Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[N:10][CH:11]=1)(C)C.C(Cl)Cl.[Si]([C:24]#[N:25])(C)(C)C>[I-].[I-].[Zn+2].O>[CH:14]([O:13][CH:5]([C:6]1[CH:11]=[N:10][C:9]([CH3:12])=[N:8][CH:7]=1)[C:24]#[N:25])([CH3:15])[CH3:16]
Reactant: Cc1ncc(C(OC(C)C)OC(C)C)cn1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: Cc1ncc(C(C#N)OC(C)C)cn1
Reaction time: 24 h

Procedure:
A solution of 5-diisopropoxymethyl-2-methyl-pyrimidine (335 mg, 1.49 mmol) in DCM (5 mL, 80 mmol) was cooled at 0° C. Zinc diiodide (47.7 mg, 0.149 mmol) TMSCN (219 uL, 1.64 mmol) were added and cooling removed. After stirring for 24 hours TLC indicated that starting materiale was present. TMSCN (60 uL, 0.45 mmol) and zinc diiodide (48 mg, 0.15 mmol) were added and the reaction was stirred for a further 3.5 hours. The reaction was poured into water (20 mL) and extracted with DCM (3×20 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography 2-Isopropoxy-2-(2-methylpyrimidin-5-yl)acetonitrile (217 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([OH:11])[CH:3]=1.S(Cl)([Cl:14])=O.CN(C)C=O>CCCCCCC>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: O=S(Cl)Cl
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1O
Temperature: 60 °C
Yield: 84.7 %

Procedure:
A suspension of 4-fluoro-2-hydroxy-benzoic acid (15 g, 96.1 mmol) in heptane (190 mL) was treated with thionyl chloride (21 mL, 288 mmol) in a dropwise manner over 30 min. A drop of N,N-dimethylformamide was added and the solution was heated for 4 h at 60° C. The excess thionyl chloride was distilled off under reduced pressure. The remaining solution was cooled to room temperature, filtered, and concentrated to give 4-fluoro-2-hydroxy-benzoyl chloride as a pale yellow crystalline solid (14.2 g, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]([C:15]([O:17]C)=[O:16])=[CH:13][CH:14]=2)=[N:7][CH:8]=1)#[N:2].O.[Li+].[OH-]>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2ccc(C#N)cn2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(C(=O)O)nc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 250 ml flask was added methyl 5-cyano-2,3′-bipyridine-6′-carboxylate (950 mg, 3.57 mmol), water (9.5 ml), tetrahydrofuran (38.4 ml) and LiOH (86 mg, 3.57 mmol). The mixture was stirred for 30 min, diluted with tetrahydrofuran (200 ml) and cooled to 0° C. (ice water batch). After an additional 30 min, the resulting suspension was filtered, washed with THF and dried under reduced pressure to afford the desired product as a light brown powder. LCMS (m/z): 226.1 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C1COCC1.CC([O-])(C)C.[Li+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([NH:43][C:39]1[S:38][CH:42]=[CH:41][N:40]=1)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Reactant: Nc1nccs1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 87.5 %

