Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC#N>[CH2:30]([O:29][C:27]([CH2:26][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)=[O:28])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)cccc2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of tert-butyl 3,4-dihydro-5-hydroxyisoquinoline-2(1H)-carboxylate (750 mg, 3.01 mmol) and K2CO3 (498 mg, 3.61 mmol) in MeCN was added ethyl 2-bromoacetate (603 mg, 3.61 mmol). The mixture was stirred at room temperature overnight, the mixture was then filtered and the filtrate was concentrated under vacuum to give the desired product (900 mg, 90%). LCMS (m/z): 336.2 [M+H]+.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[C:24]([F:35])[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12]=2[CH:11]=1)=[O:9])=C.Cl.[OH-].[Na+]>C(O)C.O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[C:24]([F:35])[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12]=2[CH:11]=1)=[O:9]
Reactant: C=COCCONC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NOCCO)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide 11s (0.039 g, 0.068 mmol) is dissolved in ethanol (2 mL) and aqueous 2 M HCl (200 uL) is added. The reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted with water and then neutralized with aqueous 2 M NaOH (˜200 uL) until pH 7 and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and brine in a separatory funnel and the layers separated. The ethyl acetate layer is dried (Na2SO4) and concentrated under reduced pressure to yield 0.034 g (91%) of the pure desired product as an off-white solid. MS ESI (+) m/z 541, 543 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.75 (s, 1H), 7.49 (d, 1H), 7.18 (dd, 1H), 6.40 (dd, 1H), 4.40 (dd, A of ABX pattern, 1H), 4.28 (dd, B of ABX pattern, 1H), 3.92 (m, X of ABX pattern, 1H), 3.66 (t, 2H), 3.35 (m, 1H), 1.89 (m, 1H), 1.76 (m, 1H), 2.28 (s, 3H), 1.54 (m, 3H), 1.30 (m, 1H). 19F NMR (376 MHz, CD3OD) −134.87 (s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCC(=O)c3ccccc3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with α-bromoacetophenone and sodium hydride in dimethylformamide there is obtained 3-[4-chloro-2-fluoro-5-(phenacyloxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 152°-153° C.;
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:23])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=1)(=[O:27])=[O:26].[Cl-].[NH4+]>O1CCCC1.[Zn].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]>[CH3:10][O:11][C:12](=[O:23])/[C:13](/[C:31]1[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=1)=[CH:14]/[CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCCCC1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.38 g, 2 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (220 mg, 2 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (6.16 g, 20 mmol) in dry tetrahydrofuran (5 mL) over 10 min. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (10 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmol) and triphenylphosphinc (520 mg, 2 mmol) in dry tetrahydrofuran (25 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (4.23 g, 18 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 24 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (150 mL), and the organic compound was extracted into ethyl acetate (3×150 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×300 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (6.01 g, 99%) as a viscous yellow oil: EI-HRMS m/e calcd for C18H24O4S (M+) 336.1395, found 336.1395.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[N:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: Cc1ccsc1Br
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccsc1-c1ccncc1
Temperature: 90 °C
Yield: 60.6 %

