Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:35]=1>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([S:40]([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)(=[O:42])=[O:41])[CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=Cc1c[nH]c(-c2c(F)cccc2F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2c(F)cccc2F)n(S(=O)(=O)c2cccnc2)c1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-1H-pyrrole-3-carbaldehyde (420 mg) in tetrahydrofuran (42 mL) was added sodium hydride (60% in oil, 244 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (1.34 g) was added dropwise and the mixture was stirred for 30 min. 3-Pyridylsulfonyl chloride hydrochloride (565 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1), and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 590 mg, 84%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22]>C(O)C>[CH2:21]([N:23]([CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)C[C@@H]1CCCN1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Solvent: CCO
Product: CCN(CC)C[C@@H]1CCCN1CC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 31 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and (S)-(+)-2-[(diethylamino)methyl]pyrrolidine to give a colorless highly viscous oil, [α]D20 =-10.5° (ethanol).
Reaction SMILES: Cl[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>O1CCOCC1>[OH:21][CH2:20][CH2:19][N:18]([C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH2:22][CH2:23][OH:24]
Reactant: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: OCCNCCO
Solvent: C1COCCO1
Product: COC(=O)c1cc(N(CCO)CCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 97 %

Procedure:
Methyl 5-chloro-2,4-dinitrobenzoate (IV) (1.24 g, 4.76 mmol) was treated with diethanolamine (1.00 g, 9.52 mmol) in dioxane (50 mL) at 50° C. for 3 h, and the residue after workup was chromatographed on silica gel. Elution with EtOAc gave methyl 5-[N,N-bis(2-hydroxyethyl)amino]-2,4-dinitrobenzoate (V) (1.52 g, 97%), mp (EtOAc/petroleum ether) 104°-106° C. 1H NMR (CDCl3) δ 8.48 (s, 1 H, H-3), 7.45 (s, 1 H, H-6), 3.95 (s, 3 H, OCH3), 3.81 (t, J=5.0 Hz, 4 H, CH2OH), 3.60 (t, J=5.0 Hz, 4 H, CH2N), 2.20 (br, 2 H, OH). 13C NMR δ 165.89 (COOMe), 147.53 (C-5), 138.67, 136.21 (C-2,4), 133.30 (C-1), 124.22, 121.65 (C-3,6), 59.34 (CH2OH), 54.59 (CH2N), 53.74 (OCH3). Anal. (C12H15N3O8) C,H,N.
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].Cl.Cl.Cl.[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[CH:23]=[C:24]([Cl:40])[C:25]([C:38]#[N:39])=[C:26]4[C:32]=3[O:31][CH:30]([CH3:33])[CH2:29][N:28]([CH:34]3[CH2:37][NH:36][CH2:35]3)[CH2:27]4)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12.C(N(CC)CC)C>CN(C)C=O>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[C:32]4[O:31][CH:30]([CH3:33])[CH2:29][N:28]([CH:34]5[CH2:37][N:36]([CH2:2][C:3]([NH2:5])=[O:4])[CH2:35]5)[CH2:27][C:26]=4[C:25]([C:38]#[N:39])=[C:24]([Cl:40])[CH:23]=3)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12
Reactant: NC(=O)CBr
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CNC2)C3)c2ncnc(N)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CN(CC(N)=O)C2)C3)c2ncnc(N)c12
Temperature: 80 °C

Procedure:
2-Bromoacetamide (0.01 g, 0.09 mmol) was added to a mixture of 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride (20 mg, 0.04 mmol) and triethylamine (20 μL, 0.18 mmol) in N,N-dimethylformamide (2 mL) and then heated to 80° C. for 2 h. The reaction was allowed to cool and was purified without work up by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compounds as two separated diastereomers: Peak #1 (Example 50): LCMS calculated for C24H29ClN9O2 (M+H)+: m/z=510.2; found: 510.2; Peak #2 (Example 51): LCMS calculated for C24H29ClN9O2 (M+H)+: m/z=510.2; found: 510.2.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CCOC(C)=O.O.C(Cl)(Cl)[Cl:31]>CN(C=O)C>[CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][Cl:31])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOP(=O)(OCC)c1cccc(-c2ccc(CO)cc2)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cccc(-c2ccc(CCl)cc2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product of step 2 (419 mg, 1.3 mmol) in CHCl3 (1 mL) was added a solution of POCL3 in DMF (0.39 mL, 3.6 mM) at 0° C. The mixture was stirred at 0° C. for 1.5 h. The reaction mixture was partionned between EtOAc and H2O. The organic phase was separated, dried over NaSO4, filtered and evaporated under reduced pressure. The title compound was obtained after flash chromatography (338 mg, 77%). Step 4: [4′-(2-benzotriazol-1-yl-3-4-[(di-tert-butoxy-phosphoryl)-difluoro-methyl]-phenyl}-2-phenyl-propyl)-biphenyl-3-yl]-phosphonic Acid Diethyl Ester
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[OH-].[Na+]>CN(C=O)C>[N:5]1([CH2:4][CH2:3][O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: Nc1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 23.5 h