Procedure:
A flask was charged with perfluorophenyl 5-(1-benzylpyrrolidin-2-yl)naphthalene-2-sulfonate (Intermediate LL, 21.5 mg, 0.040 mmol), thiazol-2-amine (4.84 mg, 0.048 mmol), and THF (403 μl) to give a clear, colorless solution. The flask was cooled in an dry ice-acetone bath for 5 min, then lithium 2-methylpropan-2-olate (1M in hexane) (89 μl, 0.089 mmol) was added dropwise. The resulting mixture was stirred for 1 min, then the flask was lowered into an ice-bath. After 1 h, the mixture was warmed to room temperature then was loaded directly onto a 5-g silica gel loading column with the aid of DCM. The column was dried under vacuum, then eluted onto a prequilibrated 12-g column with 0 to 10% MeOH/DCM to give 5-(1-benzylpyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (15.85 mg, 0.035 mmol, 87% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.97-12.23 (m, 1H), 8.51 (d, J=9.1 Hz, 1H), 8.46 (d, J=1.9 Hz, 1H), 8.09-7.96 (m, 2H), 7.83 (dd, J=2.1, 9.0 Hz, 1H), 7.69-7.61 (m, 1H), 7.29 (d, J=4.4 Hz, 4H), 7.27-7.24 (m, 1H), 7.24-7.20 (m, 1H), 6.83 (d, J=4.6 Hz, 1H), 4.16 (t, J=8.2 Hz, 1H), 3.78 (d, J=13.2 Hz, 1H), 3.15 (d, J=13.2 Hz, 1H), 3.07 (td, J=4.6, 9.1 Hz, 1H), 2.47-2.38 (m, 1H), 2.30 (q, J=8.6 Hz, 1H), 1.89-1.79 (m, 2H), 1.68-1.57 (m, 1H); m/z (ESI) 450.4 (M+H)+.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@H:6]1[C@@H:5]2[CH2:1][C@@H:2]([CH:3]=[CH:4]2)[C@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CO
Reactant: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1[C@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-endo-2,3-dicarboxylic anhydride (8.21 g, 50 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (250 mL). The mixture was stirred for 10 min. Quinidine (17.84 g, 55 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stifling, methanol (6.08 mL, 150 mmol) was added. The mixture was stirred at −55° C. for 18 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a thick oil. The oil was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (300 mL). After shaking, the layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (9.15 g, 46.6 mmol, 94%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (1H, d, J=8.4 Hz), 1.33 (1H, d, J=8.4 Hz), 3.00 (1H, s), 3.03 (1H, s), 3.21-3.29 (2H, m), 3.45 (3H, s), 6.02-6.04 (1H, m), 6.14-6.16 (1H, m), 11.86 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:27]([O:35][CH3:36])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:29]([C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[C:27]=1[O:35][CH3:36])=[O:31]
Reactant: COc1c(F)cccc1C(=O)O
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: COc1c(F)cccc1C(=O)N1CCC[C@@H](C)[C@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 3-fluoro-2-methoxybenzoic acid. MS (ESI) 281 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO.CS(C)=O>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine (41.89 mg, 0.116 mmol) in methanol (3 ml) was treated with 4 molar HCl solution in 1,4-dioxane (0.722 mL, 2.89 mmol) and stirred at ambient temperature in a capped vial overnight. The clear reaction solution was blown down under N2 and then dissolved in 1 ml 1:1 DMSO:MeOH and purified by MDAP (Method A). The appropriate fraction was evaporated under N2 in a Radleys blow down unit to afford the title compound as a white solid (31.1 mg).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Reactant: C1CSCCN1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCN2CCSCC2)cc1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and thiomorpholine are converted to the named compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[OH:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC(C)=O.Cl[Pd]Cl.O.CCO>[OH:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)c1cccc(Br)c1
Reactant: OB(O)c1cccc(O)c1
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: NC(=O)c1cccc(-c2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 5 L 3-neck round bottom flask was charged with 3-bromobenzamide (128.29 g, 0.64 mol), EtOH (1274 mL), PdCl2 (0.588 g, 3.3 mmol, 0.005 equivalents), 3-hydroxyphenyl boronic acid (93 g, 0.67 mol. 1.05 equivalents), K2CO3 (177 g, 1.28 mol, 2 equivalents) and nBu4NBr (10.3 g, 0.032 mol, 0.05 equivalents). The reaction mixture was stirred at room temperature for approximately 16 hours. Upon completion of the reaction, a 10% aqueous HCl solution was added to the reaction mixture until the pH reached 1-2. The reaction mixture was extracted with EtOAc. The organic phases were combined and filtered through celite. The organic solvents were then removed under vacuum to obtain an orange solid. The solid was dissolved in acetone (200-300 mL) and water (1700 mL) was added. The reaction mixture was stirred for 1 hour at approximately 5-10° C. The product was collected by filtration as a white solid and dried under vacuum at 40-45° C. (132.9 g, 0.62 mol, 98%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[Cl:8][SiH:9]([Cl:11])[Cl:10]>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[Cl:8][Si:9]([Cl:11])([Cl:10])[C@H:2]1[CH2:3][C@H:4]2[CH2:7][C@@H:1]1[CH2:6][CH2:5]2
Reactant: C1=CC2CCC1C2
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)[C@H]1C[C@@H]2CC[C@H]1C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.8 %

