Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]1[C:37]([F:38])=[C:36]([F:39])[C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:25][C:18]1[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[N:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]2[NH:8][C:7]3[C:2]([C:34]4[CH:33]=[C:32]([F:31])[C:37]([F:38])=[C:36]([F:39])[CH:35]=4)=[CH:3][C:4]([C:27]([F:28])([F:30])[F:29])=[CH:5][C:6]=3[N:10]=2)[C@H:12]([CH3:26])[CH2:13]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1ccc(F)c(F)c1F
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Bromo-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol (152 mg, 0.3 mmol, Example 151) and 4,5,6-trifluorophenylboronic acid (106 mg, 0.6 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 556 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].N1C=CC=CC=1.O>C1COCC1.CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:6]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NNC(=O)c1cccc(I)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: COc1cccc(C(=O)NNC(=O)c2cccc(I)c2)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 3-iodobenzohydrazide (10.0 g, 38.16 mmol) in dry THF/DMF (100.0 ml:10.0 ml) was slowly added 3-methoxybenzoyl chloride (7.0 g, 42.03 mmol) at 0° C. under nitrogen. During addition of 3-methoxybenzoyl chloride, white solid was appeared. After addition of 3-methoxybenzoyl chloride, the reaction was allowed to warm up to room temperature. The reaction mixture was stirred for 19 hours at room temperature and then pyridine (20.0 ml) was added and stirred for additional 45 min. Water (300.0 ml) was added to reaction mixture. The white solid was obtained and collected by filtration and washed with water. After dried under vacuum, product was obtained as white powder in 12.4 g (82.0%). 1H NMR (400 MHz, DMSO-d6, δ): 10.62 (s, 1H, NH), 10.56 (s, 1H, NH), 8.25 (t, J=1.6 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), (dd, J1=8.0 Hz, J2=2.4 Hz, 1H), 3.81 (s, 3H, OCH3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(O)c1ccccc1O
Temperature: 140 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium (II) chloride (1.9 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=Ph, Ar=C6H5—, 1.3 μmol, 0.33 mol %) were dissolved in xylene (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 140° C. After the mixture was cooled to room temperature, o-hydroxyacetophenone (0.4 mmol), xylene (2 mL) and an aqueous solution of sodium hydroxide (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 12 h under H2 (10 atm) at 25° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/2). Accordingly, pure 1-(o-hydroxylphenyl)ethanol was obtained and the ee value (ee=97%) was measured by GC analysis.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH3:10])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1>[Pd]>[CH:2]([O:3][CH2:4][CH:5]([OH:6])[CH2:7][OH:8])([CH2:9][CH3:10])[CH3:1]
Reactant: CCC1(C)OCC(CO)O1
Agent: [Pd]
Product: CCC(C)OCC(O)CO
Yield: 183.5 %

Procedure:
The compound obtained in the production (1) (29.2 g, 0.10 mol) and the palladium catalyst (2) (2.2 g) were charged in a 70-mL autoclave, followed by a reaction under a hydrogen pressure of 7.0MPa at 190° C. for 15 hours. After completion of the reaction, the catalyst was removed by filtration to obtain a crude product (27.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>COCCOC>[Cl:1][C:2]1[C:7]([NH:21][CH2:20][CH2:19][O:18][CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCCN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: COCCOC
Product: COCCNc1nc(N)nc(-c2ccco2)c1Cl

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and 2-methoxyethylamine in DME. ES-MS m/e (%): 271 (M{37Cl}+H+, 43), 269 (M{35Cl}+H+, 100).
Reaction SMILES: [F:1][C:2]([F:14])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].B.[O:16]1CCCC1.[OH-].[Na+].OO>>[F:1][C:2]([F:14])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:16]
Reactant: C=CCCCCCCCCC=C(F)F
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Product: OCCCCCCCCCCC=C(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Three grams (0.o15 mole) of 1,1-difluoro-1,11-dodecadiene (prepared in Example 3, Step B) was stirred while being cooled to 0° C. After this time 5 ml (0.005 mole) of borane-tetrahydrofuran complex (1 Molar in tetrahydrofuran) was added dropwise. Upon completion of addition, the reaction mixture was stirred for 30 minutes, and then, in turn, 5 ml of aqueous 3 Normal sodium hydroxide and 5 ml of aqueous 30% hydrogen peroxide were added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was stirred with 25 ml of water, and the mixture was extracted with three 15 ml portions of methylene chloride. The combined extracts were washed with two 15 ml portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was evacuated under reduced pressure at 135° C., and then it was subjected to column chromatography on silica gel. Elution was accomplished using heptane and methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure yielding 0.74 gram of 12,12-difluoro-11-dodecen-1-ol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[O:17])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35].[OH-].[Na+]>CO.O1CCOCC1>[OH:35][C:5]1[C:6]([CH2:32][CH2:33][CH3:34])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[O:17])[CH:8]=[CH:9][C:4]=1[C:3]([OH:36])=[O:2]
Reactant: CCCc1c(OCCCCCC(=O)c2ccc3cc(OC)c(OC)cc3c2)ccc(C(=O)OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCc1c(OCCCCCC(=O)c2ccc3cc(OC)c(OC)cc3c2)ccc(C(=O)O)c1O

