Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si:4]([CH3:18])([CH3:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[OH-].[K+].Cl>CO>[CH2:1]([Si:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)([CH3:18])[CH3:17])[CH:2]=[CH2:3]
Reactant: C=CC[Si](C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc([Si](C)(C)CC=C)cc1
Reaction time: 0.67 h
Yield: 89.8 %

Procedure:
1.36 g (5 mmol) of 1-(allyldimethylsilanyl)-4-trimethylsilanylethynyl benzene was suspended in 5 mL of methanol and 5 mL of methanol solution containing 330 mg (5 mmol) of potassium hydroxide was added to the resultant suspension at a temperature of 0° C. and stirred for 40 minutes. Further, the resultant solution was turned acidic by adding 5 mL of 1M hydrochloric acid thereto and subjected to extraction using ether. The organic layer thus created was then washed with saturated sodium hydrogen carbonate and also with saturated brine and dried using magnesium sulfate as a desiccating agent. After the desiccating agent was removed by filtration, the solvent was removed a rotary evaporator to obtain a crude product, which was then purified by silica gel column chromatography (developing solvent: hexane) to obtain 0.90 g (4.49 mmol) of allyl-(4-ethynyl-phenyl)-dimethyl silane (3a), which was colorless and oily. The yield was 90%.
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.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=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:29]5[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=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: OB(O)c1cccnc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cccnc5)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 pyridine-3-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.08 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:25]2[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:5][C:4]([CH3:15])([CH3:14])[C:3](=[O:16])[C:2]=2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:41][CH:42]=2)=[CH:8][CH:9]=1
Reactant: CC1(C)OC(c2ccc(Cl)cc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(Cl)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 34.6 %

Procedure:
A solution of 4-bromo-5-(4-chlorophenyl)-2,2-dimethylfuran-3(2H)-one (1.0 g, 3.30 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (1.30 g, 3.60 mmol), and Cs2CO3 (5.37 g, 16.50 mmol) in toluene (10 mL) and water (5 mL) was degassed. Then, Pd(dppf)C2 (0.54 g, 0.601 mmol) was added under an inert atmosphere and the solution was degassed again. The reaction mixture was then refluxed for 2 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4-chlorophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (520 mg, 35%) as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J=8.5 Hz, 1H), 8.02 (t, J=7.9 Hz, 2H), 7.81 (t, J=8.4 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.63 (t, J=8.2 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.18 (d, J=7.4 Hz, 2H), 7.11 (d, J=7.5 Hz, 2H), 5.39 (s, 2H), 1.44 (s, 6H). MS: [M+Na]: m/z=478.1, [M+H]: m/z=456.1. HPLC: 97%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [OH:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[CH2:18]([O:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[F:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C

Procedure:
20 g of 4-hydroxy-3,5-difluorobenzaldehyde are dissolved in dimethylsulfoxide, and potassium carbonate and benzyl chloride are added thereto. After the mixture is stirred at room temperature, water is added thereto. The mixture is extracted with ethyl acetate and evaporated to remove the solvent. The residue is purified by silica gel column chromatography to give 17.4 g of 4-benzyloxy-3,5-difluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[CH:35]=O)[CH:28]=[CH:27]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:33]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:34]=2[N:26]([CH3:25])[CH:27]=[CH:28]3)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: Cn1ccc2cccc(C=O)c21
Product: Cn1ccc2cccc(CNc3cccc(-c4c(-c5ccccc5)nnc5c(Cl)cccc45)c3)c21

