Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([O:31][C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:34][C@@H:33]([CH3:35])[C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:36])=[O:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: O=C(O)c1ccc2c(=O)[nH]cnc2c1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc2c(=O)[nH]cnc2c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 4-oxo-3,4-dihydro-quinazoline-7-carboxylic acid in tetrahydrofuran, 1.2 equivalents of 1,1′-carbonyldiimidazole are added and the mixture is stirred for 30 minutes. Then, the (S)-L-Alanine tert-butyl ester is added and the mixture is stirred for 24 hours until disappearance of starting material. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated and the residue is purified by column chromatography to give the desired compound.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=[O:18])=[CH:8][CH:7]=1)([O-])=O>O.CO.C1COCC1.[Zn]>[NH2:3][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=[O:18])=[CH:8][CH:7]=1
Reactant: O=c1ccccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc(-n2ccccc2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Ammonium chloride (4.45 g, 83.26 mmol) in water (10 mL) and methanol (20 mL) was added to a stirred solution of 1-(4-nitro-phenyl)-1H-pyridin-2-one (1.8 g, 8.3 mmol) in THF (20 mL). Zinc powder (4.3 g, 66.6 mmol) was then added portion wise and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was filtered over celite and the filtrate was concentrated and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 1.23 g (79%) of 1-(4-amino-phenyl)-1H-pyridin-2-one. 1H NMR: (DMSO-d6): δ 7.6-7.4 (m, 2H), 7.0 (d, 2H), 6.7 (d, 2H), 6.45 (d, 1H), 6.3 (t, 1H), 5.4 (s, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[N:14][C:15]([O:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18]3)=[C:10]2[CH:9]=[N:8]1.[H][H]>CCO.[Pd]>[NH:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([O:16][C:15]2[N:14]=[CH:13][N:12]=[C:11]3[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:34])([CH3:33])[CH3:1])[N:8]=[CH:9][C:10]=23)[CH2:18]1
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1ncc2c(O[C@H]3CCCN(C(=O)OCc4ccccc4)C3)ncnc21
Agent: [Pd]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ncc2c(O[C@H]3CCCNC3)ncnc21
Yield: 80.3 %

Procedure:
To a solution of (S)-benzyl 3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (200 mg, 0.41 mmol) in EtOH (10 mL) was added 10% Pd/C (40 mg) and the solution was placed under an atomsphere of hydrogen (1 psi). The reaction mixture was purged with nitrogen and filtered through a Celite pad, and the filtrate was evaporated in vacuo to give (115 mg, 79%) the titled compound which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.63 and 8.60 (2s, 1H), 8.31-8.21 (2s, 1H), 5.72 and 5.70 (2s, 2H), 5.38-5.22 (m, 1H), 3.63-3.59 (m, 2H), 3.21-3.07 (m, 1H), 2.81-2.63 (m, 2H), 2.23-2.01 (m, 2H), 1.79-1.61 (m, 2H), 1.58-1.45 (m, 2H), 0.85 (t, J=6.4 Hz, 2H), −0.91 (s, 9H). LC-MS: m/z [M+1]=350.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Mg]Cl)(C)C.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.ClCCl>[C:34]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:5]3[CH:6]=[C:7]([O:8][CH3:9])[C:2]([F:1])=[CH:3][C:4]=3[OH:10])([OH:32])[C:24]2=[O:33])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccc(O)cc1F
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution of 3-fluoro-4-methoxyphenol (Niemann, M. B. J. Am. Chem. Soc. (1941), 63:609) (4.60 g, 32.4 mmol) in tetrahydrofuran (60 mL) at 5° C. was added a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (18.0 mL, 36.0 mmol). Tetrahydrofuran was removed under reduced pressure and dichloromethane (60 mL) was added. To the solution was added a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (8.00 g, 25.5 mmol) in dichloromethane (60 mL) at 5° C. and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL). The reaction mixture was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography with 40% to 90% gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (6.60 g, 57%) as a pink solid: MS (ES+) m/z 438.3 (M−17).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1)=[O:37]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide hydrochloride (example A160) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[CH3:31][O:30][C:28]([N:15]1[CH:16]2[CH:21]([CH:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][CH2:17]2)[N:12]([C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)=[O:29]
Reactant: COC(=O)Cl
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (100.9 mg, 0.25 mmol) was dissolved in absolute CH2Cl2 (13 ml) under a nitrogen atmosphere and methyl chloroformate (28.9 mg, 0.31 mmol) was added dropwise. The solution was stirred at room temperature for 2 hours. Thereafter, the mixture was evaporated in vacuo and the residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=16 cm, V=5 ml) and was obtained as a yellow resin.
Reaction SMILES: CO[C:3](=[O:27])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:28][NH:29][C:30]([NH2:32])=[O:31].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[C:3]([NH:32][C:30]([NH:29][CH3:28])=[O:31])=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid methyl ester (196.5 mg, 0.548 mmol) and methyl urea (121.8 mg, 1.64 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 3.1 mL, 2.19 mmol). The resulting reaction mixture was then heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate then 3/1 to 1/1 hexanes/ethyl acetate gradient elution) afforded 1-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionyl]-3-methyl urea (76.9 mg, 35%) as a white foam: mp 85-88° C.; EI-HRMS m/e calcd for C26H28N2O2 (M+) 400.2151, found 400.2150.
Reaction SMILES: NC1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CI.C(=O)([O-])[O-].[K+].[K+].O.[CH3:31][N:32]([CH3:35])[CH:33]=O>>[CH3:31][N:32]([CH3:35])[C:33]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of ethyl 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate (11.8 g), methyl iodide (11.9 g) and potassium carbonate (10.7 g) in dried dimethylformamide (100 ml) was stirred at room temperature for 17 hrs. The reaction mixture was poured into water (400 ml) and extracted with diethyl ether (150 ml×2). The extract was washed with saline, dried over magnesium sulfate and evaporated in vacuo. The oily residue (12.7 g) was subjected to column chromatography on silica gel and eluted with a mixture of benzene and n-hexane (1:1) to give oily ethyl 2-[2-dimethylamino-3-(2-chlorophenoxy)phenyl]acetate (7.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]>C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:10][CH2:11][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:17][CH2:18]2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(C2=CCC3(CC2)OCCO3)cc1Cl
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(C2CCC3(CC2)OCCO3)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
Platinum oxide (200 mg) was added in one portion to a stirred solution of 2-chloro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline (3.8 g, 14.3 mmol) in ethyl acetate (50 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 8 h. The reaction mixture was filtered and concentrated in vacuo to leave the title compound (2.4 g, 63%) as a solid; 1H NMR δ 1.5-1.65 (4H, m), 1.67-1.8 (4H, m), 2.38-2.48 (1H, m), 3.88 (4H, s), 5.1 (2H, s), 6.72 (1H, d), 6.9 (1H, dd), 7.0 (1H, d); MS m/e MH+ 268.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[N:17]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])C(=O)C(F)(F)F.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][C:3]=1[NH:17][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CN(C(=O)C(F)(F)F)c1ccc(CCOC2CCCCO2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CNc1ccc(CCO)cc1Cl
Yield: 64.5 %

