Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:10])=[CH:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.Cl.[CH:12](OCC)(OCC)OCC>C(O)C>[Cl:1][C:2]1[C:3]([I:10])=[CH:4][C:5]2[NH:9][CH:12]=[N:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(I)cc1N
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CCO
Product: Clc1cc2nc[nH]c2cc1I
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-chloro-4-iodo-1,2-phenylenediamine 1-6 (8.00 g, 29.8 mmol), 2.48 mL of 12 M HCl (29.8 mmol), triethyl orthoformate (39.7 mL, 238.4 mmol) in 30 mL ethanol was split evenly between four 20 mL reaction vials; the vials were sealed and stirred at 130° C. for 10 min each. After cooling to rt, the resulting solids were collected by filtration and washed with ethanol. Then the isolated solid was dissolved in 250 mL of water by heating to 80° C. To this solution was added slowly 25 mL of saturated aqueous NaHCO3. The mixture was confirmed to have a pH >8, and then cooled in an ice-bath. The resulting white solid was collected by filtration and then dissolved in 3:1 CH2Cl2/methanol, dried (MgSO4) and evaporated. The resulting solid was sonicated with CH2Cl2 and evaporated (2×) to provide 6-chloro-5-iodobenzimidazole 1-7 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.87 (br s, 1H), 8.17 (br s, 1H), 8.28 (s, 1H), 12.66 (br s, 1H); LC-MS: calculated for C7H4ClIN2 277.9, observed m/e 279.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5](I)=[CH:4][N:3]=1.[F:26][C:27]1[CH:28]=[N:29][NH:30][C:31]=1[Sn](CCCC)(CCCC)CCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu](I)I>[NH2:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([C:28]2[NH:29][N:30]=[CH:31][C:27]=2[F:26])=[CH:4][N:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(-c3cc(I)cnc3N)nc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1CC(=O)NN=C1c1ccc2[nH]c(-c3cc(-c4[nH]ncc4F)cnc3N)nc2c1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
100 mg (0.224 mmol) of 6-[2-(2-amino-5-iodopyridin-3-yl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 252.2 mg (0.672 mmol) of 4-fluoro-5-tributylstannanyl-1H-pyrazole, 41.5 mg (0.045 mmol) of tris(dibenzylideneacetone)dipalladium(0), 23.5 mg (0.090 mmol) of triphenylphosphine, 28.5 mg (0.672 mmol) of lithium chloride and 8.5 mg (0.045 mmol) of copper iodide in 2 ml of dioxane are introduced into a nitrogen-filled reaction vessel. The mixture is stirred at 100° C. for 14 h under a nitrogen protective atmosphere. The reaction mixture is cooled to room temperature, and the solvent is removed. DCM and 2N HCl are added to the residue. The precipitate is separated off and washed with DCM/water. The precipitate is purified further via preparative RP-HPLC, giving 6-{2-[2-amino-5-(4-fluoro-2H-pyrazol-3-yl)pyridin-3-yl]-1H-benzimidazol-5-yl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one; HPLC-MS [M+H]+ 405.2;
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].C(O)CC(C)C>C(O)CCC>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Solvent: CCCCO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCCN1CCN(c2ccccc2)CC1
Yield: 66.9 %

Procedure:
2-Chloro-5-nitrobenzoic acid (179 g), 182.5 g 1-(2-aminoethyl)-4-phenylpiperazine, 138 g K2CO3, 900 ml isoamyl alcohol and CuO catalyst were refluxed for 8 hours adding a pinch of CuO periodically. The mixture was cooled overnight, diluted with butanol and filtered. The solid was dissolved in water and neutralized to pH 4-4.5 with 3N HCl to give 247 g crude product. This was recrystallized from 3.5 liters dimethylformamide and 1 liter of water to give 220 g product, m.243-6°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[NH:18][C@H:19]([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.O.[OH-].[NH4+].C(OCC)(=O)C>[C:12]1([C:11]#[C:10][C:7]2[CH:6]=[C:5]([NH:18][C@H:19]([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]([NH2:1])=[CH:9][CH:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@@H](Nc1cc(C#Cc2ccccc2)ccc1[N+](=O)[O-])C(C)(C)C
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1cc(C#Cc2ccccc2)ccc1N)C(C)(C)C
Yield: 57.3 %