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 1-methyl-1H-indole-7-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 474.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[N-:14]=[N+]=[N-].[Na+].C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][NH:14][C:10](=[O:13])[C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1)C(=O)NCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-one (5.21 g) in conc. hydrochloric acid (26 ml) was added sodium azide (1.98 g) by portions with ice-cooling, and the mixture was stirred at the same temperature for 2 hours, and then at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water and aqueous potassium carbonate was added. The mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and dried under reduced pressure to give the title compound (470 mg).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]([CH:22]([CH3:24])[CH3:23])[C:14]3=[O:25])=[N:11][C:7]=2[CH:6]=1)=[NH:4].B(F)(F)F.[CH3:37]COCC>C(OC)(OC)OC>[CH:22]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:13]([CH2:12][C:10]2[N:9]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:8]3[CH:31]=[CH:32][C:5]([C:3]4[N:4]=[CH:37][O:1][N:2]=4)=[CH:6][C:7]=3[N:11]=2)[C:14]1=[O:25])([CH3:23])[CH3:24]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=N)NO)ccc21
Reactant: CCOCC
Agent: FB(F)F
Solvent: COC(OC)OC
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(-c3ncon3)ccc21
Temperature: 80 °C
Yield: 53 %

Procedure:
A solution of N-hydroxy-2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine (65 mg, 0.15 mmol) in trimethyl orthoformate (4 mL) in the presence of BF3.OEt2 (5 μL) in a sealed tube was placed in a microwave oven (Smith Creator, Personal Chemistry) and heated at 80° C. for 5 min while stirring. The solvent was removed in vacuo and purified by flash chromatography (eluent hexane-acetone 3:1) to give 1-isopropyl-3-[1-(3-methyl-butyl)-5-[1,2,4]oxadiazol-3-yl-1H-benzoimidazol-2-ylmethyl]-1,3-dihydro-benzoimidazol-2-one (35 mg, 53%) as a white solid:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=[O:8].[H-].[Na+].[CH3:12]I.O>CN(C)C=O>[CH3:12][O:8][C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: Cn1cccc1C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccn1C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The solution of 1,325 g of 1-methylpyrrole-2-carboxylic acid in 2,400 ml of dimethylformamide is added to the suspension prepared from 568.5 g of 50% sodium hydride in mineral oil and 2,400 ml of dimethylformamide, while stirring under nitrogen and cooling with ice. Thereupon 1,000 ml of dimethylformamide are added, followed by 4,316 g of methyl iodide while stirring and keeping the temperature below 88°. Stirring is continued overnight at room temperature, whereupon the mixture is cooled to 10° and combined with 10,600 ml of water. It is extracted thrice with 5,300 ml of diethyl ether, the extract washed with 5,300 ml of 10% aqueous sodium carbonate and 5,300 ml of water, dried and evaporated, to yield the 1-methylpyrrole-2-carboxylic acid methyl ester as an oil.
Reaction SMILES: C([O:9][CH2:10][C@:11]12[C@@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:14]([O:15][CH2:16]1)[C@H:13]([N:26]1[CH:34]=[N:33][C:32]3[C:31](=[O:35])[NH:30][CH:29]=[N:28][C:27]1=3)[O:12]2)(=O)C1C=CC=CC=1.[OH-].[Na+].C(O)(=O)C>CO>[CH2:19]([O:18][C@H:17]1[C@H:14]2[O:15][CH2:16][C@:11]1([CH2:10][OH:9])[O:12][C@H:13]2[N:26]1[CH:34]=[N:33][C:32]2[C:31](=[O:35])[NH:30][CH:29]=[N:28][C:27]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OC[C@]12CO[C@@H]([C@H](n3cnc4c(=O)[nH]cnc43)O1)[C@@H]2OCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2OCc1ccccc1

Procedure:
To a solution of compound 22 in methanol (20 mL) was added 2M NaOH (2 mL) and 15 min later acetic acid (2 mL). The mixture was cooled in ice-bath, the precipitate was filtered off, washed with water and dried in vacuo. Yield: 0.69 g (85%) of compound 23 as a white solid material.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.S(Cl)(Cl)=O.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][CH2:35][CH:34]([CH3:37])[N:33]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[C:32]=2[CH:43]=1.C(N(CC)CC)C>ClCCl>[CH3:41][N:40]([CH3:42])[CH2:39][CH2:38][N:33]1[C:32]2[CH:43]=[C:28]([NH:27][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:3]4[CH:4]=[CH:5][C:6]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:7][C:2]=4[CH3:1])=[CH:19][CH:18]=3)=[O:21])[CH:29]=[CH:30][C:31]=2[O:36][CH2:35][CH:34]1[CH3:37]
Reactant: CC1COc2ccc(N)cc2N1CCN(C)C
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc5c(c4)N(CCN(C)C)C(C)CO5)cc3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.3 %

