacetaldehyde diethyl acetal is added at the same temperature as above, and stirred at that temperature for 3 hours. Water and ethyl acetate are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography (eluent: hexane-ethyl acetate=5:1) to obtain 19.0 g of methyl 4-[(2,2-diethoxyethyl)sulfanyl]-2-fluoro-3-methoxybenzoate as an oily product.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C@H:9]([CH2:21][OH:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[OH:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(N=NC(NC(C)C)=O)=O)(C)C>ClCCl>[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][C:21](=[O:22])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:23]
Reactant: CN(Cc1ccccc1)[C@H](CO)CCCNC(=O)OC(C)(C)C
Reactant: Oc1ccc2ccccc2c1
Agent: CC(C)NC(=O)N=NC(=O)NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Yield: 37.3 %

Procedure:
A μιξτυρε Oφ Nα-benzyl-Nδ-Boc-Nα-methylornithinol (168 mg), dichloromethane (10 ml), 2-naphthol (91 mg), triphenylphosphine (165 mg), and N,N′-diisopropylazodicarboxamide (124 μl) was stirred for 12 hrs at 25° C., under nitrogen. The reaction mixture was poured into dichloromethane and washed successively with saturated sodium bicarbonate and brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo. Further purification by flash chromatography gave the titled product (90 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ1.51 (s, 9H), 1.68 (m, 2H), 1.75 (m, 2H), 2.39 (s, 3H), 3.20 (m, 2H), 3.82 (d, J=13.3, 1H), 3.93 (d, J=13.2, 1H), 4.11 (dd, J=9.6; 3.6, 1H), 4.29 (dd, J=10.2; 8.4, 1H), 7.22 (m, 2H), 7.29 (t, J=7.8, 1H), 7.39 (m, 5H), 7.50 (t, J=8.0, 1H), 7.79 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClCCCl.[Fe](Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:16]2[CH:15]=[CH:14][C:13]([C:19]3([C:29]4[CH:30]=[CH:31][C:32]([C:8](=[O:9])[C:7]5[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=5)=[CH:33][CH:34]=4)[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]3)=[CH:18][CH:17]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCC1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: ClCCCl
Product: CCCCC1CCC(c2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)(c2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)CC1
Temperature: 80 °C
Yield: 55 %

Procedure:
In a 10-liters three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 629 g (3.88 mole) of iron chloride and 1.7 liters of 1,2-dichloroethane were mixed, and 595 g (3.21 mole) of paranitrobenzoyl chloride was introduced with ice cooling to be dissolved. After warming the reaction solution to 80° C., a solution of 391 g (1.34 mole) of 1,1-diphenyl-4-butylcyclohexane in 630 milliliters of 1,2-dichloroethane was added dropwise for 3 hours and 30 minutes. After the dropwise addition was ended, the solution was stirred gently at reflux for 6 hours. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was poured on 2 liters of ice, and 1 liter of a 4N-HCl aqueous solution was added and then extracted with 1.5 liters of chloroform. The solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, and dried with magnesium sulfate. After removing off chloroform by a rotary evaporator, treating with a silica gel column and purifying by recrystallization from ethyl acetate, 435 g of 1,1-bis(4-(4-nitrobenzoyl)phenyl)-4-butylcyclohexane was obtained as crystals.
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[NH:4][CH2:3][CH2:2]1.[CH2:10]([N:12]([CH2:15]C)CC)[CH3:11].ClC(OCC)=[O:19]>ClCCl>[CH2:10]([NH:12][C:15]([N:4]1[CH2:3][CH2:2][CH2:1][CH2:6][C@@H:5]1[C:7]([OH:9])=[O:8])=[O:19])[CH3:11]
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCNC(=O)N1CCCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
L-Pipecolinic acid (0.50 g, 0.004 mole) in dry dichloromethane (10 ml) was cooled to 0° C. under argon and treated with triethylamine (0.65 ml. 0.0046 mole) followed dropwise by ethyl chloroformate (0.37 ml, 0.004 mole) in dry dichloromethane (2 ml). The mixture was stirred overnight at room temperature after which it was diluted with dichioromethane, washed with 5M hydrochloric acid and the organic layer dried (magnesium sulfate) and evaporated in vacuo to afford the title compound 0.60 g (77%) as an orange oil; 1H NMR (CDCl3) 1.12-1.84 (8H, m), 2.15-2.40 (1H, m), 2.88-3.20 (1H, m), 3.90-4.28 (3H, m), 4.77-5.07 (1H, m), 5.68-6.82 (1H, br s),