Procedure:
Stir (5-Chloro-2-nitrophenyl)-(1-(R)-methyl-2,2-dimethylpropyl)amine (17.23 g, 0.067 mol), copper (I) iodide (0.64 g, 0.0034 mol), (oxydi-2,1-phenylene)bis(diphenylphosphine) (3.61 g, 0.0067 mol), phenylacetylene (12.5 mL, 0.114 mol) in DMF (200 mL) and diethylamine (50 mL) for 5 minutes. Add palladium (II) acetate (0.753 g, 0.0034 mol) and heat to 95° C. for 4 h. Cool to ambient temperature and evaporate off diethylamine under reduced pressure and pour into hexane. Filter insolubles and evaporate off hexane. Dilute with ethyl ether (1 L), filter and wash filtrate with water (2×1 L), saturated sodium chloride, dry magnesium sulfate, concentrate and purify (silica gel chromatography eluting with hexane/dichloromethane mixtures) to give 27.9 g of crude (2-nitro-5-phenylethynylphenyl)-(1-(R)-methyl-2,2-dimethylpropyl)amine that was used in the next step without further purification. To a solution of impure (2-nitro-5-phenylethynylphenyl)-(1-(R)-methyl-2,2-dimethylpropyl)amine (27.9 g) in THF (350 mL), water (100 mL), concentrated ammonium hydroxide (150 mL), Na2S2O4 (73.6 g, 0.423 mol) and stir for about 18 hours. Dilute with ethyl acetate and wash with saturated sodium chloride, dry with magnesium sulfate, concentrate and purify (silica gel chromatography with hexane/dichloromethane mixtures to give 14.51 g of the desired compound (75% for 2 Steps).
Reaction SMILES: I[C:2]1[N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH:5]=[N:4][C:3]=1[C:11]#[N:12].O.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH:5]=[N:4][C:3]=1[C:11]#[N:12]
Reactant: Nc1ccccc1B(O)O
Reactant: CC(C)Cn1cnc(C#N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)Cn1cnc(C#N)c1-c1ccccc1N
Temperature: 90 °C
Yield: 100.2 %

Procedure:
A solution of 5-iodo-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile (0.15 g, 0.54 mmol) in 1,2-dimethoxyethane (DME) (6 mL) and then water (3 mL) were added to a mixture of 2-aminophenylboronic acid hydrochloride (0.21 g, 1.2 mmol) and potassium carbonate (0.27 g, 1.9 mmol), and the mixture was evacuated and purged with nitrogen three times. Dichlorobis(triphenylphosphine)palladium(II) (16 mg, 0.02 mmol) was added, and the mixture was flushed with nitrogen and heated at reflux (90° C.) for one hour and allowed to cool to room temperature. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with water (30 mL) and dichloromethane (40 mL). The filtrate layers were separated, and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic fractions were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel to provide 0.13 g of 5-(2-aminophenyl)-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile as an amber liquid that crystallized upon standing for 20 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:10]=3[N:9]=2)[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O.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>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:11]2[N:12]([CH3:13])[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:28]4[CH:29]=[N:30][NH:31][CH:32]=4)[CH:3]=3)=[N:9][C:10]=2[CH:17]=1
Reactant: COc1ccc2c(c1)nc(-c1cncc(Br)c1)n2C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc2c(c1)nc(-c1cncc(-c3cn[nH]c3)c1)n2C
Temperature: 100 °C

