Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].I[CH2:24][CH2:25][CH2:26][CH3:27]>CS(C)=O.[Cl-].[Na+].O.O.C(OCC)(=O)C>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:24][CH2:25][CH2:26][CH3:27])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCI
Reactant: CCCCn1ccc2ccc(C(=O)O)cc21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCOC(=O)c1ccc2ccn(CCCC)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Butyl-1H-indole-6-carboxylic acid (0.450 g) was dissolved in dimethyl sulfoxide (10 mL). Potassium tert-butoxide (0.317 g) was added and the mixture was stirred for 10 min at room temperature. Iodobutane (0.33 mL) was added and the mixture was allowed to stir at room temperature for 6 h. Water was then added and the mixture was partioned between ethyl acetate, water, and brine, and dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography using heptane/dichloromethane (30/70) gave butyl 1-butyl-1H-indole-6-carboxylate (0.429 g). MS (ESI+) for C17H23NO2+H1 m/z 274.20 (M+H)+.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B(Br)(Br)Br.[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1(N=C(N(CC)CC)N(CC)CC)CCCCC1.C1(C2C=CC=CC=2)C=CC=CC=1.C(=O)=O.C(=O)([O-])N.C1(N=C=O)CCCCC1>C(OCC)C.C(Cl)Cl>[CH2:1]([NH:9][C:10](=[O:11])[NH:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CCCCCCCCN=C=O
Agent: BrB(Br)Br
Agent: CCN(CC)C(=NC1CCCCC1)N(CC)CC
Agent: NC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: CCCCCCCCNC(=O)NCCCCCCCC
Reaction time: 0.08 h
Yield: 26 %

Procedure:
This example demonstrates the preparation of n-octylisocyanate using boron tribromide as the "dehydrating agent." A 100 mL Fischer-Porter bottle was charged with octylamine (0.64 g, 5.0 mmol), cyclohexyltetraethyl guanidine (2.53 g, 10.0 mmol), biphenyl (0.15 g, 1 mmol; internal standard) and 25 mL of CH2Cl2. The reaction vessel was pressurized to 80 psig with CO2 and rapid stirring was initiated. A second Fischer-Porter bottle was charged with boron tribromide (1.26 g, 5.0 mmol) and 25 mL CH2Cl2, then pressurized to 80 psi with CO2. The solutions were stirred for 20 minutes at 21° C. after which time the carbamate salt was added to the solution of BBr3. A sample was taken after five minutes and diluted with diethyl ether and analyzed by gas chromatography. The yield of cyclohexylisocyanate was 13% relative to the biphenyl internal standard. The reaction mixture was stirred for 24 hours at the end of which time a second sample was taken giving 26% yield of cyclohexylisocyante and 30% di-n-octyl urea (85% conversion of amine) as determined by gas chromatography.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[CH:12][C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]1.C([BH3-])#N.[Na+]>CO.CS(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:19][N:24]5[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]5)=[CH:21][CH:22]=4)=[CH:12][C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cc3cc(-c4ccccc4)ccc3o2)cc1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(-c5ccccc5)ccc4o3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
A mixture of 4-(5-phenylbenzofuran-2-yl)benzaldehyde (49 mg, 0.14 mmol) and azetidine-3-carboxylic acid (30 mg, 0.28 mmol) in MeOH (1 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (60 mg, 0.28 mmol) was added in two portions and the reaction mixture was stirred for 16 h. Concentration of the solvent under reduced pressure yielded a yellow solid that was dissolved in DMSO (3 mL) and filtered to give a yellow solution that was purified by HPLC to yield 3 mg of desired product: 1H NMR (400 MHz, CD3OD) δ 8.03 (d, 2H), 7.84 (br s, 1H), 7.66-7.58 (m, 6H), 7.45 (t, 2H), 7.36-7.32 (m, 2H), 4.47 (s, 2H), 4.40-4.32 (m, 4H), 3.72 (m, 1H). MS (ESI) m/z: Calculated: 383.15; Observed: 383.9 (M++1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=O)[CH:6]=[CH:7][CH:8]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1C=CC=CC=1>[S:29]=[C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=1
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)N1CCCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: FC(F)(F)c1cccc(CC(=S)N2CCCCC2)c1
Yield: 182.4 %