Procedure:
A solution of ethyl N-[2-chloro-4-[2-((RS)-tetrahydro-pyran-2-yloxy)ethyl]phenyl]-N-trifluoroacetylaminoacetate (830 mg) and p-toluenesulfonic acid monohydrate (80 mg) in ethanol (9.0 ml) was stirred for 2 hours at 40° C. To the reaction mixture was added potassium carbonate (314 mg), and the resulting mixture was heated under reflux for 5 hours with stirring. The insoluble material was filtered off, the filtrate was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) gave ethyl N-[2-chloro-4-(2-hydroxyethyl)phenyl]aminoacetate (315 mg).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[O:9][N:8]=[C:7]([CH3:10])[CH:6]=1)=O.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[N+:3]([CH2:4][C:5]1[O:9][N:8]=[C:7]([CH3:10])[CH:6]=1)#[C-:1]
Reactant: Cc1cc(CNC=O)on1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: [C-]#[N+]Cc1cc(C)no1
Reaction time: 0.5 h

Procedure:
To a cooled and stirred solution of 5-formylaminomethyl-3-methylisoxazole (5.45 g, 39 mmol) and triethylamine (16.7 ml, 120 mmol) in dichloromethane (50 ml) was added dropwise phosphorus oxychloride (4 ml, 43 mmol) during 30 min., the temperature being kept below 0° C. Stirring was continued for 30 min., then a solution of sodium carbonate (4.55 g, 43 mmol) in water (50 ml) was added dropwise (<0° C.). Additional water (50 ml) was added and the layers were separated. The aqueous phase was extracted twice with dichloromethane (2×30 ml). The combined organic layers were dried, the solvent was evaporated, and the residue was extracted with ether (2×75 ml). The extracts were combined and the solvent was removed to give the title compound as a dark oil, 1H-NMR (CDCl3): 2.30 (s,3H), 4.75 (s,2H), 6.25 (s,1H). (Compound 16).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH3:23])[CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH3:23])[C:17]3([CH2:2][CH2:3][OH:4])[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: CN(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(c1)OCCO2)C1(CCO)CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.4 %

Procedure:
2-Bromo-ethanol (36 μL, 0.51 mmol, 1.0 eq) is added at room temperature to a stirred solution of (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-piperidin-4-yl-amine (148 mg, 0.51 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by potassium carbonate (70 mg, 0.51 mmol, 1.0 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×8 mL) and water (8 mL). pH of the aqueous layer is neutralized with a 0.1 N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 2-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidin-4-yl}-ethanol as a yellow semisolid (160 mg, 93% yield).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:31][C:32]2([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]2)[C:5]=1[O:21][CH3:22]
Reactant: COCC1(CBr)COC1
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC(F)F)c2OC)COC1
Temperature: 80 °C
Yield: 23 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103.5 mg, 0.75 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (146 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (25 mg, 23%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][CH:3]1[NH:25]C(=O)OCC1C=CC=CC=1.[Cl:36]C1C=CC(I)=NC=1>>[NH2:25][CH:3]1[C:2](=[O:1])[N:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:36])=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4]1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O)OCc1ccccc1
Reactant: Clc1ccc(I)nc1
Product: NC1N=C(c2ccccc2)c2ccccc2N(c2ccc(Cl)cn2)C1=O