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of 4.96 g (42 mmol) of benzimidazole in 250 ml of tetrahydrofuran was cooled under N2 atmosphere to 0° C. and treated sequentially with 2.12 g (44 mmol) of sodium hydride (50% dispersion in oil) and 5.0 ml (42 mmol) of benzyl bromide. The resulting suspension was stirred at ambient temperature for 16 h, washed sequentially with water and saturated brine, dried over MgSO4, and concentrated. The resulting oil was taken up in 75 ml of ethyl acetate, triturated with 300 ml of hexane, and filtered. The mother liquor was concentrated and filtered, and the combined solids were dried in vacuo at 50° C. to give 7.00 g (80%) of the desired compound. 1H NMR (CDCl3) δ 5.38 (s,2H), 7.2 (m,2H), 7.3-7.4 (m,6H), 7.83 (br d,1H), 7.96 (br s,1H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][C:17]([OH:19])=[O:18])[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].O1CCC[CH2:23]1>>[CH2:1]([C:3]1([CH2:16][C:17]([OH:19])=[O:18])[C:15]2[N:14]([CH3:23])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCC1(CC(=O)O)CCCc2c1[nH]c1ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCC1(CC(=O)O)CCCc2c1n(C)c1ccccc21
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A solution of the compound of formula 5, 1-ethyl 1,2,3,4-tetrahydrocarbazole-1-acetic acid (2.0 g, 7.4 mmole), described in Example 56, in dry tetrahydrofuran (THF, 50 ml) is added dropwise under nitrogen to a stirred suspension of sodium hydride (1 g, 50% dispersion, 0.02 mole) in dry-THF (25 ml). The reaction mixture is stirred for 15 minutes after the end of the addition. The lower alkyl halide, methyliodide (1.5 ml), is added dropwise. The reaction mixture is heated initially to 40° C. then stirred for one hour at room temperature. A small amount of water is added cautiously to destroy excess sodium hydride followed by the addition of more water (50 ml). The mixture is washed with ether then rendered acidic and extracted with ether. The ether extract is dried (MgSO4), treated with charcoal and filtered through diatomaceous earth. Evaporation of the ether gives an oil which on recrystallization from benzene affords the title compound, mp 140°-143° C., nmr (CDCl3) δ 0.72 (t, J = 7, 3H), 1.9 (m, 6H), 2.75 (m, 4H), 3.76 (s, 3H), 7.2 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[C:23]=1[CH:24]=[N:25]O.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].[C:47](OCC)(OCC)(OCC)[CH2:48][CH3:49]>>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:29][CH2:28][N:27]([CH2:11][CH:8]3[O:7][C:6]4=[C:23]5[C:2](=[CH:3][CH:4]=[C:5]4[O:10][CH2:9]3)[N:1]=[C:47]([CH2:48][CH3:49])[N:25]=[CH:24]5)[CH2:32][CH:31]=2)=[CH:34]1
Reactant: CCOC(CC)(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(C=NO)c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1ncc2c3c(ccc2n1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3

Procedure:
Toluene-4-sulfonic acid (2R)-7-amino-8-(hydroximino-methyl)2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester (1.0 g, mmole) was suspended in triethyl orthopropionate (20 mL) and the mixture refluxed under nitrogen for 18 hours. The reaction mixture was cooled and the solvent evaporated under vacuum. The residue was dissolved in methylene chloride, the solution washed with saturated sodium chloride solution, dried over magnesium sulfate and the solvent evaporated to a gum (1.5 g). This residue was dried under vacuum and dissolved in a mixture of DMF/THF 1:1 v/v (100 mL). 3-(1,2,3,6-Tetrahydro-4-pyridinyl)-1H-indole (1.2 g, 6 mmole) and sodium bicarbonate (3.0 g) were added and the mixture refluxed under nitrogen for 20 hours. The reaction mixture was cooled, and the solvent evaporated under vacuum. The residue was partitioned between methylene chloride and water. The layers were separated. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent removed under vacuum. The crude oil obtained (2.0 g) was chromatographed on silica gel using 2% methanol in chloroform, followed by 3% methanol in chloroform as eluants to give the (S)-enantiomer of the title compound (52 mg), m.p. 203-211° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][C:27](SC)=[CH:26][CH:25]=4)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH:32]1C=C(Cl)C=C(C(OO)=O)C=1.[S:43](=[O:46])(O)[O-:44].