Procedure:
4-(2-Chloro-ethyl)-morpholine hydrochloride (4.2 g, 22 mmol, 1.2 equiv) is added in one portion to a mixture of 4-aminophenol (2 g, 18.3 mmol) and finely powdered sodium hydroxide (1.87 g, 45.8 mmol, 2.5 equiv) in DMF (32 mL), under an argon atmosphere. The reaction mixture is stirred for 23.5 h at RT. The resulting dark suspension is filtered. The filtrate is diluted with DCM (200 ml) and washed with brine (2×60 mL). The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/EtOH, 95:5→7:3) provides the title compound as a yellow-brown solid: API-MS: 223.2 [MH]+; TLC: Rf=0.31 (DCM/EtOH, 9:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C1C=CN=CC=1)C.ClCl>[C:17](=[O:18])([O:19][CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: CC1(c2cc(F)ccc2O)CCCCC1
Agent: CN(C)c1ccncc1
Agent: ClCl
Product: COC(=O)Oc1ccc(F)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)phenol (23.5 g, 113 mmol), TEA (31 mL, 226 mmol) and DMAP (700 mg, 5.7 mmol) in CH2 Cl2(250 mL) was added methyl chloroformate dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured onto crushed ice and extracted with CH2Cl2(100 mL×3). The organic layer was washed with brine, dried over MgSO4, evaporated under vacuum. The crude product was purified by chromatography on silica gel diluted with (hexane:ethyl acetate=100:1) to give 4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as red brown oil (43.9 g, 72.1% yield). 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=3.2, 11.2 Hz, 1 H), 7.05-7.02 (m, 1H), 6.93-6.88 (m, 1H), 3.91 (s, 3H), 2.02-1.96 (m, 2H), 1.66-1.36 (m, 8H), 1.23 (s, 3H).
Reaction SMILES: [C:1]([CH:4]([C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1)C(OC(C)(C)C)=O)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12](=[O:22])[CH:4]=[C:1]([OH:3])[CH3:2])=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCc1ccc(CC(=O)C(C(C)=O)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(CC(=O)C=C(C)O)cc1

Procedure:
4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined Patent Publication 63-233975) was dissolved in dichloromethane (15 ml), and thereto were added oxalyl chloride (6.0 ml) and N,N-dimethylformamide (one drop). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene to give a crude 4-ethylphenylacetyl chloride, which was used in the subsequent step without further purification. (2) A suspension of magnesium chloride (1.74 g) in dichloromethane (30 ml) was cooled to 0° C., and thereto were added t-butyl acetoacetate (3.03 ml) and pyridine (2.96 ml), and successively was added a solution of the above 4-ethylphenylacetyl chloride in dichloromethane (30 ml). The mixture was stirred at the same temperature for 2.5 hours, and an aqueous citric acid solution was added thereto. The mixture was extracted with chloroform. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate (4.75 g) as pale yellow oil. APCI-Mass m/Z 322 (M+NH4). (3) A solution of the above t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate in trifluoroacetic acid (60 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (4.00 g) as yellow oil. APCI-Mass m/Z 205 (M+H). (4) A solution of the above 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (3.98 g) and hydrazine hydrate (4.0 ml) in toluene (20 ml) was stirred under heating at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=2:1) to give 3-(4-ethylphenylmethyl)-5-methyl-1H-pyrazole (3.12 g) as yellow oil. APCI-Mass m/Z 201 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][C:5]#[N:6].C#C.[CH:10]1[CH:15]=CC=[CH:12][CH:11]=1>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Co+2]>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:15][N:6]=1
Reactant: c1ccccc1
Reactant: CN(C)CCC#N
Agent: [Co+2]
Agent: C#C
Agent: c1cc[cH-]c1
Product: CN(C)CCc1ccccn1
Temperature: 170 °C

