Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON(C)[C:8]([C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:14]=1)=[O:9]>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:13]2[CH:14]=[C:10]([C:8](=[O:9])[CH2:1][CH3:2])[CH:11]=[N:12]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(Cn2cc(C(=O)N(C)OC)cn2)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Reaction time: 1 h
Yield: 96.7 %

Procedure:
According to Scheme 3 Step 2: Ethylmagnesium bromide (3N, 37.2 mmol, 12.4 mL) was added dropwise at room temperature to a solution of N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide (33.8 mmol, 9.30 g) in THF (80 mL) and the reaction mixture was stirred for 1 hour. Then ethylmagnesium bromide (3N, 37.2 mmol, 12.4 mL) was added and the reaction mixture was stirred for 1 hour. Finally some more ethylmagnesium bromide (3N, 74.4 mmol, 24.8 mL) was added and the reaction mixture was stirred for 1.5 hour at 50° C. The reaction was quenched with HCl (1 N, 300 mL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated to yield 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)propan-1-one (32.7 mmol, 8.00 g, 97%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CC(N(C)C)=O.[C:17]12([CH2:27][NH2:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:17]12([CH2:27][NH:28][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH2:1])[N:7]=3)=[O:10])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(=O)O)n1
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: CC(=O)N(C)C
Product: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-aminopyridine-2-carboxylic acid (10 g, 72.4 mmol) in DMF (200 mL) at RT, is sequentially added 25.2 mL of DMA (144.8 mmol), 12 g of 1-admantylmethylamine (72.4 mmol) and 38.4 g of BOP (86.88 mmol). The resulting mixture is stirred at RT for 16 h. The reaction mixture is added to 400 mL of ice/water. Filtration affords the title compound which is used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([F:13])[CH:6]=1>C(O)C>[CH3:1][NH:2][N:3]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([Cl:4])=[CH:6][C:7]=1[F:13]
Reactant: CNN
Reactant: O=Cc1ccc(Cl)cc1F
Solvent: CCO
Product: CNN=Cc1ccc(Cl)cc1F
Reaction time: 1 h
Yield: 94 %

Procedure:
5.5 g (0.12 mol) of methylhydrazine were added to a solution of 19 g (0.12 mol) of 4-chloro-2-fluorobenzaldehyde in 120 ml of ethanol. After 1 hour, the mixture was concentrated, and the residue was subsequently treated with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and finally concentrated. Yield: 94%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[C:17]1([CH2:27][NH2:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:28][CH2:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: NCc1cccc2ccccc12
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Yield: 75.4 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 1-naphthalenemethylamine (0.24 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2: 1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.44 g, 76%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.74 (3H, s); 4.47 (2H, d, J=6.0 Hz); 6.69 (1H, d, J=16.0 Hz); 7.32-8.32 (13H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(F)cccc1F
Reactant: COC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1c(F)cccc1F
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
40% Methanolic Triton B (0.49 mL, 1.07 mM) was added to a solution of the 9-[(2,6-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (290 mg, 0.82 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (259 mg, 1.65 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with H2O and the resultant white precipitate collected by filtration, triturated with diethyl ether/hexanes, and dried in vacuo to afford 228 mg (65%) of the {9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ 7.65 (d, 1H, J=8 Hz), 7.45-7.2 (m, 5H), 6.85 (t, 2H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.0 (br s, 1H), 5.5 (s, 2H), 4.9 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3432, 3170, 1762, and 1675. MS (ES) m/e 425.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH2:19].C(N(CC)CC)C>CCO>[Br:1][C:2]1[C:6]2[C:7]([NH:19][CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: Clc1nccc2scc(Br)c12
Reactant: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Brc1csc2ccnc(NCc3ccccn3)c12
Temperature: 25 °C
Yield: 4.5 %

