Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1>CN(C)C=O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: COc1ncc(Br)cc1Br
Solvent: CN(C)C=O
Product: COc1ncc(Br)cc1-c1ccccn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
100 ml of a dimethylformamide solution containing 6.3 g of 3,5-dibromo-2-methoxypyridine and 8.1 g of 2-tributyl stannyl pyridine was incorporated with 1.0 g of tetrakistriphenylphosphine palladium, followed by stirring at 120° C. for 2 hours in nitrogen atmosphere. After the mixture was returned to room temperature, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1:3), to give 2.8 g of the title compound as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.[CH3:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:24]=1[NH2:25].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC([O-])(C)C.[Na+]>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].O.C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:24]=1[NH:25][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2
Reactant: Cc1cccc(C)c1N
Reactant: Brc1cccc2ccc(-c3cccc4ccccc34)nc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1Nc1cccc2ccc(-c3cccc4ccccc34)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 8-bromo-2-(1-naphthyl)quinoline (2.03 g, 6 mmol), 2,6-dimethylaniline (0.83 mL, 6.9 mmol), Pd(dba)2 (0.072 g, 0.12 mmol), L=(N-[2′-(dicyclohexylphosphino)[1,1′-biphenyl]-2-yl]-N,N-dimethylamine) (0.094 g, 0.24 mmol), NaOtBu (0.72 g, 7.2 mmol) and toluene (15 mL) is stirred for 8 h under an argon atmosphere at 100° C. in an oil bath. The mixture is then poured into water and extracted with benzene (3×50 mL). The combined organic phase is washed with water and brine, and then concentrated. The residue is purified by column chromatography (silica gel 40, hexane/toluene 2:1). Yield: 1.59 g (71%).
Reaction SMILES: [C:1]([CH:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].[OH:28]O.[OH-].[Na+]>C(Cl)(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C@H:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:28])[NH2:2]
Reactant: OO
Reactant: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 20.4 %

Procedure:
In 40 ml of chloroform is dissolved 3.54 g of (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone as obtained in Example 20 and, following addition of 3.4 g of tetra-n-butylammonium hydrogen sulfate, 2.3 g of 30% hydrogen peroxide and 15 ml of 1N sodium hydroxide are added under ice-cooling and stirring. The mixture is stirred vigorously for 30 minutes and the organic layer is taken out, while the aqueous layer is extracted twice with chloroform. The organic layers are combined, washed with water and treated in the same manner as Example 19 to give 0.76 g of (3S,4S)-4-carbamoyl-3-tritylamino-2-azetidinone. The IR and NMR spectra of this compound are identical with those of the compound obtained in Example 17.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:16]=2)=[C:11]([Cl:31])[CH:10]=1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[OH-].[OH-].[Pd+2]>[Cl:31][C:11]1[CH:10]=[C:9]([NH2:8])[CH:14]=[CH:13][C:12]=1[C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[N:22]2)=[C:17]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:16]=1
Reactant: Clc1cc(NCc2ccccc2)ccc1-c1cc2ncccc2c(N2CCOCC2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Nc1ccc(-c2cc3ncccc3c(N3CCOCC3)n2)c(Cl)c1
Temperature: 80 °C

Procedure:
To a mixture of 4 and benzyl-[3-chloro-4-(5-morpholin-4-yl-[1,6]naphthyridin-7-yl)-phenyl]-amine (164 mg, 0.32 mmol, 1 eq) in dry EtOH (3 mL) was added Pd(OH)2 (60 mg, 40% w/w) and 1,4-cyclohexanediene (600 μL, 6.30 mmol, 20 eq) under Ar(g). The mixture was heated at 80° C. overnight. Additional quantities of Pd(OH)2 (60 mg, 40% w/w) and 1,4-cyclohexanediene (400 μL, 4.10 mmol, 15 eq) were added, and the mixture was again heated at 80° C. overnight. Once cooled down, the reaction mixture was filtered through a short celite pad, eluted with MeOH (10 mL). The solvent was removed in vacuo and the residue was further purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (1:0-49:1), to furnish the product, F, as a pale yellow solid (8.1 mg, 8%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH3:21])[C:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CCO>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[C:11]1[N:10]([CH3:21])[C:9]2[CH:22]=[CH:23][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[N:12]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1c(Cl)cccc1Cl)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(-c2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (400 mg) in EtOH (8 mL) was added 1.0 N NaOH (2.0 mL) and the mixture was stirred at 60° C. for 90 min. The ethanol was removed under reduced pressure and water (10 mL) was added. Any insoluble material was filtered and 2.0N HCl (2.0 mL) was added to the filtrate. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid as a white solid, mp>250° C.; MS (m/z) 321 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[CH2:13])[C:11]3([CH2:18][CH2:17][N:16]([C:19](OC4C=CC=CC=4)=[O:20])[CH2:15][CH2:14]3)[O:10][C:9]2=[O:28])=[CH:4][CH:3]=1.[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[CH2:13])[C:11]3([CH2:14][CH2:15][N:16]([C:19]([N:35]4[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][OH:29])[CH2:33][CH2:34]4)=[O:20])[CH2:17][CH2:18]3)[O:10][C:9]2=[O:28])=[CH:6][CH:7]=1
Reactant: C=C1N(c2ccc(Cl)cc2)C(=O)OC12CCN(C(=O)Oc1ccccc1)CC2
Reactant: OCCN1CCNCC1
Solvent: Cc1ccccc1C
Product: C=C1N(c2ccc(Cl)cc2)C(=O)OC12CCN(C(=O)N1CCN(CCO)CC1)CC2
Yield: 67 %