Procedure:
(R)-2-Methoxy-2'-di(4-chlorophenyl)phosphino-1,1'-binaphthyl prepared in Example 3 (7.93 mg, 14.78 mmol) and allylpalladium chloride dimer (1.35 mg, 3.69 μmol=7.38 μmol of palladium) were dissolved in toluene (6.95 g). In the solution, norbornene (6.95 g, 73.81 mmol) was added. After adding trichlorosilane (12.00 g, 88.59 mmol) at 0° C., the mixture was warmed to room temperature, followed by stirring at room temperature for 12 hours. Thereafter, from the reaction mixture, the solvent was evaporated off at 100° C. under reduced pressure of 1 Torr to obtain (1S, 2S, 4R)-2-trichlorosilylnorbornane (16.41 g). Isolation yield, 97%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17]2[C:12](=[C:13]([OH:28])[CH:14]=[CH:15][CH:16]=2)[N:11]=1.[Na].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]1>C(O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([N:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])[C:17]2[C:12](=[C:13]([O:28][CH2:38][CH2:37][CH2:36][N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: ClCCCN1CCOCC1
Reactant: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2cccc(O)c2n1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2cccc(OCCCN3CCOCC3)c2n1
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
2-(2-Methyl-4-fluorophenylamino)-4-(N-methylphenylamino)-8-hydroxyquinazoline (1.6 g, 4.3 mmol) was suspended in ethanol (25 ml) and to the stirred suspension was added a solution of sodium (0.1 g, 4.3 mmol) in ethanol (15 ml). Stirring was continued for 15 minutes and the mixture evaporated to dryness. The residue was dissolved in toluene (50 ml) and heated to reflux temperature. To this refluxing solution was added a freshly prepared solution of 3-morpholinopropyl chloride base (from 1.28 g, 6.4 mmol of hydrychloride salt) in toluene (20 ml). Refluxing was continued overnight and after cooling the mixture was washed with sodium carbonate solution and water, dried and evaporared. The residual oil was chromatographed on silica gel using CH2Cl2 as eluting solvent. After evaporation of the relevent fractions the residue was crystallised from diethyl ether/pentane to give the title compound (1.5 g, 71%) m.p. 133°-134°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([CH3:24])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([CH3:24])=[CH:12][CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(NCc3ccccc3)c3c(nc2c1)CCCC3=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(NCc3ccccc3)c3c(nc2c1)CCCC3O
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a cooled suspension of 3.6 g of 9-benzylamino-3,4-dihydro-6-methylacridin-1(2H)-one in 80 ml of tetrahydrofuran was added 6 ml of 1M solution of lithium aluminum hydride in THF. This was stirred for 1 hour, and thereafter quenched with 7 ml of saturated ammonium chloride solution. The inorganics were filtered and rinsed with ethyl acetate and the combined organics were dried over anhydrous magnesium sulfate. The resulting solid was triturated with ethyl ether to obtain 3.15 g of a solid, mp 148°-153° C. This was recrystallized from toluene (70 ml) to obtain 2.5 g of an analytically pure solid, mp 149°-152° C.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:13]3[C:18]([C:19](=[O:20])[C:3]=12)=[CH:17][CH:16]=[CH:15][CH:14]=3.C(=O)([O-])[O-].[Li+].[Li+].Cl.[CH2:28]([N:30]([CH2:34]C)[CH2:31][CH2:32][SH:33])C.CN(C)C=O>O>[CH3:28][N:30]([CH2:31][CH2:32][S:33][C:2]1[C:11]2[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:13]3[C:18]([C:19](=[O:20])[C:3]=12)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:34]
Reactant: CCN(CC)CCS
Reactant: O=C1c2ccccc2-c2nc3ccc(O)cc3c(Cl)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSc1c2c(nc3ccc(O)cc13)-c1ccccc1C2=O
Temperature: 90 °C
Reaction time: 5 h
Yield: 63.2 %

Procedure:
A mixture of 400 mg (1.4 mmol) of 10-chloro-8-hydroxy-11H-indeno[1,2-b]quinolin-11-one, 629 mg (8.5 mmol) of lithium carbonate, 963 mg (5.7 mmol) of 2-diethylaminoethanethiol hydrochloride and 8 ml of N,N-dimethylformamide was stirred for 5 hours with heating at 90° C. After completion of the reaction, the reaction mixture was added to water, and precipitated crystals were collected by filteration. The crystals were recrystallized from ethanol, giving 310 mg of the title compound (yield: 57.7%). The property values are shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12]O.C(Cl)Cl.[Br:17]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[Br:17][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1c[nH]c2ccc(F)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc2[nH]cc(CCBr)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-(5-Fluoro-1H-indol-3-yl)-ethanol (20.0 g, 112 mmol) was dissolved in abs. CH2Cl2 (250 ml), and tetrabromomethane (56.0 g, 170 mmol) was added at RT. Triphenylphosphine (44.0 g, 165 mmol) was then added in portions at RT, while cooling with water. The solution was stirred at RT for 2.5 h and then concentrated i. vac. The residue was absorbed on to silica gel and divided into two equal portions. The crude product was purified by flash chromatography over 2 columns each with 500 g of silica gel and cyclohexane/ethyl acetate (9:1→4:1). Yield: 25.4 g (93%), red solid
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[Cl:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:12]=[C:11]([Cl:10])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
To a mixture of 4,6-dichloro-pyrimidin-2-yl-amine (0.304 g, 2.0 mmol), 5-chloro-2-methoxy-phenyl boronic acid (0.373 g, 2.0 mmol), palladium (II) acetate (0.068 g, 0.30 mmol) and triphenylphosphine (0.157 g, 0.60 mmol) was added a solution of sodium carbonate (1.36 g, 12.8 mmol) in water (5 ml) followed by glyme (20 ml). The mixture was stirred under an atmosphere of argon for 1 hour. Filtration and concentration of the filtrate provided a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine (0.314 g, 58% yield) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.Cl.[CH3:34][O:35][NH:36][CH3:37].C(N(CC)CC)C.CONC>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH3:34][O:35][N:36]([CH3:37])[C:8]([C:6]1[CH:5]=[CH:4][C:3]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[C:2]([CH3:1])[CH:7]=1)=[O:9]
Reactant: CNOC
Reactant: Cc1cc(C(=O)O)ccc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Yield: 22.5 %