Procedure:
3-Bromo-4-chloro-thieno[3,2-c]pyridine (409 mg, 16.5 mmol) was dissolved in anhydrous EtOH (20 ml), and 2-picolylamine (184 μl, 17.9 mmol) and triethylamine (241 μl, 17.3 mmol) were added. The reaction was heated to reflux and this was maintained for 24 h. The reaction was then allowed to cool to room temperature. The solvent was removed in vacuo and the residue partitioned between DCM (20 ml) and a saturated sodium, chloride solution (20 ml). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was subjected to flash column chromatography (eluent petroleum spirit 40-60° C.:EtOAc, 3:1, Rf 0.3). This afforded the title compound as a yellow solid (236 mg, 44%).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([CH:19]1[CH2:23][CH2:22][C:21]([CH3:27])([C:24](O)=[O:25])[C:20]1([CH3:29])[CH3:28])=[O:18]>C(N(CC)CC)C>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:24]([C:21]1([CH3:27])[CH2:22][CH2:23][CH:19]([C:17]([O:16][CH3:15])=[O:18])[C:20]1([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)C1CCC(C)(C(=O)O)C1(C)C
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)OC)C1(C)C
Temperature: 60 °C

Procedure:
To a 20-mL scintillation vial containing a magnetic stir bar were added the product from Example 92B (637 mg, 3.00 mmol), racemic 3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid (Maybridge, 771 mg, 3.60 mmol), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, Bachem, 1.16 g, 3.60 mmol). Anhydrous acetontirile (8 mL) was added to form a white slurry. Neat triethylamine (Aldrich, 1.09 g, 10.8 mm0l) was added via syringe to form a tan solution. The reaction flask was heated to 60° C. in a shaker block and mixed for 2 hours. The volatiles were removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 2-20% ethyl acetate in hexanes) to afford the title compound. 1H NMR (DMSO-d6) δ ppm 0.50 (s, 3H), 0.90 (t, J=7.5 Hz, 3H), 1.21 (s, 3H), 1.24-1.36 (m, 2H), 1.30 (s, 3H), 1.41-1.51 (m, 1H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.73-1.87 (m, 1H), 2.01-2.11 (m, 1H), 2.62-2.67 (m, 2H), 2.70-2.81 (m, 1H), 2.85-2.91 (m, 1H), 3.60 (s, 3H), 8.50 (s, 1H). MS (ESI+) m/z 409 (M+H)+. Anal. calcd. for C22H36N2O3S: C, 64.67; H, 8.88; N, 6.86. Found: C, 64.20; H, 8.71; N, 6.59.
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][C:21]=1[F:22]>>[F:15][C:16]1[CH:17]=[C:18]([CH:2]2[C:6]3[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=3[CH2:4][CH2:3]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: Fc1ccc([Mg]Br)cc1F
Product: CCOC(=O)c1cc2c([nH]1)C(c1ccc(F)c(F)c1)CC2

Procedure:
The title compound was synthesized in two steps. First, ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate was reacted with (3,4-difluorophenyl)magnesium bromide according to General Procedure 3. The resulting product was converted to the title compound by hydrogenation according to General Procedure 6.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([F:38])[CH:36]=5)[C:31]([Cl:39])=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:39].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([F:38])[CH:36]=5)[C:31]([Cl:39])=[CH:30][C:29]4=[O:40])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(F)cc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1cc(Cl)c2ccc(F)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C

Procedure:
To 5 mL of an ethyl acetate solution containing 0.76 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 5 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature. The resulting solid was filtered to give 572 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-chloro-7-fluoroquinolin-2(1H)-one hydrochloride as a brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH2:11](Br)[CH:12]([CH3:14])[CH3:13].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: c1ccsc1
Reactant: CC(C)CBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)Cc1cccs1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of thiophene (1.12 mL, 14.26 mmol) in 35 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (6.28 mL, 2.5 M in hexanes) and the resulting solution stirred at −78° C. for 20 minutes. Isobutylbromide (1.63 mL, 15.00 mmol) was added dropwise and the resulting solution stirred while warming to room temperature over 2 h before being poured into 100 mL 1 N hydrochloric acid. Organics were extracted with hexanes (3×100 mL), washed with 0.1 N hydrochloric acid (3×50 mL), water and brine (50 mL each), dried with magnesium sulfate, filtered and concentrated to give crude 2-isobutylthiophene. Used without further purification or characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[C@@H:7]2[CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C(#N)C.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([OH:41])=[O:40]
Reactant: COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Temperature: 25 °C
Yield: 108.4 %