Procedure:
A mixture containing 4.0 g of 3-(4-chlorophenyl)-4-methylene-2-oxo-8-phenoxycarbonyl-1-oxa-3,8-diazaspiro[4,5]decane and 6.13 ml of N-(2-hydroxyethyl)piperazine in 20 ml of ortho-xylene is refluxed under nitrogen for 60 hours. After cooling down, the reaction mixture is diluted with 20 ml of xylene and the organic solution is washed first with an aqueous saturated sodium chloride solution containing 5% by weight of sodium hydroxide and then with aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and then evaporating the solvent under reduced pressure the crude product obtained is recrystallized from a mixture of benzene and hexane under clarifying by activated carbon to give the title compound in 67% yield, m.p.: 185°-186° C.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH2:20][O:21][Si](C(C)(C)C)(C)C)[C@H:11]1[O:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCOC(C)=O.CO>CO>[C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH2:20][OH:21])[C@H:11]1[O:29][C:30](=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1N[C@@H]2[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H](CO)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a suspension of (3 aS,4R,5R,6R,7aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (3.29 g, 6.27 mmol) in dry MeOH (50 mL) at room temperature was added a solution of HCl in 4:1 EtOAc-MeOH (1.5 M, 28 mL, 41.8 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 60-80% EtOAc in hexanes to give (3aS,4R,5R,6R,7aS)-6-(hydroxymethyl)-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (1.87 g, 73%). MS m/z 434.1 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=7.8 Hz, 2H), 7.87 (d, J=7.8 Hz, 2H), 7.49 (t, J=7.8 Hz, 2H), 7.33 (t, J=7.8 Hz, 4H), 6.37 (s, 1H), 5.45 (dd, J=9.7 Hz, 6.8 Hz, 1H), 5.31 (t, J=10.0 Hz, 1H), 4.90-4.92 (m, 1H), 3.88 (t, J=6.8 Hz, 1H), 3.74 (dd, J=12.1 Hz, 2.5 Hz, 1H), 3.57 (dd, J=12.1 Hz, 2.0 Hz, 1H), 2.39 (d, J=13.8 Hz, 1H), 2.19-2.32 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:22]=3)[CH2:9]2)[N:5]=[C:4]([NH2:23])[N:3]=1.[F:24][C:25]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:23][C:4]1[N:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:24])[CH:32]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:22]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc4cnccc4[nH]3)C2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc5cnccc5[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A mixture of 4-chloro-6-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-4-morpholinyl]-2-pyrimidinamine (403 mg, 1.21 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (390 mg, 1.58 mmol), Na2CO3 (322 mg, 3.04 mmol) and Pd(PPh3)4 (140 mg, 0.121 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave conditions with stirring for 1 hour. The mixture was filtered, washed by EtOAc (150 mL), and evaporated to give a yellow solid which was chromatographed to afford the title compound (430 mg) as a yellow solid. LC-MS (ES) m/z=417 [M+H]+.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([OH:12])=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:9]([C:5]1[C:4]([OH:12])=[C:3]([NH:2][S:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH:8]=[CH:7][CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cccc(C(C)=O)c2O)cc1
Reaction time: 18 h
Yield: 83.4 %

