Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1([CH3:34])[CH2:18][O:17][CH:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH:29]([CH2:31][CH2:32][CH3:33])[OH:30])[O:15][CH2:14]1.[CH3:35][C:36]([CH3:42])([CH2:40][CH3:41])[C:37](Cl)=[O:38]>C1COCC1>[CH3:12][C:13]1([CH3:34])[CH2:14][O:15][CH:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH:29]([O:30][C:37](=[O:38])[C:36]([CH3:42])([CH3:35])[CH2:40][CH3:41])[CH2:31][CH2:32][CH3:33])[O:17][CH2:18]1
Reactant: CCC(C)(C)C(=O)Cl
Reactant: CCCC(O)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(OC(=O)C(C)(C)CC)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
A 1.4M solution of n-butyllithium in hexane (2.6 mL, 3.61 mmol) was added dropwise under a nitrogen atmosphere to a solution of (E)-2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]-3,5-dimethyl-α-propylbenzenemethanol (956.8 mg, 3.01 mmol) in 100 mL of dry THF. After the addition, the solution was stirred at room temperature for 15 minutes. 2,2-Dimethylbutyryl chloride (500 μl, 3.61 mmol) was then added and the solution stirred at room temperature for 30 minutes. The reaction was partitioned between 1N HCl-EtoAc and extracted. The organic layer was washed with water (two times), dried (anh. K2CO3) and the solvent removed under reduced pressure. Purification of the residual oil on 250 g of silica gel (Merck, 230-400 mesh) using 3:2 CH2Cl2 -hexane as an eluent gave 2,2-dimethylbutanoic acid (E)-1-[2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]-3,5-dimethylphenyl]butyl ester (534 mg, 43%) as an oil: IR (film) 2945, 2860, 1720 and 1605 cm-1 ; NMR (DMSO-d6) δ 0.68-0.80 (6H, m), 0.86 (3H, t, J=6 Hz), 1.07 (3H, s), 1.08 (3H, s), 1.12 (3H, s), 1.14-1.44 (2H, m), 1.46-1.66 (3H, m), 1.68-1.86 (1H, m), 1.18 (3H, s), 2.23 (3H, s), 3.54 (2H, d, J=10 Hz), 3.64 (2H, d, J=10 Hz), 5.09 (1H, d, J=5 Hz), 5.68 (1H, dd, J=5, 15 Hz), 5.74-5.86 (1H, m), 6.78 (1H, d, J=15 Hz), 6.98 (2H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH:23][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:13]
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: Nc1c(Cl)cccc1Cl
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(Cl)cccc1Cl)c1ccccc1CO2
Yield: 88.1 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of Compound A and 0.76 g of 2,6-dichloroaniline in place of aniline to obtain 1.38 g of Compound 6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=[O:11])[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:26]I>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:26])[C:9](=[O:11])[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(=O)[nH]c3cc(Cl)cnc32)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)n([C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-(6-chloro-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (110 mg, 0.33 mmol) in dry THF (5 mL) was added 60% NaH in oil (20 mg, 0.5 mmol). The mixture was stirred at rt for 5 min and MeI (0.02 mL, 0.33 mmol) was added. The mixture was stirred overnight, diluted with EtOAc (100 mL), washed with brine (2×10 mL) and dried over Na2SO4. Removal of the solvent left an oil (118 mg) which was applied to a 2-g silica SPE cartridge. The cartridge was eluted sequentially with 0, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to afford 5 fractions. Fractions 2 & 3 were pooled and concentrated to give (R)-tert-butyl 3-(6-chloro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (109 mg, 95%) as a red oil. LC-MS Method 1 tR=1.82 min, m/z=353, 279.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:22](=O)[CH3:23])[C:15]([O:17][CH:18]1[CH2:21][CH2:20][CH2:19]1)=[O:16].[NH2:25][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][C:28]#[N:29].CC(C)([O-])C.[K+]>CC(O)C>[C:28]([C:27]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH:18]2[CH2:19][CH2:20][CH2:21]2)=[O:16])=[C:22]([CH3:23])[NH:25][C:26]=1[C:30]([F:33])([F:32])[F:31])#[N:29]
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OC1CCC1
Reactant: N#CC=C(N)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1=C(C(=O)OC2CCC2)C(c2cccc3c(=O)cc(C)oc23)C(C#N)=C(C(F)(F)F)N1