Procedure:
(R)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid (50 g) is dissolved in acetonitrile (500 ml) and treated with sodium methoxide (30% strength in methanol, 32.4 ml) and then stirred under reflux for 60 h. After cooling to room temperature, the mixture is concentrated to one half in vacuo, then it is adjusted to pH 7.5 using hydrochloric acid (20% strength, ca. 20 ml), MIBK (200 ml) is added and it is readjusted to pH 7 using hydrochloric acid (20% strength). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated in a rotary evaporator to give a hard foam. The residue is dissolved in ethanol (150 ml) and concentrated, then again dissolved in ethanol (150 ml) and concentrated. A total of 54.2 g of (±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are thus obtained in quantitative yield as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[Br:17].[F:19][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([F:19])=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[Br:17]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1Br
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1c(F)c(O)c2cc(F)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of (1-bromo-6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (135 mg, 0.433 mmol) in acetonitrile (4 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (230 mg, 0.650 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, then diluted with water (10 mL), and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (30% ethyl acetate in petroleum ether) to give (1-bromo-3,6-difluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (60 mg, 42%) as a yellow solid. MS cald. for C13H9BrF2O3 330, obsd. (ESI+) [(M+H)+] 331.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[C:17]([O:21][C:22](=[O:31])[NH:23][CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:5]1([O:4][C:2](=[O:3])[NH:30][CH:27]2[CH2:28][CH2:29][CH:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:31])[CH2:25][CH2:26]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine in DCM. The reaction mixture is cooled to 0° C. and a solution of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at RT for 1 hour. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water (×2), (sat)NaHCO3(aq) and brine. The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]([O:24][CH2:25][CH2:26][CH2:27]Br)(=[O:23])[CH3:22]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[CH:17][C:16]([O:19][CH2:27][CH2:26][CH2:25][O:24][C:21](=[O:23])[CH3:22])=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)OCCCBr
Reactant: CCCCCCOc1c(O)c2cc(O)ccc2oc1=O
Product: CCCCCCOc1c(O)c2cc(OCCCOC(C)=O)ccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-hexyloxy-4,6-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-hexyloxy-4-hydroxy-6-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]([C:23]([O:25]CC)=[O:24])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]([C:23]([OH:25])=[O:24])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCNc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)O
Yield: 81.1 %

Procedure:
After refluxing for 1 hour a mixture of 106.4 g (0.29 mol) of ethyl 2-(4-benzylpiperazino)-4-ethylaminopyrimidine-5-carboxylate (the compound synthesized in Referential Example 64), 38.0 g (0.58 mol) of a 85% aqueous solution of potassium hydroxide, 100 ml of water and 400 ml of ethanol, ethanol was distilled off under reduced pressure. The residue was added with water and then neutralized with hydrochloric acid. The precipitated crystals were collected by filtration and were then dried to obtain 80.3 g of the above-identified compound (yield: 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:30]#[C:31]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][CH:10]=3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)#[N:30]
Reactant: N#CBr
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(C#N)CC4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (39 mg, 0.10 mmol), Cyanogen Bromide (13 mg, 0.12 mmol) and Potassium Carbonate (28 mg, 0.20 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was poured into water (5 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The crude product was purified by reverse phase HPLC to give N-(5-(4-cyanopiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 176. MS m/z 413.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.39(d, 1 Hz), 7.96(s, 1H), 7.89(d, 1H),7.68(d, 2H), 7.58(s, 1H), 7.50(d, 1H), 7.46(d, 2H), 7.37(dd, 1H), 3.74(s, 2H), 3.35(t, 4H), 3.18(t, 4H),2.55(s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=O)[C:7]2=[O:12].[C:13]12[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:18]C(=O)O[C:14]2=[O:15].CN(C1C=CC=CN=1)C.Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[C:8](=[N:18][C:19]3[C:13]([C:14]1=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]2=[O:12]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1c2cccc(F)c2-n2c1nc1ccccc1c2=O
Yield: 14 %