Procedure:
Intermediate 2A was prepared as described in Intermediate 1A using 5-chloro-2-iodopyridine. The racemate was purified by preparative SFC chromatography (Berger SFC MGII, CHIRALCEL® OJ-H 250×30 mm ID, 5 μm, 80/20 CO2/MeOH, 85 mL/min) to give Intermediate 3A. RT=3.44 min (H2O/CH3OH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=3 min, wavelength=220 and 254 nm); MS(ES):m/z=497 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:38]1([C:44](=[O:52])[CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:49]3[CH2:50][CH2:51][N:46]([CH2:45][C:44]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[O:52])[CH2:47][CH2:48]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give the title compound. HR-MS (ES, m/z) calculated for C37H41N5O4F3Cl2 [(M+H)+] 746.2482, observed 746.2483.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)#[CH:28]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:28]#[C:27][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: C#Cc1ccccn1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(C#Cc3ccccn3)c2CC1)C(F)(F)F
Yield: 90.3 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with 2-ethynyl-pyridine (0.20 mL, 2 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 7-chloro-6-pyridin-2-ylethynyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (342 mg, 90%). MS (ES+) m/z: 379 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[NH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:19]([O:18][C:16](=[O:17])[CH2:15][NH:14][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)c1ccnc(C=O)c1
Product: CCOC(=O)c1ccnc(CNCC(=O)OC(C)(C)C)c1

Procedure:
Prepared by General Procedure A from ethyl 2-formylpyridine-4-carboxylate and tert-butyl 2-aminoacetate. Title compound isolated as yellow oil by column chromatography (EtOAc/hexanes). 1H-NMR (300 MHz, MeOH-d4): δ 8.7 (d, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 4.4 (s, 2H), 4.3 (q, 2), 3.8 (s, 2H), 3.3 (s, 2H), 1.4 (s, (H), 1.3 (t, 3H). ES-MS: 295 [M+1].
Reaction SMILES: [CH2:1]([Sn:5]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=[CH:7][CH2:8][CH2:9][C:10]([O:12][Sn](CCCC)(CCCC)CCCC)=[O:11])[CH2:2][CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[F:49][C:50]1[C:55]([F:56])=[CH:54][C:53]([F:57])=[C:52]([F:58])[C:51]=1O>C1COCC1>[CH2:30]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=[CH:7][CH2:8][CH2:9][C:10]([O:12][C:51]1[C:50]([F:49])=[C:55]([F:56])[CH:54]=[C:53]([F:57])[C:52]=1[F:58])=[O:11])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](C=CCCC(=O)O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCC[Sn](C=CCCC(=O)Oc1c(F)c(F)cc(F)c1F)(CCCC)CCCC
Reaction time: 8 h

Procedure:
To a solution of tri-n-butylstannyl 5-(tri-n-butylstannyl)-4-pentenoate acid (1.0 equiv.) in anhydrous THF at room temperature is added dicyclohexylcarbodiimide (1.2 equiv.) (Aldrich) and 2,3,5,6-tetrafluorophenol (1.2 equiv.) (Aldrich). The resulting solution is stirred overnight. The mixture is filtered, the filtrate is concentrated, and the residue is chromatographed to provide 2,3,5,6-tetrafluorophenyl 5-(tri-n-butylstannyl)-4-pentenoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[NH:8])=[O:7])[CH3:2].[I:11][C:12]1[C:13]([NH2:21])=[N:14][CH:15]=[C:16]([CH:20]=1)[C:17](O)=[O:18].C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:21][C:13]1[N:14]=[CH:15][C:16]([C:17]([N:8]=[S:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])([CH3:9])=[O:7])=[O:18])=[CH:20][C:12]=1[I:11]
Reactant: CCOC(=O)CS(C)(=N)=O
Reactant: Nc1ncc(C(=O)O)cc1I
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Temperature: 70 °C

Procedure:
A solution of ethyl(S-methylsulfonimidoyl)acetate was dissolved in anhydrous DMF (1 mL) and treated with 5-iodo-6-amino-nicotinic acid (82 mg, 1.05 eq), diisopropylamine (0.1 mL, 2 eq), and BOP (149 mg, 1.1 eq) with stirring. The reaction mixture was heated to 70° C. for 6 hours and then partitioned between EtOAc and aq NH4Cl. The organic layer was separated, washed with saturated aq NaHCO3 (1×) and brine (1×), and dried over Na2SO4. The organic phase was filtered and concentrated. The residue as purified by gradient column chromatography (EtOAc-Hexane 1:9 to 2:3). Concentration of the product containing fractions provided the title compound as a brown oil (24 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:29])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: CC(=O)c1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-acetylbenzoic acid.