Procedure:
A solution of 345 mg (1.06 mmol) of cyclobutyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate in 30 ml of 2-propanol is mixed with 143.85 mg (1.06 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 17.8 mg (0.16 mmol) of potassium tert-butoxide and stirred under reflux for 12 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). After concentration of the product fractions, the residue is crystallized from diethyl ether. 50.9 mg (10.8% of theory) of the title compound are obtained as white crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:12][CH2:13][NH2:14].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21].O>CN(C)C=O>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][NH:14][CH2:13][CH2:12][C:11]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:9]([O:8][CH3:7])[CH:10]=1)[CH3:21]
Reactant: CCOC(CBr)OCC
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CNCCc1ccc(OC)c(OC)c1)OCC
Reaction time: 1 h
Yield: 71 %

Procedure:
To a stirred suspension of anhydrous potassium carbonate (300 g) and 3,4-dimethoxyphenethylamine (148 g, 0.818 m) in dimethylformamide (750 ml) under N2 at 110° C. was added dropwise over 30 min bromoacetaldehyde diethylacetal (167.5 g, 0.850 m). During the addition, the temperature was allowed to rise to 130° C., maintained at 125°-130° C. for 1.5 hours, then the solution cooled. At ca 40° C., 70 ml of water were added, the mixture was stirred for 1 hour, then the inorganic salts were removed by filtration and the solvent evaporated. n-Hexane (750 ml) was added, the precipitated solid was filtered and the filtrate evaporated to an oil, 247 g. This material was vacuum-distilled to give three fractions: (1) b.p. 30°-154° C./0.1 mm, 17.0 g; (2) b.p. 154°-157° C./0.1 mm, 171.6 g; (3) b.p. 157°-174° C./0.1 mm, 37.3 g. Fraction (2) contained the product in 71% yield and 86% purity (GLC).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7](F)[C:6]=1[F:14]>CO>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([O:2][CH3:1])[C:6]=1[F:14]
Reactant: O=Cc1ccc(Br)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)ccc(Br)c1F
Yield: 93.9 %

Procedure:
Sodium methoxide (28% methanol solution, 69.1 g) was added to a solution of 4-bromo-2,3-difluorobenzaldehyde (52.8 g) in methanol (600 mL) at room temperature. The mixture was refluxed under nitrogen atmosphere for 2 hours and concentrated in vacuo to about 1/4 volume. The mixture was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (52.3 g).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]>[Cu]I>[C:1]1([C:7]#[C:8][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Product: O=[N+]([O-])c1cccc(C#Cc2ccccc2)c1
Temperature: 56 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
Example 1 was repeated except phenylacetylene ##STR9## was employed as the sole alkyne (25 mmols); the amount of CuI was increased to 0.25 mmol; and the reaction temperature was increased to 56° C. After 24 hours, the bromonitrobenzene was totally converted, giving an 84% yield of phenyl-3-nitrophenylacetylene ##STR10## Example 16 shows that it is not predictable (when Ex. 16 is compared with Exs. 13-15) which charge stocks will react with which halogenated arenes.
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH2:14].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: Nc1cc2c3c(c1)CCCC3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4CCC3)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
5,6,6a,7,8,9-Hexahydro-4H-2-phenalenylamine (0.100 g) was added with ethyl 2-chloropyrimidine-5-carboxylate (0.101 g) and potassium carbonate (0.400 g), and the mixture was stirred overnight at 110° C. The reaction mixture was left to cool and then added with water, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:20) to obtain the title compound (0.167 g, yield: 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:12][CH:11]1[CH:13]1[CH2:15][CH2:14]1)([O-])=O.[H][H]>C(O)C.[Pt].[C]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:12][CH:11]1[CH:13]1[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: Nc1ccccc1C1CC1C1CC1
Reaction time: 2.5 h
Yield: 102.5 %