Procedure:
A solution of 7-fluoroisatin (300 mg, 1.8 mmol), isatoic anhydride (1.2 g, 7.3 mmol), and dimethylaminopyridine (222 mg, 2 mmol) in 5 mL of pyridine were heated at reflux temperature for 64 h. 50 mL of 0.2N HCl and 100 mL of chloroform were added and the chloroform layer was separated. The water layer was extracted with chloroform and the combined organic extracts were concentrated. Chromatography on silica gel eluting with chloroform gave the title compound in 14% yield: mp 264-267° C.; 1H NMR (300 MHz, CDCl3) δ 8.46 (d, 1H) 8.02 (d, 1H) 7.82-7.92 (m, 1H) 7.79 (d, 1H) 7.64-7.74 (m, 1H) 7.52-7.64 (m, 1H) 7.40-7.49 (m, 1H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]([O:22][CH3:23])[O:24][CH3:25])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(OC)OC)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCC(=O)OC(C)(C)C)n(CC(OC)OC)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-cyclohexyl-1-(2,2-dimethoxyethyl)-2-(2-formylphenyl)-1H-indole-6-carboxylate (prepared as described in Example 20, Step 2) in DCE (0.09 M), tert-butyl glycinate hydrochloride salt (1.5 eq) was added followed by NaBH(OAc)3 (3 eq). The solution was stirred at RT for 2 days. The reaction was quenched with aqueous NaHCO3 and extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a viscous oil (quantitative); MS (ES+) m/z 565 (M+H)+
Reaction SMILES: [C:1]([CH:4]([NH:35]C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][C@@H:8]([C:27]([NH:29][C@@H:30]([C:32]([OH:34])=[O:33])[CH3:31])=[O:28])[NH:9][C:10]([NH:12][CH2:13][CH:14]([C:24]([OH:26])=[O:25])[NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])([OH:3])=[O:2]>C(O)(C(F)(F)F)=O>[C:1]([CH:4]([NH2:35])[CH2:5][CH2:6][CH2:7][C@@H:8]([C:27]([NH:29][C@@H:30]([C:32]([OH:34])=[O:33])[CH3:31])=[O:28])[NH:9][C:10]([NH:12][CH2:13][CH:14]([C:24]([OH:26])=[O:25])[NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])([OH:3])=[O:2]
Reactant: CCCCCCC(=O)NC(CNC(=O)N[C@@H](CCCC(NC(=O)OC(C)(C)C)C(=O)O)C(=O)N[C@H](C)C(=O)O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCC(=O)NC(CNC(=O)N[C@@H](CCCC(N)C(=O)O)C(=O)N[C@H](C)C(=O)O)C(=O)O

Procedure:
To 85.9 mg of 1b-5 under argon is treated with 500 μl of TFA according to Example 80. The volatiles are evaporated to a residue which is triturated with ether 3x and the ether is decanted. The residue is dried to give 77.9 mg of 1b-11 as a white solid. NMR(CD3OD) δ 0.80(t,3H), 2.16(t,2H), 3.22(br s,5H), 3.58(m,2H), 3.85(m,1H), 4.15(m,1H), 4.30(d,1H), 4.40(m,1H); MS(HR--FAB) m/z 526.2482 (M+H, calcd for C21H38N5O9 526.2489).