Procedure:
1.0 gm. of cobaltocene (0.005 mole) and 71.5 gm. of β-dimethylaminopropionitrile (0.7 mole) was saturated with 12 atm. of acetylene at 20° C. (as in Example 13) and heated to 170° C. The admixture was stirred for another hour at a constant acetylene pressure of 12 atm. after a pressure drop to 11 atm. Upon distillative processing of the reaction product, 4.4 gm. of benzol, 5 gm. of β-dimethylaminoproprionitrile and 80.1 gm. of 2-(β-dimethylaminoethyl)-pyridine were obtained. This corresponded to a conversion of 93.0 percent of β-dimethylaminopropionitrile and a yield of 72.7 percent of 99.4 percent 2-(β-dimethylaminoethyl)-pyridine.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([C:17]2[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=2)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:25][NH2:26]>C(O)C>[C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]2[C:17]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:26][N:25]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cccnc1Cl)c1cccn1S(=O)(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cccc1-c1n[nH]c2ncccc12
Temperature: 90 °C

Procedure:
A mixture of (1-benzenesulfonyl-1H-pyrrol-2-yl)-(2-chloro-pyridin-3-yl)-methanone (150 mg) and hydrazine hydrate (0.15 mL) in ethanol (3.5 mL) was heated at 90° C. for overnight. The reaction was concentrated, diluted with ethyl acetate, washed with base and water, dried and concentrated to give 75 mg of the titled compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][C:2]1=O.F[B-](F)(F)F.C([O+](CC)CC)C.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:28][CH2:29][NH2:30]>C(O)C.C(Cl)Cl>[N:30]1[CH2:29][CH2:28][N:1]2[CH2:6][CH2:5][S:4][CH2:3][C:2]=12
Reactant: O=C1CSCCN1
Reactant: NCCBr
Agent: Br
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: C1CN2CCSCC2=N1
Reaction time: 6 h
Yield: 66.2 %

Procedure:
A solution of 23.4 g. (0.20 moles) of 3-thiomorpholinone in 150 ml. dry CH2Cl2 is added dropwise with stirring to a solution of 44 grams of triethyloxonium fluoroborate in 100 ml. of CH2Cl2 maintained at 0°-5°C. Stirring is continued for six hours as temperature is allowed to come to 25°C; K2CO3 (46 g.) is added and the methylene chloride solution is decanted and the residue of K2CO3 is washed with CH2Cl2. The combined organic solutions are dried over anhydrous K2CO3, filtered and solvent evaporated. Distillation of the concentrate gives 17.9 g. of the lactam ether. The lactam ether is added to a solution of 24.6 grams (0.12 moles) of 2-bromo-ethylamine hydrobromide in 150 ml. absolute ethanol and the resulting solution heated on a steam bath for two hours. The solvent is evaporated and the residue washed with ether. The resulting crystalline material is washed with acetone and air dried under suction. The crude crystalline product (28.5 g.) is dissolved in 200 ml. ethanol and sodium methoxide (.07 mole in 50 ml. methanol is added; the resulting solution is heated under reflux with stirring for two hours prior to evaporation of the solvent under reduced pressure. To the residue is added 75 ml. water and the solution made basic with potassium carbonate; the basic solution is extracted with chloroform (3 × 100 ml.). The combined extracts are dried over anhydrous Na2SO4, filtered and the solvent evaporated. Distillation of the concentrate gives 2,3,5,6-tetrahydro-8H-imidazo[2,1-c] [1,4] thiazine (11.3 g.). The hydrochloride and oxalate salts are prepared, respectively, by dissolving 1 g. of the product in the minimum volume of absolute ethanol at 45°C. and adding dropwise an aqueous 1 molar solution of the respective acid; the resulting salts are collected by filtration, washed with ethanol and dried.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[CH3:2]>C(O)C.[Pd]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[S:7][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc(CC)sc1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(CC)sc1Nc1ccccc1N