Procedure:
2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268A1) (77 mg, 0.26 mmol) was treated with thionyl chloride (5 ml) and the mixture heated under reflux under Ar for 1 hour, then concentrated in vacuo to afford a yellow solid. This was dissolved in dichloromethane (5 ml) and treated with a solution of 6-amino-3,4-dihydro-4-(2-dimethylaminoethyl)-3-methyl-2H-1,4-benzoxazine (D14, 61.7 mg, 0.26 mmol) and triethylamine (0.11 ml, 0.78 inmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature under Ar for 24 hours, then washed with brine/saturated potassium carbonate solution (30 ml of a 1:1 solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to afford a brown oil. This was chromatographed on SiO2, eluting with 0-8% methanol/dichloromethane to afford the title compound as a light yellow oil (72.2 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[SH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1Sc1ccc(O)cc1
Temperature: 100 °C
Yield: 107.3 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (0.44 g, 2.0 mmol), 4-mercaptophenol (0.303 g, 2.4 mmol), and cesium carbonate (1.56 g, 4.8 mmol, 2.4 eq) in dimethylformamide (10 mL) was heated in a 100° C. oil bath for 3 hours and then cooled to room temperature. The reaction mixture was poured over ice water (50 mL), adjusted to pH 3 by the addition of 1N aqueous hydrochloric acid, and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated to provide the title compound as a thick yellow oil (0.70 g, >100%) that was utilized without further purification.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C([O-])([O-])=O.[Na+].[Na+].O.Cl>O1CCOCC1>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
(−)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.00 g, 2.6 mmol, prepared in example 1a), 4-carboxybenzene boronic acid (485 mg, 2.9 mmol), Na2CO3/H2O (4.4 mL, excess), tetrakis(triphenyl phosphine)palladium(0) (206 mg, 0.2 mmol) and dioxane (20 mL) were mixed together in a 50 mL single neck flask and stirred at 80° C. for 4 hours. The reaction was cooled to room temperature and poured into 1N HCl and the desired product was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 871 mg as a foam. This material was purified via silica gel chromatography employing the chromatotron and using a 4000 micron rotor while eluting with a solvent of methylene chloride/methanol 9:1 to yield the title compound (500 mg, 51%) as a tan solid. Ion spray M.S. 378.1 (M*−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[C:35]2[C:30](=[CH:31][C:32]([NH2:36])=[CH:33][CH:34]=2)[NH:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:36][C:32]3[CH:31]=[C:30]4[C:35]([C:27]([C:26]([F:38])([F:37])[F:25])=[N:28][NH:29]4)=[CH:34][CH:33]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc2c(C(F)(F)F)n[nH]c2c1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc2c(C(F)(F)F)n[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
82 mg (0.23 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 51 mg (0.25 mmol, 1.1 eq.) of 3-(trifluoromethyl)-1H-indazole-6-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 30 mg (25% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15]I>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][CH2:14][C:13]([F:18])([F:17])[F:12])[N:6]=[C:5]2[I:11]
Reactant: Clc1ccc2[nH]nc(I)c2c1
Reactant: FC(F)(F)CCI
Product: FC(F)(F)CCn1nc(I)c2cc(Cl)ccc21
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 5-chloro-3-iodo-indazole and 1,1,1-trifluoro-3-iodopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.73-2.85 (2H, m), 4.59 (2H, t, J=7.2 Hz), 7.31 (1H, d, J=9.2 Hz), 7.43 (1H, dd, J=1.6, 8.4 Hz), 7.48 (1H, d, J=1.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[CH:23][C:24]3[N:28]=[C:27]([C@@H:29]4[CH2:34][C@@H:33]5[C@@H:31]([CH2:32]5)[N:30]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[NH:26][C:25]=3[CH:42]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:22]1[CH:21]=[CH:42][C:25]3[N:26]=[C:27]([C@@H:29]4[CH2:34][C@@H:33]5[C@@H:31]([CH2:32]5)[N:30]4[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[NH:28][C:24]=3[CH:23]=1)[CH:6]=[N:5]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: Clc1cnc2cc(Br)ccc2n1