Procedure:
Combine 2-methyl-4′-trifluoromethyl-biphenyl-4-carboxylic acid (2.31 g, 8.25 mmol) and di-imidazol-1-yl-methanone (1.47 g, 9.08 mmol) in tetrahydro-furan (15 mL) and stir twenty minutes. In a separate reaction vessel, combine O,N-dimethyl-hydroxylamine hydrochloride (0.885 g, 9.08 mmol) and triethyl-amine (1.3 mL, 9.08 mmol) in N,N-dimethyl-formamide (20 mL). Add O,N-dimethyl-hydroxylamine solution to the 2-methyl-4′-trifluoromethyl-biphenyl-4-carboxylic acid solution and stir sixteen hours. Dilute reaction with ethyl acetate, wash with 0.5 N HCl, 0.1N NaOH, and saturated sodium chloride solution. Dry organic fraction with Na2SO4, filter and concentrate under reduced pressure to provide 0.6 g (23%) of title compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40]([OH:42])=O)[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:46][CH2:47][CH2:48][OH:49]>>[OH:49][CH2:48][CH2:47][NH:46][C:40]([CH:37]1[C@@H:36]2[C@H:38]1[CH2:39][N:34]([C:32]([N:12]1[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[O:43][CH2:44][CH3:45])=[O:33])[CH2:35]2)=[O:42]
Reactant: NCCO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)O)[C@@H]2C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)NCCO)[C@@H]2C1

Procedure:
In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with 2-aminoethanol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H44Cl2N5O4 [(M+H)+] 692.2765, observed 692.2768.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.CN(C=O)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1>CCOC(C)=O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:6]2[CH:5]=[C:4]3[C:8]([C:9]([C:11]([NH2:13])=[O:12])=[CH:10][C:2]([F:1])=[CH:3]3)=[N:7]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: NC(=O)c1cc(F)cc2cn[nH]c12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)cc2cn(-c3ccc(Br)cc3)nc12
Temperature: 180 °C

Procedure:
To a solution of D2 (1.0 eq) in DMF (0.2 M) K2CO3 (1.3 eq) and 4-bromofluorobenzene (10.0 eq) were added and the reaction mixture was heated under MW conditions at 180° C. for 20 min. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with brine; dried (Na2SO4). Evaporation of the solvent gave (D3) which was purified by chromatography on silica gel eluting with 50-70% EtOAc/Petroleum ether to obtain the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 300K) δ 9.34 (1H, s), 8.50 (1H, br. s), 8.17 (2H, d, J=9.0 Hz), 8.03 (1H, br. s), 7.90-7.80 (4H, m). MS (ES+) C14H9BrFN3O requires: 334/336. Found: 335/337 (M+H)+.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:5][C:6](=[O:27])[C:7](=[CH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[NH4+].[OH-]>C1COCC1.[Cu]I>[CH2:3]([O:5][C:6](=[O:27])[CH:7]([CH:13]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)[CH3:2])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: [Li]C
Reactant: CCOC(=O)C(=CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
MeLi (5.34 mL, 8.54 mmol, 1.6 M in diethyl ether) was added dropwise to a slurry of CuI (0.74 g, 3.88 mmol) in THF (5 mL) at −78° C. under argon and the mixture was stirred for 30 min. A solution of 2-(1-tert-butoxycarbonyl-piperidin4-ylmethylene)-malonic acid diethyl ester (0.69 g, 1.94 mmol) in THF (5 mL) was added dropwise and the reacton mixture was stirred for 120 min at −78° C. and was then allowed to warm to room temperature during 60 min. Concentrated aqueous NH4OH was added and the mixture was then extracted with EtOAc, washed with concentrated aqueous NH4OH and brine, dried and concentrated under reduced pressure. The crude was purified by flash chromatography (heptane/EtOAc, 3:1→1:6) to give 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-ethyl]-malonic acid diethyl ester (0.39 g, 54%).