Procedure:
A mixture of 2-bromo-3-methylthiophene (5 g, 28.24 mmol), pyridin-4-ylboronic acid (4.2 g, 33.89 mmol), and saturated sodium bicarbonate (70.60 mL of 1.2 M, 84.72 mmol) in DMF (100 mL) was degassed with nitrogen. PdCl2(dppf) (1.239 g, 1.694 mmol) was added and the reaction mixture heated at 90° C. under an atmosphere of nitrogen for 14 hours. After cooling, the mixture was poured into a saturated NaHCO3 solution, which was extracted with EtOAc. The organics were washed with saturated NaHCO3, dried over MgSO4, and the volatiles were removed by evaporation. The residue was purified by medium pressure silica gel chromatography, eluting with 1%-50% EtOAc/hexanes, to afford 4-(3-methylthiophen-2-yl)pyridine (3 g, 61% yield) as slightly yellow oil; 1H NMR (300 MHz, CDCl3): δ 8.54 (dd, J=1.6, 4.5 Hz, 2H), 7.30 (dd, J=1.7, 4.5 Hz, 2H), 7.23 (d, J=5.1 Hz, 1H), 6.88 (d, J=5.1 Hz, 1H) and 2.32 (s, 3H). This compound (3 g, 17.12 mmol) was dissolved in acetonitrile (100 mL) and NBS (3.047 g, 17.12 mmol) was added at RT. The reaction mixture was stirred at RT for 24 hours and the reaction quenched by adding an aqueous solution of Na2SO3 and saturated NaHCO3 solution. The resulting precipitate was collected and washed with water. After drying under high vacuum, 4-(5-bromo-3-methylthiophen-2-yl)pyridine (Compound 1067, 4 g, 92%) was obtained as yellow solid; ESMS (M+H)=254.05; 1H NMR (300 MHz, DMSO-d6): δ 8.74 (dd, J=1.5, 5.0 Hz, 2H), 7.78 (dd, J=1.5, 5.0 Hz, 2H), 7.46 (s, 1H) and 2.46 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([CH3:6])([OH:5])[CH3:4].C([Li])CCC.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:15](=[O:16])([O:5][C:3]([CH3:6])([CH3:4])[C:2]([F:8])([F:7])[F:1])[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (1.0 g) in THF (30 ml) was added a 2M solution of n-butyl lithium in n-hexane (3.9 ml) and then 4-nitrophenyl chloroformate (2.4 g) at −75° C. The mixture was warmed to room temperature and diluted with ethyl acetate, washed with water, dried over sodium sulfate, and filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc/Hexane) to give 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-yl carbonate as a pale yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]([S:22]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][N:29]=[CH:30]2)(=[O:24])=[O:23])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)(C)(C)C.[ClH:35].CO>>[ClH:35].[CH:30]1[C:31]2[C:26](=[C:25]([S:22]([N:12]([CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][CH2:10][CH2:9][NH2:8])(=[O:23])=[O:24])[CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NCCCN(CCCc1ccccc1)S(=O)(=O)c1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: NCCCN(CCCc1ccccc1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 0.42 h

Procedure:
Intermediate 2 (913 mg) was added with 10% hydrogen chloride/methanol solution (18 ml, Tokyo Kasei Kogyo) at room temperature and stirred for 25 minutes under reflux by heating. After the reaction, the solvent was evaporated under reduced pressure, and the residue was crystallized from a mixed solvent of methanol and diethyl ether to obtain the title compound (653 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11].[CH3:15][C:16]([OH:20])([C:18]#[CH:19])[CH3:17].[Cl-].[Na+]>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.[Cu]I.C(N(CC)CC)C>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([C:19]#[C:18][C:16]([OH:20])([CH3:17])[CH3:15])=[CH:13][C:6]=1[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11]
Reactant: COC(=O)NCc1cc(Br)ccc1Cl
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cc(C#CC(C)(C)O)ccc1Cl
Temperature: 90 °C
Reaction time: 30 h
Yield: 85.6 %

Procedure:
A mixture comprising 3.50 g of methyl N-(5-bromo-2-chlorobenzyl)carbamate, 2.11 g of 2-methyl-3-butyn-2-ol, 0.79 g of dichlorobis(triphenylphosphine)palladium, 0.38 g of copper(I) iodide and 40 ml of triethylamine, was stirred at 90° C. for 30 hours in an autoclave. This reaction solution was poured into a saturated sodium chloride aqueous solution and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.03 g of methyl N-[2-chloro-5-(3-hydroxy-3-methyl-1-butynyl)benzyl]carbamate as a brown viscous liquid.
Reaction SMILES: [H-].[Na+].Br[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17]1([CH2:23][C:24]([O:26][CH2:27]C)=[O:25])C=CC=CC=1.C(OCC)(=O)C=C>CCOCC.C(OC)(=O)C=C.O.CO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2([C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH:23]2[C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: COC(=O)C(Br)c1ccc(OC)cc1
Agent: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C=CC(=O)OC
Solvent: CO
Product: COC(=O)C1CC1(C(=O)OC)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred slurry of NaH (4.4 g, 60% in mineral oil) in anhydrous Et2O (0.3 I) was added methanol (10.3 mL) followed by a solution of bromo ester obtained in Prep. 3a, methyl bromo(4-methoxyphenyl)acetate (29 g) in methyl acrylate (19.8 mL) (for examples starting from an ethyl phenylacetate derivative ethanol and ethyl acrylate were used, respectively) and methanol (3 mL) at 0° C., over a 30 min. The mixture was stirred at 25° C. for 24 h and then unreacted NaH was decomposed with 3 mL methanol. Water was added (75 mL), the organic phase separated, dried over Na2SO4 and filtered. Volatiles were evaporated in vacuo to give 31.5 g of the title compound as an oil, which was used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:27][CH:26]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: O=C(Nc1cccc(F)c1C(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
In analogy to example 1,2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoic acid was prepared from 2-amino-6-fluoro-benzoic acid and 4-phenoxy-benzoyl chloride [1623-95-6]. MS (m/e): 350.1 (M−H−, 100%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=[O:6])[CH3:2].[CH:8]1[C:13]2=[N:14][S:15][N:16]=[C:12]2[C:11]([NH:17][C:18]2[NH:22][CH2:21][CH2:20][N:19]=2)=[C:10]([Cl:23])[CH:9]=1>C(O)(C)C>[CH:8]1[C:13]2=[N:14][S:15][N:16]=[C:12]2[C:11]([NH:17][C:18]2[NH:22][CH2:21][CH2:20][N:19]=2)=[C:10]([Cl:23])[CH:9]=1.[CH2:1]([O:3][CH2:4][C:5]([O-:7])=[O:6])[CH3:2]
Reactant: CCOCC(=O)O
Agent: Clc1ccc2nsnc2c1NC1=NCCN1
Solvent: CC(C)O
Product: CCOCC(=O)[O-]
Temperature: 2.5 °C