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: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3cnc4cc(Br)ccc4n3)cc2[nH]1
Temperature: 110 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
Pd(Ph3P)4 (28.5 mg, 0.025 mmol) was added to a degassed solution of 6-bromo-2-chloroquinoxaline (60 mg, 0.246 mmol), (1R,3S,5R)-tert-butyl 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (115 mg, 0.271 mmol) and sodium bicarbonate (62.1 mg, 0.739 mmol) in dioxane (1 mL) and H2O (0.2 mL) and the mixture was stirred at 110° C. for 2 h and then at 120° C. for 2 h. The reaction was diluted with MeOH, filtered and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield (1R,3S,5R)-tert-butyl 3-(6-(6-bromoquinoxalin-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (102.2 mg, 0.202 mmol, 82% yield) as bright yellow solid. LC-MS retention time 2.31 min; m/z 506 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[O:19][CH:20]=[C:21]([C:23](O)=[O:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:11].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.CC1C=CC(C)=CC=1CC(N1CCC(C2SC=C([C:67]([N:69](C)[C@@H:70]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[CH2:71][CH3:72])=O)N=2)CC1)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([N:69]([CH3:67])[C@@H:70]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[CH2:71][CH3:72])=[O:24])[N:22]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Reactant: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(C(=O)O)co3)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1coc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-[1-[(2,5-dimethylphenyl)acetyl]-4-piperidinyl]-4-oxazolecarboxylic acid (i.e. the product of Example 9, Step F) (245 mg, 0.72 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 80 mmol) and 4-methylmorpholine (88 μL) in 3 mL of dichloromethane were stirred at room temperature for 15 minutes. (α,R)-α-Ethyl-N-methylbenzenemethanamine (i.e. the product of Example 1, Step C) (0.80 mmol, 119 mg) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with dichloromethane, washed with 1 N aqueous hydrochloric acid and water, dried over MgSO4 and concentrated under reduced pressure. The products were purified by silica gel chromatography using 50-100% ethyl acetate in hexanes as eluant to give 90 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH2:8][C:7]2=[O:20])([O-:3])=[O:2].CO.[BH4-].[Na+]>O>[N+:1]([C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH2:8][CH:7]2[OH:20])([O-:3])=[O:2]
Reactant: COCC1(C)CC(=O)c2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC1(C)CC(O)c2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To 10 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman-4-one, 100 ml of methanol was added and 1.3 g of sodium borohydride was added at 0° C., followed by stirring at 0° C. for one hour. The reaction solution was poured into water and then extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, 10.1 g of the objective compound was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][O:20][CH2:21]3)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH2:31][CH2:32][O:33][CH2:34][CH:35]=1)CCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:33]1[CH2:32][CH:31]=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:5]=[C:4]([N:17]3[CH:18]4[CH2:24][CH2:23][CH:22]3[CH2:21][O:20][CH2:19]4)[CH:3]=2)[CH2:35][CH2:34]1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3C4CCC3COC4)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc(C3=CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Temperature: 150 °C
Yield: 65.6 %

Procedure:
In a 20 mL microwave vial was placed 8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (36, 500 mg, 1.442 mmol) in toluene (15 ml) to give a yellow suspension. The mixture was degassed with a stream of nitrogen and tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (646 mg, 1.730 mmol) and Pd(PPH3)4 (167 mg, 0.144 mmol) were added. The reaction mixture was heated under microwave irradiation at 150° C. for 1 hour. The mixture was concentrated and the crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (25-70%). Collected fractions were concentrated to give 373 mg of a yellow solid. HRMS: 395.1707 [M+H]+. For [M+H]+ mass error=−0.6 mDa or −1.51 ppm.