Procedure:
In a hydrogenation reactor, 1 g of 2-(2-nitrophenyl)-bicyclopropane (4.9 mmol, trans:cis ratio: 4.1:1), dissolved in 20 ml of ethanol, is hydrogenated at ambient temperature using 0.1 g of 5% platinum-carbon catalyst. After 2.5 hours and after 101% of the amount of hydrogen theoretically required for the reduction has been taken up, the reaction is stopped. Following filtration of the reaction mixture, the solvent is removed by concentration by evaporation. 0.87 g of 2-(2-aminophenyl)-bicyclopropane (100% of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.4:1).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][O:9][C:8]2([CH:18]([Br:19])[CH2:17][CH2:16][C:15]3[N:14]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[O:7]1)([CH3:3])[CH3:2].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[CH:1]([N:4]([CH2:5][CH:6]1[CH2:10][O:9][C:8]2([CH:18]([Br:19])[CH2:17][CH2:16][C:15]3[N:14]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[O:7]1)[C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CNC(C)C)O2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CN(C(=O)c3ccccc3)C(C)C)O2)cc1
Reaction time: 14 h
Yield: 91.5 %

Procedure:
A solution of 4'-isopropylaminomethyl-1-p-toluenesulfonyl-5-bromo-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane (100 parts) dissolved in pyridine (343 parts) is prepared and placed in a three necked flask equipped with a stirrer and a thermometer. Benzoyl chloride (35 parts) is added dropwise at 0° C. to 5° C. After standing at room temperature for 14 hours, the reaction mixture is evaporated to remove pyridine at below 70° C. Obtained residue is dissolved in dichloromethane (300 parts) and washed three times with water (50 parts). Aqueous washings are combined and washed with dichloromethane (50 parts). Dichloromethane solution and dichloromethane washing are combined, washed with water (30 parts), are dried over anhydrous sodium sulfate. After 1 hour, the drying agent is removed by filtration, and obtained filtrate is concentrated to dryness under reduced pressure. Obtained residue (132 parts) is dissolved in dichloromethane (270 parts), allowed to stand for half an hour with active charcoal (30 parts), and filtered through Florisil filter-bed. The resulting filtrate is concentrated under reduced pressure to dryness at below 30° C. and the obtained residue is triturated in a small amount of a mixture of benzene and dichloromethane to give amorphous powder. The product is collected by filtration and dried to give 4'-(N-isopropyl-N-benzoylaminomethyl)-1-p-toluenesulfonyl-5-bromo-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane (111 parts) in 91.5% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:2].C1(C)C=CC=CC=1.O.[NH2:27][NH2:28]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([NH:27][NH2:28])=[O:14])[CH3:2]
Reactant: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Reactant: NN
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a 100 mL volume three-necked flask, ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate ((9-a) (10.0 g)) and toluene (35 ml) were added. Hydrazine hydrate (2.13 ml) was added dropwise thereto at 60° C. and the obtained mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature, water was added thereto and the organic layer was removed. The aqueous layer was extracted with toluene. The organic layers were combined and concentrated under reduced pressure to give 9.40 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:13]1[CH2:16][CH:15]([NH:17][C:18]([CH2:20][NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:19])[CH2:14]1>>[N:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([N:13]3[CH2:16][CH:15]([NH:17][C:18]([CH2:20][NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)=[O:19])[CH2:14]3)[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(n2ccnc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3ccnc3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-imidazol-1-yl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[CH:19][C:18]=3[CH3:31])=[CH:13][C:8]=2[C:7](=[O:32])[N:6]([CH3:33])[C:5]2[CH:34]=[CH:35][CH:36]=[N:37][C:4]1=2)[CH3:2].Cl.O1CCOCC1>>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=3[CH3:31])=[CH:13][C:8]=2[C:7](=[O:32])[N:6]([CH3:33])[C:5]2[CH:34]=[CH:35][CH:36]=[N:37][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(CCOc3ccc(NC(=O)OC(C)(C)C)cc3C)cc2C(=O)N(C)c2cccnc21
Agent: Cl
Solvent: C1COCCO1
Product: CCN1c2ncc(CCOc3ccc(N)cc3C)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of 1,1-dimethylethyl N-{4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]-3-methylphenyl}carbamate (540 mg, 1.07 mmol) and 4 N HCl in 1,4-dioxane (5.0 mL, 20 mmol) was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was taken in water (6 mL) and the resulting solution was washed with EtOAc. The aqueous layer was rendered basic (pH 9) with aqueous 2 N NaOH solution and the mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to yield the title compound (398 mg, 92% yield) as a beige foam.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[CH:12]=[CH:11][C:10]=1[NH:22][C:23]([N:25]1[CH2:29][C@@H:28]([C:30]([F:33])([F:32])[F:31])[C@H:27]([CH2:34][NH2:35])[CH2:26]1)=[O:24].[Cl:36][C:37]1[S:41][C:40]([C:42](O)=[O:43])=[CH:39][CH:38]=1>>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[CH:12]=[CH:11][C:10]=1[NH:22][C:23]([N:25]1[CH2:29][C@@H:28]([C:30]([F:31])([F:32])[F:33])[C@H:27]([CH2:34][NH:35][C:42]([C:40]2[S:41][C:37]([Cl:36])=[CH:38][CH:39]=2)=[O:43])[CH2:26]1)=[O:24]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1C(F)(F)F)c1ccc(Cl)s1