Procedure:
To a solution of 2.0 g of ethoxyacetic acid in 4 ml of isopropyl alcohol, 3.0 g of the tizanidine base (99.15% HPLC) are added. After brief heating to boil a solution results, from which a crystalline precipitated product starts to separate. After cooling to 0 to 5° C. and aspiration 3.8 g of tizanidine ethoxyacetate are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH3:27])[CH:34]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: COc1cc(B(O)O)ccn1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccnc(OC)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methoxy-4-pyridineboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=466 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=2[O:18][CH2:19][CH3:20])[C:5]2[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1.[C:27](OC)(=[O:30])[C:28]#[CH:29]>CO>[CH3:26][O:25][C:21]1[C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=3[O:18][CH2:19][CH3:20])=[N:7][CH2:8][C:2]3[N:3]([CH:29]=[CH:28][C:27](=[O:30])[N:1]=3)[C:4]=2[CH:24]=[CH:23][CH:22]=1
Reactant: CCOc1ccc(C2=NCC(N)=Nc3cccc(OC)c32)c(OCC)c1
Reactant: C#CC(=O)OC
Solvent: CO
Product: CCOc1ccc(C2=NCc3nc(=O)ccn3-c3cccc(OC)c32)c(OCC)c1

Procedure:
In the manner given in Example 1, 2-amino-6-methoxy-5-(2,4-diethoxyphenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 8-methoxy-7-(2,4-diethoxyphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[NH:15]1[CH2:25][CH2:24][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:16]1>>[CH2:22]([O:21][C:19]([CH:18]1[CH2:24][CH2:25][N:15]([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:16][CH2:17]1)=[O:20])[CH3:23]
Reactant: O=CCCc1ccc2c(n1)COC2=O
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(CCCc2ccc3c(n2)COC3=O)CC1
Yield: 82.7 %

Procedure:
In a process similar to that described in Preparation 8 3-(5-oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (76 mg, 0.4 mmol) and ethyl isonipecotate (62 μL, 0.4 mmol) are reacted to provide the title compound as white solid (110 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([N:6]=[C:23]=[O:25])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1c(Cl)cc(F)c(N)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(N=C=O)c1[N+](=O)[O-]