Procedure:
To a solution of 2-(5-bromo-pyridin-3-yl)-5-methoxy-1-methyl-1H-benzoimidazole (0.15 g, 0.00047 mol) in ethanol toluene water (6 ml, 3 ml, 1.5 ml, respectively) mixture in a sealed tube was added 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.18 g, 0.000942 mol) and Na2CO3 (0.14 g, 0.0014 mol) and argon was purged for 15 min. Then Pd (PPh3)4 (0.027 g, 0.000023 mol) was added and heated at 100° C. for 24 h. The solvent was evaporated and the resulting residue was added water. The aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain title compound 5-methoxy-1-methyl-2-[5-(1H-pyrazol-4-yl)pyridin-3-yl]-1H-benzimidazole as an off white solid. 1H NMR (400 MHz, DMSO-d6), δ: 13.11 (s, 1H), 9.01 (s, 1H), 8.79 (s, 1H), 8.44 (s, 1H), 8.38 (s, 1H), 8.13 (s, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.22 (s, 1H), 6.95 (d, J=8.8 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H). MS (M+1): 306.1, Purity 99.0%.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:7]=1)C.[OH-].[Li+]>CO.O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:11]=[CH:10][CH:9]=2)=[C:14]([CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:15]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Oc2cccc(CC(=O)O)c2)c(CN2CCOC2=O)c1

Procedure:
Hydrolysis of {3-[4-methyl-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester with lithium hydroxide in MeOH and H2O at 60° C. provided the desired product.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=2)=[O:21])=[N:4][N:3]=[N:2]1.[CH3:33][N:34]([CH3:39])[C:35](=[O:38])[CH2:36]O.C(O)(=O)C>CN(C)C=O.O>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([O:30][CH2:36][C:35](=[O:38])[N:34]([CH3:39])[CH3:33])=[O:29])=[CH:31][CH:32]=2)=[O:21])=[N:1][N:2]=[N:3]1
Reactant: O=C(O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Reactant: CN(C)C(=O)CO
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Yield: 38.5 %

Procedure:
In 15 ml of N,N-dimethylformamide was dissolved 1.2 g of 4-[2-[2-(1H-tetrazol-5-yl)phenylthio]phenylcarbamoyl]p-henoxyacetic acid (prepared in Example 6), followed by addition of 0.44 g of N,N'-carbonyldiimidazole with ice-cooling and stirring. The mixture was stirred with ice-cooling for 20 minutes, then 0.42 g of N,N-dimethylglycolamide was added, and the mixture was stirred at room temperature overnight. This reaction mixture was acidified with acetic acid and diluted with water and the crystals separated out therefrom were collected by filtration and recrystallized from N,N-dimethylformamide-ethyl acetate to give 0.55 g of the title compound as white crystals.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].[N:12]1[C:17]2[NH:18][C:19]3[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=3[N:21]([C:23]([C:25]3[CH:30]=[CH:29][C:28](F)=[CH:27][C:26]=3[C:32]([F:35])([F:34])[F:33])=[O:24])[CH2:22][C:16]=2[CH:15]=[CH:14][CH:13]=1>CCCCCC>[C:3]([C:7]1[CH:11]=[CH:10][N:9]([C:28]2[CH:29]=[CH:30][C:25]([C:23]([N:21]3[C:20]4[CH:36]=[CH:37][CH:38]=[CH:39][C:19]=4[NH:18][C:17]4[N:12]=[CH:13][CH:14]=[CH:15][C:16]=4[CH2:22]3)=[O:24])=[C:26]([C:32]([F:33])([F:35])[F:34])[CH:27]=2)[N:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Reactant: CC(C)(C)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(C)(C)c1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(C(F)(F)F)c2)n1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Sodium hydride (60% suspension in oil, 0.12 g, 3.0 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (10 mL). 3-tert-butylpyrazole (0.20 g, 1.6 mmol) was added in one portion at ambient temperature, and the stirring was continued until the gas evolution subsided. The (6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-[4-fluoro-2-trifluoromethyl-phenyl]-methanone of Example 4, Step B (0.50 g, 1.3 mmol) was added in one portion to the clear solution. The mixture was placed in an oil bath (preheated at 130° C.) for 30 minutes and then heated at reflux for 5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The crude residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 25% ethyl acetate in hexane provided the title product (0.23 g) as a foam which crystallized by trituration with hexane-ether, m.p. 136-140° C.
Reaction SMILES: BrC1N=C(C=O)C=CC=1.C(C1C=CC=C(C(C)C)C=1N)(C)C.[Br:23][C:24]1[N:29]=[C:28](/[CH:30]=[N:31]/[C:32]2[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=2[CH:41]([CH3:43])[CH3:42])[CH:27]=[CH:26][CH:25]=1.[BH3-]C#N.[Na+]>C(O)C.O.CO.C(O)(=O)C>[Br:23][C:24]1[N:29]=[C:28]([CH2:30][NH:31][C:32]2[C:37]([CH:38]([CH3:39])[CH3:40])=[CH:36][CH:35]=[CH:34][C:33]=2[CH:41]([CH3:43])[CH3:42])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(Br)n1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: O=Cc1cccc(Br)n1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1
Temperature: 25 °C