Procedure:
77.3 Using general method E, (3R,4S)-3-aminomethyl-4-trifluoromethyl-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide trifluoro acetate was coupled with 5-chlorothiophene-2-carboxylic acid to give (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-trifluoromethyl-pyrrolidine-1-carboxy-lic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 443.0 ([M+H]+)
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]([CH2:27][CH2:28][NH2:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:20]([CH2:27][CH2:28][NH:29][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCOc1ccccc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCOc3ccccc3)s2)c(C)[nH]c1=O
Yield: 78 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-phenoxy-ethylamine as described in Step 5, Example 24 to give the title compound as a yellow-orange solid (78% yield). LC/MS: RT 3.00 min; m/e 419 (M+H); 1H NMR (δ, ppm): 11.82 (1H, s), 8.18 (1H, m), 7.58 (1H, dd), 7.23-7.29 (3H, m), 7.15 (1H, dd), 6.86-6.94 (3H, m), 3.99 (2H, t), 3.28 (2H, t), 2.40 (2H, q), 2.29 (3H, s), 1.09 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[NH:17][N:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(C(C)C)CC)(C)C.[CH3:32][O:33][CH2:34]Cl>ClCCl>[CH3:32][O:33][CH2:34][N:17]1[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16]1
Reactant: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)[nH]n1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)n(COC)n1

Procedure:
Ethyl 5-(3,4,5-trimethoxyphenyl)pyrazole-3-carboxylate (1.70 g) was dissolved in dichloromethane (50 mL), and to the solution diisopropylethylamine (933 mg) was added at 0° C., and chloromethyl methyl ether (581 mg) was then added thereto. The resultant mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:16]C(=O)OC(C)(C)C)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[NH2:16][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCN(Cc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 1-benzyl-2-oxoazocan-3-ylcarbamate (9.0 mg, 0.027 mmol) in DCM (0.2 mL) at rt was added TFA (0.2 mL). The clear solution was stirred at rt for 1 hr. The reaction mixture was concentrated and dried under vacuum to give (S)-3-Amino-1-benzylazocan-2-one trifluoroacetate (6.3 mg, 0.027 mmol, 100% yield) as a colorless oil. Anal. Calcd. for C14H20N2O m/z 232.3. found: 233.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[S:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>>[F:19][C:18]1[C:2]([C:29]#[C:28][C@@:26]([OH:30])([C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH3:27])=[CH:3][C:4]2[C:10]3[S:11][C:12]([C:14]([NH2:16])=[O:15])=[CH:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1cc2c(s1)-c1cc(Br)c(F)cc1OCC2
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)OCCc2cc(C(N)=O)sc2-3)no1
Yield: 41 %

Procedure:
Methyl 9-bromo-8-fluoro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate was subjected to General Procedure L to afford 484 mg 9-bromo-8-fluoro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide in quantitative yield. 9-bromo-8-fluoro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.1 g) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similarly to as described in General Procedure F with non-critical modifications to afford 50 mg (41%) of 8-fluoro-9-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-4,5-dihydrothieno[3,2-d][1]benz oxepine-2-carboxamide. M+1=413; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.03 (d, J=10.4 Hz, 1H), 6.55 (s, 1H), 6.35 (d, J=1.0 Hz, 1H), 4.34 (t, J=5.6, 4.5 Hz, 2H), 3.18 (t, J=5.1 Hz, 2H), 2.41 (d, J=1.0 Hz, 3H), 1.80 (s, 3H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:30]([O:29][CH3:28])[CH3:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: COC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: COC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (84 mg, 78%), MS (ISP) m/z=431.5 [(M+H)+], mp 168.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (RS)-3-methoxybutanoic acid.