Procedure:
4-Chloro-6-fluoro-3-methoxy-2-nitroaniline (0.5 g, 2.27 mmol) was dissolved in anhydrous toluene (30 ml) and triethylamine (0.46 g, 4.54 mmol) was added. This solution was slowly added to a stirred solution of triphosgene (0.67 g, 2.27 mmol) in toluene (30 ml) and the solution refluxed for 2 hr. The solution was cooled and filtered. Clear filtrate was evaporated in vacuo to afford the title compound. 1H NMR (CDCl3, 3.00 MHz) 3.96 (3H, s), 7.38 (1H, d, J=8.8 Hz) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1[CH2:22][CH2:21][O:20][CH2:19]C1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH2:22][CH:21]1[O:20][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCOCC1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1CC1CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a solution of L-proline benzyl ester (156 mg, 0.49 mmol) in DMF (2 mL), cooled to 0° C., NMM (56 μL, 0.53 mmol) and HOBt (198 mg, 1.47 mmol) were added. The solution was stirred at 0° C. for 15 minutes and a solution of glycidic acid21 (100 mg, 1.13 mmol) in CH2Cl2 (2 mL) was added. Finally a solution of DCC (253 mg, 1.23 mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred 16 h at room temperature and filtered to remove the precipitate. The residue was diluted with CH2Cl2 (10 mL) and washed with 10% KHSO4 (10 mL), 5% NaHCO3 (10 mL) and NaCl (10 mL, sat), dried (Na2SO4), filtered and concentrated. The crude oil was purified by column chromatography (silica gel, EtOAc/Hexanes 1/1) to yield 120 (95 mg, 70%) as white foam. Rf 0.26 (AcOEt/Hexanes 1/1). 1H-NMR (500 MHz, CDCl3): mixture of rotamers 1.87-1.92 (m, 2H), 1.91-1.98 (m, 2H), 1.99-2.03 (m, 1H), 2.19-2.20 (m, 2H), 2.20-2.22 (m, 1H), 2.66-2.68 (m, 1H), 2.80-2.82 (m, 1H), 2.94-2.95 (m, 2H), 3.30-3.31 (m, 1H), 3.56-3.57 (m, 2H), 357-370 (m, 2H), 3.72-3.85 (m, 1H), 4.57-4.59 (m, 1H), 4.70-4.72 (m, 1H), 5.16 (s, 2H), 5.22-5.29 (m, 2H), 7.25-7.38 (m, 10H). 13C-NMR (125 MHz, CDCl3): 22.2, 24.9, 28.7, 30.9, 31.5, 45.9, 46.3, 46.4, 47.2, 48.0, 48.5, 58.7, 59.3, 66.9, 67.4, 128.1, 128.2, 128.4, 128.5, 128.7, 170.0, 182.3. HRMS m/z cald for C15H17NO4a (M+Na): 298.1055 found 298.1047.
Reaction SMILES: C([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[O:23]C2C=CC=C3C=2N(C(C2C=CC=CC=2)C2C=CC=CC=2)C(C)=C3)[CH:16]=[C:15]1[CH3:47])(C1C=CC=CC=1)C1C=CC=CC=1>CO.C1(C)C=CC=CC=1.[OH-].[Pd+2].[OH-]>[CH3:47][C:15]1[NH:14][C:22]2[C:17]([CH:16]=1)=[CH:18][CH:19]=[CH:20][C:21]=2[OH:23]
Reactant: Cc1cc2cccc(Oc3cccc4cc(C)n(C(c5ccccc5)c5ccccc5)c34)c2n1C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc2cccc(O)c2[nH]1
Yield: 50.1 %

Procedure:
Benzhydryl-2-methyl-1H-indol-7-yl-ether (85 mg, 0.271 mmol) in methanol (MeOH) (3 mL) and toluene (3 mL) was hydrogenated in the presence of 20% palladium hydroxide (Pd(OH)2) (40 mg) at 40 p.s.i for 70 min at room temperature. The catalyst was filtered off, filtrate concentrated and the residue purified by silica gel flash chromatography to give subtitled compound (20 mg).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[CH2:14]([O:16][C:17](=[O:36])[C@H:18]([CH3:35])[CH2:19][C@H:20]([NH2:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH3:15]>C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:36])[C@H:18]([CH3:35])[CH2:19][C@H:20]([N:34]=[C:2]=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH3:15]
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O
Reaction time: 0.25 h

Procedure:
To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (30 mL) at 0° C. is added triphosgene (114 mg, 0.384 mmol). After stirring the mixture at 0° C. for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 29: 400 mg, 1.15 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester.
Reaction SMILES: [Cu]C#N.[C:4]([Mg]Cl)([CH3:7])([CH3:6])[CH3:5].[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][N:17]=2)[CH:11]=1.[OH-].[NH4+]>C1COCC1>[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:18][N:17]=2)[CH:11]=1
Reactant: Brc1ccc(-c2cccc(-c3ccccc3)c2)nc1
Reactant: CC(C)(C)[Mg]Cl
Agent: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cccc(-c3ccccc3)c2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a suspension of copper(I) cyanide (17.3 g, 11 mmol) in 1730 mL of anhydrous THF in an oven-dried, five liter, three-necked flask equipped with a mechanical stirrer and a nitrogen inlet was added tert-butylmagnesium chloride (200 mL, 2.0 M, 400 mmol) via an addition funnel, and the mixture was stirred at −78° C. for 30 min. A solution of 2-(biphenyl-3-yl)-5-bromopyridine (15.0 g, 48 mmol) in 100 mL of dry THF was then added dropwise, and the mixture was stirred for 3 hours at −78° C. and then overnight at room temperature. Saturated aqueous ammonium hydroxide was then added to quench the reaction mixture, the pH was adjusted to 10 with aqueous sodium hydroxide, and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and evaporated to dryness to give 9.0 g of light yellow liquid that was purified by flash silica gel chromatography with a 2.5/97.5 to 7.5/92.5 ethyl acetate/hexane gradient as the eluent, affording 2.6 g (19%) of 2-(biphenyl-3-yl)-5-tert-butylpyridine as a colorless liquid.