Procedure:
A solution of 85.0 g (457 mmol) of 6-bromopyridine-2-carbaldehyde and 80.9 g (457 mmol) of 2,6-diisopropylaniline in 1000 ml of ethanol was refluxed for 8 h. The obtained solution was evaporated to dryness, and the residue was re-crystallized from 200 ml of methanol. In argon atmosphere, to thus obtained 113.5 g (329 mmol) of N-[(1E)-(6-bromopyridin-2-yl)methylene]-2,6-diisopropylaniline were added 33.16 g (526 mmol) of NaBH3CN, 9 ml of acetic acid and 1000 ml of methanol. This mixture was refluxed for 12 h, then cooled to room temperature, poured into 1000 ml of water, and crude product was extracted with 3×200 ml of ethyl acetate. The combined extract was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate=10:1, vol.). Yield 104.4 g (66%) of a yellow oil. Anal. calc. for C18H23BrN2: C, 62.25; H, 6.68; N, 8.07. Found: C, 62.40; H, 6.87; N, 7.90. 1H NMR (CDCl3): δ 7.50 (m, 1H, 4-H in Py), 7.38 (m, 1H, 5-H in Py), 7.29 (m, 1H, 3-H in Py), 7.05-7.12 (m, 3H, 3,4,5-H in 2,6-iPr2C6H3), 4.18 (s, 2H, CH2NH), 3.94 (br.s, 1H, NH), 3.33 (sept, J=6.8 Hz, 2H, CHMe2), 1.23 (d, J=6.8 Hz, 12H, CHMe2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH2:19]O)=[CH:7]2.O=S(Cl)[Cl:23]>C(Cl)(Cl)Cl>[Cl:23][CH2:19][C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CO
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1CCl