Procedure:
A mixture of 135.6 g of 1-[[3-(trifluoromethyl)phenyl]acetyl]piperidine, 101.1 g of Lawesson's reagent and 400 ml of benzene was heated at reflux for 6 hours, cooled and concentrated in vacuo. The residue was taken up in dichloromethane, filtered through a bed of neutral alumina with 3 liters of dichloromethane elution. The filtrate was concentrated in vacuo. The resulting oil was vacuum distilled giving 131 g of 1-[1-thioxo-2-[3-(trifluoromethyl) phenyl]ethyl]piperidine, bp 181°-182° C. (3.0 mmHg).
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[N:9]=[C:10]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[O:11][CH:12]=1)=O)C.CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl.C1(C)C=CC=CC=1.O>[C:16]([SiH2:15][O:14][C:13]([CH3:21])([CH3:20])[C:10]1[O:11][CH:12]=[C:8]([CH:6]=[O:5])[N:9]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1coc(C(C)(C)O[SiH2]C(C)(C)C)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(C=O)co1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazole-4-carboxylic acid ethyl ester (283 mg, 0.99 mmol) in CH2Cl2 (5.0 mL) was treated at −78° C. with DiBAL (1.85 mL of a 1M sol in toluene, 1.85 mmol) and the reaction mixture was stirred for 1 h at −78° C. MeOH (70 μL) and H2O (100 μL) were added and the reaction mixture was allowed to warm to rt. The reaction mixture was filtered, and the solvent removed under reduced pressure to give the title compound as a colorless oil. TLC:rf (1:1 hept-EA)=0.61. LC-MS-conditions 02: tR=1.03 min; [M+H2O+H]+=260.50.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1([B-](F)(F)F)[CH2:12][CH2:11]1.[K+].C([O-])([O-])=O.[Cs+].[Cs+].C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH:10]1([C:2]2[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: F[B-](F)(F)C1CC1
Reactant: Cc1ccnc(Br)c1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(C2CC2)c1N
Temperature: 80 °C

Procedure:
Following a modified synthetic procedure reported in J. Org. Chem. 2003, 68, 5534, a mixture of 2-bromo-4-methylpyridin-3-amine (1.0 eq.), potassium cyclopropyltrifluoroborate (2.0 eq.), Cs2CO3 (3.0 eq.) and PdCl2(dppf)-CH2Cl2 adduct (0.1 eq.) in 10:1 solution THF:H2O (0.14M) was put in a 10-mL glass vial equipped with a small magnetic stirring bar. The reaction vessel was fitted with a rubber septum, was evacuated and back-filled with argon and sealed with an aluminum/Teflon crimp top. The reaction mixture was then heated for O/N at 80° C. After completion of the reaction, the vial was cooled to RT before it was opened. The reaction mixture was diluted with EtOAc and filtered on a pad of Solca Floc®200FCC. The crude product was purified by flash chromatography eluting with 10-100% EtOAc/petroleum ether affording the titled compound as brown oil. 1H-NMR (400 MHz, DMSO-d6, 300K) δ 7.55 (1H, d, J=4.7 Hz), 6.75 (1H, d, J=4.7 Hz), 4.89 (2H, br. s), 2.13-2.04 (4H, m), 0.85-0.68 (4H, m). MS (ES) C9H12N2 requires: 148, found: 149 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:7]4[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH:27](O)=[O:28]>>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:8]1[C:7]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([NH:1][CH:27]=[O:28])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: O=CO
Reactant: Nc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Product: O=CNc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Yield: 54 %

Procedure:
Amine (919) prepared as described in example 467 and formic acid were reacted using the procedure described in example 468 with a reaction time of 4 h to give the formamide (921) (54%) as a yellow powder, mp 293–297° C. 1H NMR δ [(CD3)2SO] 12.11 (s, 0.5H), 12.08 (s, 1H), 11.12 (s, 0.5H), 11.08 (s, 1H), 10.34 (s, 1H), 10.30 (s, 0.5H), 9.03 (d, J=1.9 Hz, 1H), 8.69 (m, 0.5H), 8.31 (d, J=1.8 Hz, 1.5H) 7.92 (dd, J=8.8, 1.9 Hz, 1H) 7.42–7.65 (m, 9.5H). Found: C, 64.78; H, 3.53; N, 9.96. C21H12ClN3O3.1/4 THF requires: C, 64.86; H, 3.44; N, 10.32.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Yield: 59.9 %