Procedure:
A solution of 3'-amino-2'-hydroxyacetophenone hydrobromide (1.282 g, 5.52 mmol) in pyridine (25 ml) was added at 0° C. with 4-methoxybenzenesulfonyl chloride (1.18 g, 5.71 mmol) dissolved in the minimum amount of pyridine and the mixture was left at room temperature for 18 h. Afterwards it was evaporated to dryness, redissolved in dichloromethane, washed with 1M HCl, dried and the solvent was evaporated off under reduced pressure, thereby obtaining 1.479 g of the title compound (81% yield).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[CH3:8][S:9][C:10](SC)=[CH:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O>CC(O)C>[CH3:8][S:9][C:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[NH:7][C:5](=[O:6])[C:4]=1[C:2]#[N:3]
Reactant: CSC(=CC(=O)c1cccnc1)SC
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CC(C)O
Product: CSc1cc(-c2cccnc2)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
Sodium (0.408 g, 17.75 mmol) was added to 2-propanol (100 mL) and the mixture was stirred at room temperature under nitrogen for 24 h. Additional sodium (0.25 g) was added. After 17 h at room temperature, the mixture was heated to 60° C. for 1 h to dissolve the rest of the Na metal and then cooled to room temperature. 2-Cyanoacetamide (2.15 g, 25.6 mmol) was added. After 30 min at room temperature, 3,3-bis(methylthio)-1-(pyridin-3-yl)prop-2-en-1-one (5.7124 g, 25.4 mmol) was added. The mixture was stirred at room temperature for 30 min, at reflux for 2 h, and concentrated. The solid residue was dissolved in water (100 mL) and acidified with aqueous HCl (0.3 N, 100 mL) to give a suspension. The brown solid was collected by filtration and dried under vacuum to give 4-(methylthio)-2-oxo-6-(pyridin-3-yl)-1,2-dihydropyridine-3-carbonitrile (5.1267 g, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.68 (1H, br. s), 9.03 (1H, s), 8.74 (1H, dd, J=4.77, 1.51 Hz), 8.24 (1H, δ, J=8.03 Hz), 7.59 (1H, dd, J=8.03, 4.77 Hz), 6.70 (1H, br. s), 2.71 (3H, s); MS (ES+) m/z: 244 (M+H); LC retention time: 1.912 min (analytical HPLC Method A).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]1[NH:29][CH:30]=[C:31]([CH2:33][OH:34])[N:32]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]1[NH:29][CH:30]=[C:31]([CH:33]=[O:34])[N:32]=1
Reactant: OCc1c[nH]c(-c2cccs2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1c[nH]c(-c2cccs2)n1
Temperature: 25 °C

Procedure:
Dess-Martin periodinane (4.71 g, 11.1 mmol) was added to a stirred suspension of (2-Thiophen-2-yl-1H-imidazol-4-yl)-methanol (2.00 g, 11.1 mmol) dissolved in Methylene chloride (111 mL) at rt under Ar. The mixture turned dark and was stirred at rt ON. More DCM (100 ml) and sat NaHCO3 (100 mL) were added and the phases were separated after filtration to remove some solid. The organic layer was loaded onto silica gel and was purified by silica gel chromatography (Eluent: 0-100% EtOAc in n-heptane). Yield 0.57 g of the title compound as a red solid. LC-MS: m/z=178.6 (MH+), tR=0.31 min, method C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20](O)=[O:21])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH2:67]([CH2:69][NH2:70])[OH:68]>CN(C=O)C>[OH:68][CH2:67][CH2:69][NH:70][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:28][CH:27]=3)=[N:10][C:11]=2[CH:17]=1
Reactant: NCCO
Reactant: O=C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
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: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
A mixture of 2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-benzoic acid (0.050 g, 0.121 mmol), BOP (0.059 g, 0.133 mmol), DIPEA (0.07 mL, 0.363 mmol) and ethanolamine (0.011 g, 0.182 mmol) in DMF (0.5 mL) was stirred at rt for 12 hours. The crude product was purified by chromatography (silica, CH2Cl2: MeOH, 5:1) to afford the title compound as a brown oil (0.043 g, 78%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.64-7.59 (m, 3H), 7.54-7.46 (m, 4H), 7.41 (td, 1H, J=8.2 Hz, J=1.6 Hz), 7.35 (dd, 1H, J=8.0 Hz, J=1.6 Hz), 7.15 (d, 2H, J=8.0 Hz), 5.42 (s, 2H), 5.24 (s, 1H), 3.91 (t, 2H, J=6.0 Hz), 3.24 (t, 2H, J=6.2 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H21F3N3O3: 456.4 (M+H), Found 456.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:22][CH2:23][CH3:24]>>[CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:22][CH2:23][CH3:24]
Reactant: CCC
Reactant: COC(=O)C=Cc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCOc1cc(F)ccc1C=CC(=O)OC
Yield: 100 %