Procedure:
Prepared according to Procedure C using (8-methyl-2-o-tolylquinolin-3-yl)-methanol (670 mg, 2.5 mmol) and SOCl2 (0.91 mL, 5 eq) in CHCl3 (10 mL). After isolation, the resultant oil was carried on crude without purification for the next step.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[N:14]([CH2:21][CH:22]1[C:31]2[C:26](=[C:27]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39](=[O:41])[NH2:40])=[CH:35][N:34]=3)[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(C)(C)C>C(Cl)Cl>[CH3:19][CH:18]([CH3:20])[CH2:17][CH2:16][CH2:15][NH:14][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][C:26]2[C:27]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([NH2:40])=[O:41])=[CH:35][N:34]=3)=[CH:28][CH:29]=[CH:30][C:31]1=2
Reactant: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCCNCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
Add TFA (540 mg, 4.73 mmol) to a solution of [5-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamic acid tert-butyl ester (114 mg, 0.236 mmol) and DCM (3 ml) stirring under nitrogen at ambient temperature. After 18 hours, concentrate the mixture, redissolve in EtOAc and wash with 1M aq. K2CO3, water, and brine. Dry (MgSO4), concentrate, and purify on silica gel (5% (1N NH3/MeOH)/DCM) to obtain the title compound (80 mg) as an off-white solid. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.56 (s, 1H), 8.15 (d, 1H), 7.21-7.13 (m, 2H), 6.90 (m, 2H), 6.04 (br. s, 2H), 3.01 (m, 1H), 2.90-2.79 (m, 2H), 2.68-2.55 (m, 3H), 2.49-2.41 (m, 1H), 1.84-1.64 (m, 4H), 1.57-1.46 (m, 3H), 1.19 (m, 2H), 0.87 (d, 6H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1)(=[O:3])[CH3:2].[Br:22]Br>CC(O)=O>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[C:9]([Br:22])=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCC1CN(C(C)=O)c2cc(C)cc(C)c21
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)CCC1CN(C(C)=O)c2cc(C)c(Br)c(C)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-Acetyl-3-(2-ethoxycarbonylethyl)-4,6-dimethylindoline (3.3 g) was dissolved in AcOH (30 ml) and Br2 (0.93 ml) was added, which was followed by stirring for 30 min. The reaction mixture was poured into ice water and precipitated crude crystals were collected by filtration. The obtained crystals were dissolved in CHCl3 (100 ml). After washing with water, the mixture was dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 3.0 g of 1-acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-4,6-dimethylindoline.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:3].[H-].[Na+].Cl[CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].O>C1COCC1.CCCCCC>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3=[N:17][S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][N:13]3[CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)[CH3:1]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)Oc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A mixture of 3-[4-(1-methylethoxy)phenyl]pyridin-2-amine (350 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 307 mg) and 2-chloroethanesulfonyl chloride (750 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (360 mg) as a white solid. The obtained solid was crystallized from THF, acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N([CH2:20][CH3:21])CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C@@H:20]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH3:21])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C[C@H](C)N(CC(=O)OCC)Cc1ccccc1
Temperature: 0 °C
Yield: 41275.6 %

Procedure:
To ethanol (55 ml) cooled to 0° C. was added acetyl bromide (41 ml, 0.6 mol) dropwise, followed by a solution of (S)-4-methyl-dihydro-furan-2-one (Tetrahedron 1983, 39, 3107; 18.6 g, 0.2 mol) in ethanol (20 ml). The ice bath was removed and the reaction allowed to reach room temperature. After 2 h of stirring the reaction was concentrated, the residue redissolved in dichloromethane, washed with sat. aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated affording (S)-4-bromo-3-methyl-butyric acid ethyl ester (33.6 g, quantitative). This was redissolved in ethanol (100 ml), cooled to 0° C. and N-benzylglycine ethyl ester (28.2 g, 0.14 mol) and triethylamine (22.4 ml, 0.16 mmol) were added. The reaction was then warmed to 75° C. for 4 d after which time the reaction was concentrated, the residue redissolved in dichloromethane, washed with sat. aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 5:95) afforded the titled product as a light gold oil (20.3 g, 43%). MS (ISP)=322.2 (M+H)+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[C:16]1[N:24]2[CH:20]3[CH2:21][CH2:22][CH:23]2[CH2:25][CH:18]([CH2:19]3)[C:17]1=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC.C1(C)C=CC=CC=1>[C:1]1([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]2[N:24]3[CH:20]4[CH2:21][CH2:22][CH:23]3[CH2:25][CH:18]([CH2:19]4)[C:17]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1C(=Cc2ccccc2)N2C3CCC2CC1C3
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C1C2CC3CCC(C2)N3C1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a 100 ml three-necked round-bottomed flask equipped with a rubber septum and nitrogen inlet were added 5 ml dry toluene and 4.43 ml (13.3 mmol) of a 3.0M solution of phenyl magnesium bromide in ether. The solution was cooled to 0° C., and a solution of 2.07 g (8.87 mmol) 8-benzylidene-9-azatricyclo[4.3.1.04,9 ]decan-7-one in 20 ml toluene was added over 5 min. The reaction was allowed to stir at 0° C. for 1 hour and then poured into saturated aqueous ammonium chloride. The mixture was extracted into ethyl acetate, and the organic layer washed with saturated aqueous ammonium chloride and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluent and the product fractions combined to afford 1.47 g (53%) of a white solid, mp 137°-138° C.