Procedure:
To a 25-mL RB flask, equipped with a condensor, was added tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate (1.0 g), 4-nitrophenylboronic acid (0.71 g), sodium carbonate (0.430 mL of 2M solution), lithium chloride (0.382 g), tetrakis(triphenylphosphine)-palladium (0) (0.173 g) and ethylene glycol dimethyl ether (10 mL). The reaction mixture was flushed with Argon three times, then the reaction mixture was heated to 100° C. for 3 hrs. After cooling to room temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3×20 mL) and the combined organic extracts were washed with sat NH4Cl (20 mL) and brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography (6:1=hexane:ethyl acetate with 1% NH3) to afford the product (0.55 g, 59.9%) as a yellow oil. The compound is not stable at room temperature and should be used as prompt as practical: 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 2H, J=8.6 Hz), 7.51 (d, 2H, J=8.6 Hz), 6.24 (m, 1H), 4.13 (m, 2H), 3.67 (apparent t, 2H, J=5.5 Hz), 2.55 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:19].[H-].[Na+].[Cl:24][C:25]([Cl:29])=[CH:26][CH2:27]Cl>CN(C)C=O>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:19][CH2:27][CH:26]=[C:25]([Cl:29])[Cl:24]
Reactant: CCOc1cccc(Oc2ccc(O)c(C(F)(F)F)c2)c1
Reactant: ClCC=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Oc2ccc(OCC=C(Cl)Cl)c(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a solution prepared by dissolving 0.44 g of 2-trifluoromethyl-4-(3-ethoxyphenoxy)phenol in 10 ml of N,N-dimethylformamide, 0.062 g of sodium hydride (60% oil-based) was added with stirring under ice cooling. After 10 minutes, a solution prepared by dissolving 0.24 g of 1,1,3-trichloro-1-propene in 5 ml of N,N-dimethylformamide was added dropwise under ice cooling. After stirring at room temperature for 10 hours, the reaction solution was poured into ice-water, and extracted twice with 50 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 0.37 g of 2-trifluoromethyl-4-(3-ethoxyphenoxy)-1-(3,3-dichloro-2-propenyloxy)benzene, yield 62%; nD23.6 1.5369.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[C:8]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:33]1[C:38]([I:39])=[CH:37][N:36]=[CH:35][N:34]=1>CS(C)=O.O>[I:39][C:38]1[C:33]([O:31][C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:15][N:16]=3)=[CH:30][CH:29]=2)=[N:34][CH:35]=[N:36][CH:37]=1
Reactant: Clc1ncncc1I
Reactant: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Ic1cncnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a brown mixture of cesium carbonate (2.79 g, 8.58 mmol) and 4-(4-phenylphthalazin-1-ylamino)phenol hydrochloride (1.00 g, 2.86 mmol) in 10 mL DMSO was added 4-chloro-5-iodopyrimidine (0.687 g, 2.86 mmol). The reaction was allowed to stir at RT for 1 h. The reaction was heated to and maintained at 70° C. overnight. The reaction was cooled and diluted with water. The solid was filtered and dried in vacuo to give N-(4-(5-iodopyrimidin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine as a gray solid. MS m/z=518 [M+H]+. Calc'd for C24H16IN5O: 517.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: COC(=O)c1cc(N)ccc1C
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-n2cccc2)ccc1C
Yield: 89.9 %

Procedure:
158 mg of methyl 3-amino-6-methylbenzoate was dissolved in 3 ml of acetic acid, and 139 mg of 2,5-dimethoxytetrahydrofuran was added. The mixture was heated under reflux for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography Wakogel C-200, 10 g; eluting solvent: hexane/ethyl acetate=10/1) to give 185 mg (yield 87%) of methyl 3-(1-pyrrolyl)-6-methylbenzoate, m.p. 56°-57° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13](=[O:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:18][CH2:19][CH:14]([C:13]([O:12][CH3:11])=[O:20])[CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1CCN(Cc2ccc(OC)cc2)CC1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
4-Methoxybenzyl chloride (1.10 g, 6.98 mmol) was added dropwise to a solution of isonipecotic acid methyl ester (1.00 g, 6.98 mmol) and triethylamine (1.40 g, 14 mmol) in THF (30 ml) and the mixture was stirred at 60° C. for 72 h. 5% strength sodium bicarbonate solution (50 ml) was then added to the reaction mixture and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (2:1).
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:19])[C:8]2[CH2:14][CH2:13][CH:12](O)[N:11]([C:16](=[O:18])[CH3:17])[C:9]=2[N:10]=1)(=[O:3])[CH3:2].[NH2:20][C:21]1[CH:40]=[CH:39][C:24]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])=[CH:23][CH:22]=1.CO.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl.CCO.C1C=CC=CC=1.C(O)(=O)C>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:19])[C:8]([CH2:14][CH2:13][CH2:12][NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])=[CH:39][CH:40]=2)=[C:9]([NH:11][C:16](=[O:18])[CH3:17])[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(c(=O)[nH]1)CCC(O)N2C(C)=O
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(NC(C)=O)nc(NC(C)=O)[nH]c2=O)cc1)C(=O)OC