[Na+]>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][C:27]([S:43]([CH3:32])(=[O:46])=[O:44])=[CH:26][CH:25]=4)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cccc3c(OC4CCN(C(=O)OC(C)C)CC4)ccnc23)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2ccnc3c(-c4ccc(S(C)(=O)=O)cc4)cccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL round-bottomed flask immersed in an ice-bath was placed a stir bar and Compound F2 (16 mg, 0.037 mmol) in CH2Cl2 (5 mL). A solution of mCPBA (19 mg, 0.081 mmol) dissolved in CH2Cl2 (1 mL) was added at 0° C. The mixture was stirred at 0° C. for 30 min. A solution of sodium bisulfite was added. The organic phase was separated, dried and concentrated to give the crude product. The crude was purified by HPLC. 1H NMR (CDCl3, 400MHz) δ 1.29 (d, 6H), 2.04 (m, 2H), 2.20 (m, 2H), 3.16 (s, 3H), 3.59 (m, 2H), 3.85 (m, 2H), 4.97 (m, 1H), 5.14 (m, 1H), 7.23 (s, 1H), 7.66 (d, 2H), 7.92 (m, 2H), 8.12 (d, 2H), 8.48 (d, 1H), 9.08 (d, 1H). Exact mass calculated for C25H28N2O5S 468.17, found 469.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)=[CH:30][CH:29]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 82.1 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (5.0 g, 18.0 mmol) was reacted with 4-((4-methylpiperazin-1-yl)methyl)aniline (4.0 g, 19.0 mmol) to afford the desired product (6.7 g, 82%) as a yellow foam: 1H NMR (300 MHz, CDCl3) δ 11.96 (s, 1H), 9.11 (s, 1H), 7.85-7.72 (m, 1H), 7.71-7.57 (m, 2H), 7.40-7.29 (m, 2H), 7.14-7.02 (m, 2H), 3.53 (s, 2H), 2.77 (s, 3H), 2.58-2.44 (br s, 8H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3](=[CH2:6])[CH:4]=[O:5].[CH2:9]([O:11][C:12](=[O:16])[CH2:13][N+:14]#[C-:15])[CH3:10]>>[CH2:9]([O:11][C:12]([CH:13]1[CH:4]([C:3]([C:2]([CH3:8])([CH3:7])[CH3:1])=[CH2:6])[O:5][CH:15]=[N:14]1)=[O:16])[CH3:10]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=C(C=O)C(C)(C)C
Product: C=C(C1OC=NC1C(=O)OCC)C(C)(C)C

Procedure:
The starting material is manufactured as follows: Reaction of 3,3-dimethyl-2-methylene-butanal with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(3,3-dimethylbuten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 17 to 2-formylamino-3-hydroxy-4-tert.-butyl-4-pentenoic acid ethyl ester. Subsequent reaction with thionyl bromide followed by treatment with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-tert.-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH:27]([CH2:30][CH3:31])[CH2:26][NH:25][C:24](=[O:32])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[CH2:30]([CH:27]1[CH2:26][NH:25][C:24](=[O:32])[C:23]2[CH:22]=[C:21]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[N:12]=[C:11]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:20]=[CH:19]4)[NH:29][C:28]1=2)[CH3:31]
Reactant: CCC1CNC(=O)c2cc(-c3cccc4ccc(Cl)nc34)[nH]c21
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCC1CNC(=O)c2cc(-c3cccc4ccc(Oc5ccccc5)nc34)[nH]c21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a slurry of NaH (60% in mineral oil; 0.064 g, 1.611 mmol) in 1 mL DMF was added phenol (0.152 g, 1.611 mmol). After 10 min, rac-2-(2-chloroquinolin-8-yl)-7-ethyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 22; 0.075 g, 0.230 mmol) was added, and the reaction was heated to 70° C. After 2 h, the reaction was cooled and treated with TFA (0.124 ml, 1.611 mmol) and 1 mL DMSO, and the solution was filtered and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fraction was treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-7-ethyl-2-(2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.035 g, 0.091 mmol, 40% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (1H, br. s), 8.50 (1H, d, J=8.8 Hz), 8.14 (1H, dt, J=7.5, 0.7 Hz), 7.80 (1H, dt, J=8.0, 0.7 Hz), 7.35-7.64 (7H, m), 6.90-7.00 (1H, m), 6.82-6.91 (1H, m), 3.38-3.45 (1H, m), 3.12-3.20 (1H, m), 2.24-2.34 (1H, m), 1.13-1.34 (2H, m), 0.82 (3H, t, J=7.3 Hz). m/z (ESI, +ve) 384.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:19].[BH4-].[Na+].O>CO.O1CCCC1>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:19])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:7]2[OH:12]
Reactant: Cc1cc2c(cc1C)C(=O)N(c1cccnc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1C)C(O)N(c1cccnc1)C2=O
Yield: 78.7 %

Procedure:
The product of above-mentioned (7-a) (0.50 g, 2.0 mmol) was suspended in methanol (10 ml) and tetrahydrofuran (10 ml), and sodium borohydride (75 mg, 2.0 mmol) was added by portions thereto with stirring under ice cooling, followed by stirring at the same temperature for 30 minutes. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.40 g of 5,6-dimethyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][CH:8]=[CH:7]2.[CH3:14][C@@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[N:9]([CH2:14][C@H:15]([OH:16])[CH3:17])[CH:8]=[CH:7]2
Reactant: C[C@@H]1CO1