Procedure:
Ethyl 5-ethyl-2-(2-nitroanilino)-thiophene-3-carboxylate (20.7 g) in ethanol (150 ml) was catalytically reduced over 10% palladium on charcoal (2.0 g) at 60 p.s.i. The catalyst was removed by filtration and the solvent removed by distillation in vacuo. The title product so obtained had a melting point of 50°-52° C. (hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Li]CCCC.[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([O:37][CH3:38])[C:31]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[C:30]3[Cl:50])=[O:26])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]([C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([O:37][CH3:38])[C:31]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:45]=2)=[C:30]3[Cl:50])([C:7]2[C:2]([CH3:1])=[N:3][C:4]([CH3:8])=[CH:5][CH:6]=2)[OH:26])[CH2:24]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1cccc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A flask containing 2,6-dimethylpyridine (277 mg, 1.49 mmol) and THF (5 mL) was cooled to −78° C. and then n-BuLi (2.5 M in hexanes, 0.610 mL, 1.52 mmol) was added dropwise producing a homogeneous orange solution. After 3 minutes, tert-butyl 3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate (505 mg, 0.94 mmol, Intermediate 61: step b) in 3 mL THF was introduced. After 5 minutes, the −78° C. bath was replaced with an ice-water bath. After 30 minutes, the reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. This material was combined with a batch from a duplicate experiment for chromatography on silica gel (5% acetone-DCM increasing to 30% acetone with 1% MeOH) which provided the title compound as an off white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.7, 1.5 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.37 (dd, J=25.7, 8.4 Hz, 4H), 7.05 (d, J=8.0 Hz, 1H), 4.34 (s, 2H), 4.12-4.02 (m, 5H), 3.93-3.84 (m, 1H), 3.78-3.71 (m, 1H), 3.59-3.49 (m, 1H), 2.70 (s, 1H), 2.51 (s, 3H), 2.14 (s, 3H), 1.41 (s, 9H); MS (ESI): mass calcd. Chemical Formula: C34H35ClF3N3O4, Exact Mass: 641.2. m/z found 641.9 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[CH2:13][C:12]2[C:7](=[C:8]([Cl:17])[C:9]([Cl:16])=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=O.[OH-].[Na+].Cl>CO>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]12[CH2:19][CH2:20][C:21](=[O:23])[CH:22]=[C:6]1[C:7]1[C:12](=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[C:8]=1[Cl:17])[CH2:13]2
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCCl)(CCC(C)=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCCCl)C2

Procedure:
2-(3-Chloropropyl)-6,7-dichloro-2,3-dihydro-5-methoxy-2-(3-oxobutyl)-1H-inden-1-one (36 g, 0.0053 mole) was dissolved in methanol (4.75 ml) containing 10% aqueous sodium hydroxide (190 ml). Then stirred and refluxed for 3 hours. The solution was cooled, poured into crushed ice, acidified with hydrochloric acid and the solid that separated removed by filtration. The solid washed on the filter with water, dried and recrystallized from a mixture of tetrahydrofuran and ether to give 9a-(3-chloropropyl)-5,6-dichloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one, 15 g, m.p. 183°-185° C.
Reaction SMILES: [C:1]([C:4](=[CH:10][CH2:11][CH2:12][CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:12]([C:11]1[O:3][C:1]([CH3:2])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=1)[CH3:13]
Reactant: CCCC=C(C(C)=O)C(=O)OCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(CC)oc1C
Yield: 91.1 %

Procedure:
A mixture of 3.69 g (0.02 mole) ethyl 2-acetyl-2-hexenoate and 3.56 g (0.02 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 4 hours. After cooling, the succinimide was removed by filtration and the solution concentrated in vacuo. Distillation of the crude product gave 3.32 g (91%) of ethyl 5-ethyl-2-methyl-3-furoate, bp 99°-101° C. (10 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:25][CH2:24]4)[CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[CH:4][CH:3]=1.[S-:31][C:32]#[N:33].[K+].BrBr>C(O)(=O)C>[NH2:33][C:32]1[S:31][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:15][C:16](=[O:28])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5([C:26]#[N:27])[CH2:25][CH2:24]5)[CH:18]=4)[CH:10]=[CH:11][C:12]=3[O:13][CH3:14])[CH:29]=[CH:30][C:2]=2[N:1]=1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution (10 mL) of N-[3-(4-aminophenoxy)-4-methoxyphenyl]-3-(1-cyanocyclopropyl)benzamide (1.74 g, 4.36 mmol) in acetic acid was added potassium thiocyanate (1.46 g, 15.0 mmol), and the mixture was stirred at room temperature for 30 min. To the obtained transparent solution was added dropwise bromine (1.20 g, 7.50 mmol) under ice-cooling, and the reaction mixture was stirred at room temperature for 18 hr. The precipitated yellow powder was filtered off through celite, and the filtrate was concentrated under reduced pressure. To the residue was added 0.1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (1.08 g, 54%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.C([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(CN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
A mixture of 2.0 g 3-methoxy benzylchloride, 2.9 g 1-Boc piperazine, 5 mL triethylamine, and 20 mL tetrahydrofuran was stirred at room temperature for 20 minutes. The mixture was concentrated, and the residue was added to 20 mL trifluoroacetic acid and stirred at room temperature for 20 minutes. The trifluoroacetic acid was evaporated, and the residue was suspended in methanol and neutralized with an aqueous saturated sodium bicarbonate solution. The solvent was evaporated, and the residue was suspended in dichloromethane and purified by NH silica gel chromatography to give 2.4 g of the title compound as a white solid.