Procedure:
3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (110.5 mg) was reacted with K2CO3 (111 mg) and propane iodide (0.1 ml) at 80° C. overnight as described above to yield title compound (134 mg, 100%)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[C:17]([C:24]([N:26]([C:37]3[CH:42]=[CH:41][C:40]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])=[CH:39][CH:38]=3)[C:27]3[CH:28]=[C:29]4[CH:35]=[CH:34][N:33]([CH3:36])[C:30]4=[N:31][CH:32]=3)=[O:25])[CH:16]=2)=[C:11]([C:51]([N:53]2[C@H:62]([CH2:63][N:64]3[CH2:69][CH2:68][O:67][CH2:66][CH2:65]3)[CH2:61][C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:54]2)=[O:52])[CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[Si:44]([O:43][C:40]1[CH:41]=[CH:42][C:37]([N:26]([C:27]2[CH:28]=[C:29]3[CH:35]=[CH:34][N:33]([CH3:36])[C:30]3=[N:31][CH:32]=2)[C:24]([C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=3[C:51]([N:53]3[C@H:62]([CH2:63][N:64]4[CH2:65][CH2:66][O:67][CH2:68][CH2:69]4)[CH2:61][C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH2:54]3)=[O:52])[N:23]3[C:18]=2[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:25])=[CH:38][CH:39]=1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCc5ccccc5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(O)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Reaction time: 15 h

Procedure:
0.9 g of Pd/C 10% is added to a solution, in 100 mL of ethanol, of 8.88 g (8.4 mmol) of the compound obtained in Step C, whilst bubbling through argon. The reaction mixture is placed under 1.2 bars of hydrogen at ambient temperature for 15 hours. The catalyst is filtered off and the solvent is evaporated off under reduced pressure to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([I:30])[C:21]=3[C:31]3[CH:32]=[C:33]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([O:47]C)=[O:46])=[CH:41][C:40]=4[CH3:49])[CH:34]=[CH:35][C:36]=3[O:37][CH3:38])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O[Li].O.CCOC(C)=O.CCCCCC>O1CCOCC1>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([I:30])[C:21]=3[C:31]3[CH:32]=[C:33]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][C:40]=4[CH3:49])[CH:34]=[CH:35][C:36]=3[O:37][CH3:38])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3c(I)cc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1c(I)cc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the title compound from Step G (0.016 g, 0.0188 mmol) in dioxane (2 ml) at room temperature, an aqueous solution of LiOH.H2O (0.007 g, 0.16 mmol) (1 ml) was added. The mixture was stirred at room temperature for 5 h. TLC (EtOAc:hexane/2:8) showed no starting material. The solvent was removed. 1N HCl (1 ml) was added. The mixture was extracted with EtOAc (3×15 ml). The combined EtOAc layers were dried over sodium sulfate. The title compound was obtained by preparative reverse phase HPLC. 1H NMR (CDCl3, 500 MHz): δ2:1 mixture of atropisomers 8.21 (s, 1H), 8.01 (s, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.89 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.45 (m, 1H), 7.37 (m, 1H), 7.14 (m, 1H), 7.00 (m, 1H), 5.60 (d, J=8 Hz, 0.66H), 5.54 (d, J=8 Hz, 0.33H), 4.82 (d, J=7.5 Hz, 0.33H), 4.79 (d, J=8 Hz, 0.66H), 3.99 (d, J=10 Hz, 0.33H), 3.96 (d, J=9.5 Hz, 0.66H), 3.91 (m, 1H), 3.90 (s, 2H), 3.86 (s, 1H), 2.42 (s, 1H), 2.41 (s, 2H), 0.60 (d, J=7 Hz, 1H), 0.55 (d, J=6.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: Cc1ccc(F)c(N)c1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1ccc(F)c(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-fluoro-5-methylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-fluoro-5-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (77%) as a colorless solid: mp 214-216° C.; 1H NMR (300 MHz, CDCl3) δ 8.25-8.06 (m, 2H), 7.65-7.57 (m, 1H), 7.47-7.33 (m, 2H), 7.33-7.26 (m, 1H), 7.22-7.12 (m, 2H), 7.07-6.86 (m, 4H), 6.46 (s, 1H), 6.40 (s, 1H), 5.27 (s, 2H), 4.95 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.52 (t, J=8.7 Hz, 2H), 2.96 (t, J=8.5 Hz, 2H), 2.36 (s, 3H); MS (ES+) m/z 543.1 (M+23).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:19]([NH:25][NH2:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1>C(O)(=O)C>[Cl:17][C:18]1[C:19]([N:25]=[N:26][C:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[OH:16])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: NNc1ncc(Cl)cc1Cl
Solvent: CC(=O)O
Product: Oc1c(N=Nc2ncc(Cl)cc2Cl)c2ccccc2c2ccccc12
Temperature: 105 °C

Procedure:
Next, a reaction flask was loaded with acetic acid (15 ml) and 9,10-phenanthrenequinone (5.0 g), and the temperature was raised to 105° C. with stirring to dissolve 9,10-phenanthrenequinone. To the resultant, the crystals of 3,5-dichloro-2-hydrazinopyridine (4.6 g) was added in 30 minutes. After stirring at 105 to 110° C. for one hour, the reaction mixture was filtrated. The filtrated crystals were washed with methanol, and then dried to give intended crystals (5.1 g).