Reactant: Fc1cc2cc[nH]c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ccc2cc(F)c(F)cc21
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A suspension of 0.12 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 5,6-difluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.46 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 60 hours and subsequently treated with water. The mixture was diluted with ether, washed twice with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 35 g of silica gel with toluene-ethyl acetate (19:1). 0.46 g (66.5%) of (R)-1-(5,6-difluoro-indol-1-yl)-propan-2-ol was obtained as yellowish crystals with m.p. 114°-116°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])C)([CH3:4])([CH3:3])[CH3:2].Br[CH:22](CC)[CH2:23]C.C(ONC(=O)OC(C)(C)C)C1C=CC=CC=1>>[CH2:13]([O:12][N:7]([CH:8]([CH2:9][CH3:11])[CH2:22][CH3:23])[C:6](=[O:20])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: CCC(Br)CC
Agent: CC(C)(C)OC(=O)NOCc1ccccc1
Product: CCC(CC)N(OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
Using the general method of Compound 54 Part B, 3-bromopentane (15.0 mL, 121 mmole) was reacted with tert-butyl N-benzyloxycarbamate (25.1 g, 112 mmole) to provide tert-butyl N-benzyloxy-N-(1-ethylpropyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:24](I)=[C:23]4[C:18]([N:19]=[CH:20][CH:21]=[CH:22]4)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].C1[CH2:33][O:32][CH2:31][CH2:30]1.[NH4+:34].[Cl-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:24]([C:33]4[O:32][CH:31]=[CH:30][N:34]=4)=[C:23]4[C:18]([N:19]=[CH:20][CH:21]=[CH:22]4)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc4ncccc4c3I)CC2)ccc1Cl
Reactant: [NH4+]
Reactant: C1CCOC1
Agent: [Cl-]
Product: COc1cc(N2CCN(C(=O)Cn3nc4ncccc4c3-c3ncco3)CC2)ccc1Cl
Temperature: 25 °C

Procedure:
To a mixture of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridine-2-yl)-ethanone (0.071 mmol, 1 eq.) and tetrakis triphenylphosphine palladium (0.025 mmol, 0.35 eq.) under nitrogen atmosphere was added 0.5 mL of THF and 2-oxazole-(tri-n-butyl)Tin (0.48 mmol, 6.7 eq.). The resultant mixture was heated in a sealed tube at 80° C. for 48 h. The reaction solution was cooled to rt, diluted with 30 mL of NH4Cl sat. aq. solution, and extracted with 300 mL of EtOAc. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0% to 15% MeOH in EtOAc) to provide 12.3 mg the title compound: 1H NMR (400 MHz, CDCl3) δ 8.77 (dd, 1H), 8.51 (dd, 1H), 7.81 (d, 1H), 7.22 (m, 3H), 6.52 (d, 1H), 6.48 (dd, 1H), 6.01 (s, 2H), 3.90 (s, 3H), 3.80 (m, 4H), 3.27 (m, 4H). LCMS observed for (M+H)+: 453.5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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(OCC)(=O)C>[CH2:26]1[O:27][C:21]2[CH:20]=[CH:19][C:24]([C:2]3[CH:3]=[CH:4][C:5]4[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:23][C:22]=2[O:25]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCO2
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: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2OCC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
In 1,2-dimethoxyethane(12 ml) were dissolved methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (566 mg, 2.00 mmol) and 3,4-methylenedioxyphenyl borate (465 mg, 2.80 mmol). To the mixture were added sodium carbonate (424 mg, 4.00 mmol), water (2 ml) and tetrakis(triphenylphosphine)palladium (162 mg, 0.14 mmol), and the mixture was stirred at 80° C. for 14 hours. To the mixture was added ethyl acetate (30 ml), and the mixture was extracted with water (5 ml×2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 15 g, ethyl acetate/hexane=1/19), and the desired fraction was concentrated under reduced pressure. To the residue was added diisopropylether, and the insoluble materials were filtered, which were washed with diisopropylether and dried under reduced pressure to give methyl 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (434 mg, 1.34 mmol, 67%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH:16]1([C:19]2[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=2)[CH2:18][CH2:17]1>>[CH:16]1([C:19]2[CH:24]=[CH:23][C:22]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][C:3]=3[C:8]3[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:18][CH2:17]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(C2CC2)cc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C2CC2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-cyclopropylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C19H16N4, 301. Found, 301.