Procedure:
A solution of 4.2 g (0.0085 mole) of 2-hydroxy-4-[[6-(6,7-dimethoxy-2-naphthalenyl)-6-oxohexyl]oxy]-3-propylbenzoic acid methyl ester in 100 mL of methanol, 50 mL of dioxane and 34 mL (0.034 mole) of 1N sodium hydroxide was stirred at reflux for 8 hours. The reaction mixture was concentrated under reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated and the crude product was recrystallized from a methanol and water mixture to give 3.48 g, mp 144°-146°, of 2-hydroxy-4-[[6-(6,7-dimethoxy-2-naphthalenyl)-6-oxohexyl]oxy-3-propylbenzoic acid.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[CH:18][C:19]([OH:22])=[C:20]([OH:21])[C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>C(O)C.C(O)(=O)C>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[CH:18][C:19]([OH:22])=[C:20]([OH:21])[C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN1CCc2c(ccc(O)c2O)C(c2cccc3ccoc23)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCc2c(ccc(O)c2O)C(c2cccc3c2OCC3)C1

Procedure:
0.5 g (0.0016 mol) 1-(benzofuran-7-yl)-6,7-dihydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in a mixture of 25 ml ethanol and 2 ml acetic acid. 0.2 g catalyst (10% Pd/C) was added and the mixture was submitted to hydrogenation in a Parr apparatus at a pressure of 50 psi. After 24 h the catalyst was filtered off and the solution was concentrated in vacuo. The residue was redissolved in dichloromethane, the solution was washed subsequently with NaHCO3-solution, water and brine. Evaporation in vacuo gave 1-(2,3-dihydrobenzofuran-7-yl)-6,7-dihydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as an offwhite foam.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:18])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:23]2[CH2:24][CH2:25][N:20]([C:9]([C:8]3[C:7]([CH3:18])=[CH:6][C:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:13]([CH:12]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:21][CH2:22]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)c(C)cc1C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a round-bottom flask was added a solution of 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 230.2, 2.10 g, 8.46 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.88 g, 8.44 mmol, 1.00 equiv), EDC.HCl (3.22 g, 16.8 mmol, 2.00 equiv), and 4-dimethylaminopyridine (3.10 g, 25.4 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred overnight at 25° C., then diluted with 100 mL of ethyl acetate. The mixture was washed with 2×30 mL of NH4Cl (aq., sat.) and 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (0:1-1:3) as eluent to yield 3.20 g (91%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:17][C:18]([F:42])([F:41])[C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)=[CH:21][CH:20]=1>>[F:41][C:18]([F:17])([F:42])[C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)=[CH:39][CH:40]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccc(C(F)(F)F)cc2)c1

Procedure:
267 mg of compound 34 was obtained in a similar manner to those described in the Examples 1 and 2 using 563 mg of ethyl 4-(2-aminophenoxy)butyrate and 451 mg of 3-[1-(4-trifluoromethylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:28][CH2:29][CH3:30])[CH:14]3[CH2:19][CH2:18][N:17]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH2:16][CH2:15]3)[CH2:10]2)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:28][CH2:29][CH3:30])[CH:14]3[CH2:15][CH2:16][N:17]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH2:18][CH2:19]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OC)cc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.3 %

Procedure:
To a −78° C. solution of {4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone (300 mg, 0.72 mmol) and tetrabutylammonium iodide (292 mg, 0.79mmol) in dichloromethane (20 mL) under an inert atmosphere was added boron trichloride (1M, 2.5 mL, 2.5 mmol) dropwise. The reaction was warmed to room temperature and stirred for 2.5 h. The reaction was quenched by slow addition of water and the organic layer separated and dried (MgSO4). This was concentrated onto silica (1.5 g) and placed on top of a flash column. Chromatography eluting with 30% acetone in hexanes afforded {4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone (128 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:5].[NH4+].[OH-].[NH2:26]C1C=C(F)C([N+]([O-])=O)=CC=1C(NC1C=C2C(C=NN2)=CC=1)=O>O1CCOCC1.O>[NH2:26][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]([C:4]([NH:6][C:7]2[CH:15]=[C:14]3[C:10]([CH:11]=[N:12][NH:13]3)=[CH:9][CH:8]=2)=[O:5])=[C:2]([Cl:1])[CH:19]=1
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]

Procedure:
A solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (2 mmol) in dioxane (4 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was complete, the volatiles were removed in vacuo. The residue obtained was suspended in cold water with stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]#[N:27]>>[CH3:20][N:21]1[C:25]([C:6]2[CH:5]=[CH:4][C:3]3[C:2](=[O:1])[CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=2)=[CH:24][CH:23]=[C:22]1[C:26]#[N:27]
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: Cn1cccc1C#N
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)CCCC2=O

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ES) m/z 251.2; HRMS: calcd for C16H14N2O+H+, 251.11789; found (ESI, [M+H]+), 251.1186.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[C:5]([C:6](=[O:15])[CH:7]=[CH:8][CH:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH2:10]2)=[C:4]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O>[CH2:31]([O:1][C:2]1[CH:17]=[C:16]([OH:18])[C:5]([C:6](=[O:15])[CH:7]=[CH:8][CH:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH2:14]2)=[C:4]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:3]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)COc1cc(O)cc(O)c1C(=O)C=CC1C=CC=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OCc2ccccc2)cc(O)c1C(=O)C=CC1C=CC=CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4′,6′-dihydroxy-2′-(methoxycarbonylmethoxy)dihydrochalcone (0.6 g) in N,N-dimethylformamide (10 mL) were added potassium carbonate (0.26 g) and benzyl bromide (0.22 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (0.53 g).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([NH:19][C:20]([O:12][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=Nc1ccncc1O
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CN(C)C=Nc1ccncc1OC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a warm solution of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (3.0 g) in dry tetrahydrofuran (60 mL) was added phenyl isocyanate (2.05 mL). The reaction mixture was stirred at room temperature for 1.5 hours and filtered. The solid was washed with dry diethyl ether, air dried, and dried under high vacuum and refluxing ethanol for 4 hours to yield 4.19 g of solid, m.p. 151 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=[O:18])=[C:9]2Cl)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=[O:18])=[C:9]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2cccc(Br)c2)c2ccccc12
Product: O=Cc1c(N2CCNCC2)n(-c2cccc(Br)c2)c2ccccc12
Yield: 31 %

Procedure:
1-(3-bromo-phenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-bromophenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (31% yield). ESI/MS 384 (M), 386 (M+2); RT 2.70 min; NMR (CDCl3) 10.31 (1H, s); 8.28 (1H, d, J=9 Hz); 7.67 (2H, m); 7.63-7.16 (5H, m); 7.01 (1H, d, J=9 Hz); 3.31 (4H, m); 2.82 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.[NH3:18]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH2:18])[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nc(Cl)nn2ccc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 2,4-dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (0.500 g, 1.89 mmol) in THF (5 mL), NH3 gas was bubbled at −20° C. for 15 min. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to remove THF and water (30 mL) was added to the resulting residue. The aqueous solution was extracted with EtOAc (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 40 g, 45% EtOAc/petroleum ether) to afford 2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.300 g, 64.8%). LCMS Condition B-81: retention time 2.14 min, [M+1]=245.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.98 (br s, 1H), 6.75 (d, J=2.4 Hz, 1H), 7.38-7.43 (m, 2H), 7.46-7.52 (m, 3H), 7.80 (d, J=2.4 Hz, 1H), 8.40 (br s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17]1[N:18]=[C:19]([NH:22][C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[O:24])[S:20][CH:21]=1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:33].[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][NH:25][C:23](=[O:24])[NH:22][C:19]1[S:20][CH:21]=[C:17]([CH:9]2[NH:8][CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10]2)[N:18]=1
Reactant: CC(=O)OC1C[C@H](c2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)O[C@H]1CNC(c2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)C1
Reaction time: 8 h

Procedure:
The product obtained in Step 2 was dissolved in 4M HCl in 1,4-dioxane (7 mL). After stirring overnight the reaction mixture was concentrated and the residue was crystallized from THF/Et2O to afford Intermediate 58: acetic acid (R)-5-{2-[3-(3,4-dichloro-benzyl)-ureido]-thiazol-4-yl}-pyrrolidin-3-yl ester hydrochloride, as a white solid (224 mg, 52% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[NH:11][C:10]1=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[N:11]([S:38]([CH:35]2[CH2:37][CH2:36]2)(=[O:40])=[O:39])[C:10]1=[O:24]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1ncnc2c(F)c3c(cc12)[nH]c(=O)n3-c1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncnc2c(F)c3c(cc12)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a solution of 3-(2-fluoro-4-iodophenyl)-4-fluoro-8-methyl-1H-imidazo[4,5-g]quinazolin-2(3H)-one (50 mg, 0.12 mmol) in THF (10 ml) at −78° C. was added LiHMDS (0.16 ml, 1 M in THF, 0.16 mmol). The reaction mixture was stirred at −78° C. for 10 min and cyclopropylsulfonyl chloride (25 mg, 0.18 mmol) was added to the mixture. The reaction was slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl solution (10 ml) and extracted with EtOAc (2×10 ml). The combined organic solution was washed with brine (20 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yields 46 mg (75%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=[O:15].O.[OH-].[Li+:19]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([O-:16])=[O:15].[Li+:19].[Li+:19]
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])c1ccc2cc(C(=O)[O-])ccc2c1

Procedure:
Lithium 2,6-naphthalenedicarboxylate was synthesized by repeating the procedure of Experimental Example 1. The starting materials used were 2,6-naphthalenedicarboxylic acid and lithium hydroxide monohydrate (LiOH.H2O). Methanol (100 mL) was added to lithium hydroxide monohydrate (0.556 g), and it was stirred. After the lithium hydroxide monohydrate was dissolved, 2,6-naphthalenedicarboxylic acid (1.0 g) was added, and it was stirred for one hour. After stirring, the solvent was removed, and the residue was dried in vacuo at 150° C. for 16 hours to yield a white powder sample.