Procedure:
A mixture of 2.30 g (7.6 mmol) of 2-acetamido-8-acetyl-5,6,7,8-tetra hydro-7-hydroxypyrido[2,3-d]pyrimidin-4(3H)-one, 2.40 g (8.15 mmol) of dimethyl N-(4-aminobenzoyl)-L-glutamate, 5 g of 3A molecular sieves, 150 ml of methanol, and 4 ml of acetic acid was stirred with protection from moisture for 3 hours when "imine" formation was complete. Sodium cyanoborohydride (0.38 g) and 8 ml of acetic acid was added to the reaction. After 15 hours a trace of intermediate "imine" was detected by TLC and an additional 50 mg of sodium cyanoborohydride was added. After 1 hour the reaction was diluted with 500 ml of chloroform and filtered through a Celite pad to remove the insolubles. The chloroform solution was washed with four 50 ml portions of 5% aqueous sodium bicarbonate, two 50 ml portions of water, one 50 ml portion of brine, dried over magnesium sulphate and spin evaporated in vacuo. The resultant foam was triturated with 50 ml of ethyl acetate to give white crystals; yield, 2.75 g (65%), mp 144°-150°. Recrystallization from ethanol gave chromatographically pure material; yield, 1.70 g (40%), mp 135°-142°. An analytically pure sample was obtained from a previous run with mp 140°-143°; TLC: (C6H6 : EtOH/10:1); NMR (DMSO-d6)δ11.69 (br s, 2H, 2AcNH) 9.68 (br s, 1H, ring NH), 8.24 (br d, 1H, ArCONH), 7.65 (d, 2H, ArH), 6.53 (d, 2H, ArH), 6.17 (br t, 1H, CH2NH), 4.39 (m, 1H, CHCO2CH3), 3.63 (s, 3H, CO2CH3), 3.58 (s, 3H, CO2CH3), 3.01 (m, 2H, CH2NHAr), 2.43 (m, 2H, CH2CO2CH3), 2.1 (4H, pyrimidine --CH2 and CHCH2, masked by AcNH peaks), 2.14 (s, 3H, Ac), 2.01 (s, 3H, Ac), 1.72 (m, 2H, CH2CH2CH2).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:44])=[C:41]([CH:43]=1)[NH2:42]>O1CCCC1>[Br:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:44])=[C:41]([NH:42][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)=[CH:26][CH:25]=2)[CH:43]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: O=C(Cl)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Br)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 4-(4-phenylquinazolin-2-ylamino)benzoyl chloride (1.0 g, 2.8 mmol) and Hunig's base (600 μL, 3.4 mmol) in tetrahydrofuran (25 mL) was added 5-bromo-2-methylaniline (600 mg, 3.2 mmol), and the reaction was allowed to stir at rt overnight. The mixture was concentrated on a rotary evaporator and purified by flash column chromatography to give N-(5-bromo-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (1.0 g, 70%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.77 (s, 1H), 8.18 (d, 2), 7.98 (d, 2H), 7.82 (m, 6H), 7.65 (m, 4H), 7.41 (dt, 1H), 7.35 (dd, 1H), 7.25 (d, 1H), 2.24 (s, 3H). MS (EI) for C28H21BrN4O: 511.2 (MH+).
Reaction SMILES: [CH:1]1([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:22]=[CH:21][O:20][N:19]=4)=[CH:14][CH:13]=3)[C:10](=[O:23])[C:9]([OH:24])=[C:8]2[C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN.O[N:40]1[C:44]2C=CC=CC=2N=N1.CN(C)C1C=C[NH+]=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O.C(OCC)(=O)C.CN(C=O)C>[CH:1]1([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:22]=[CH:21][O:20][N:19]=4)=[CH:14][CH:13]=3)[C:10](=[O:23])[C:9]([OH:24])=[C:8]2[C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH:40][CH3:44])=[CH:28][CH:27]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(-c4ccon4)cc3)C2C2CCCCC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(-c4ccon4)cc3)C2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a mixture of 5-cyclohexyl-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-4-(4-carboxybenzoyl)-1,5-dihydropyrrol-2-one (0.095 g, 0.2 mmol) and DMF (2 mL) was added, methylamine hydrochloride (0.020 g, 0.3 mmol), 1-hydroxybenztriazole (0.041 g, 0.3 mmol), 4-dimethylaminopyridinium (0.005 g, 0.04 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.058 g, 0.3 mmol) and triethylamine (0.042 mL, 0.3 mmol). The mixture was stirred at r.t. for 1 hr. Ethyl acetate and water were added, and the precipitate was collected by filtration to give 5-cyclohexyl-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-4-(4-methylcarbamoylbenzoyl)-1,5-dihydropyrrol-2-one (0.062 g, 64%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=C(OCC)C=1[N:46]1[CH:50]=[CH:49][CH:48]=[CH:47]1)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1[N:46]1[CH:50]=[CH:49][CH:48]=[CH:47]1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1F
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), N-piperidin-4-yl-3-(1H-tetrazol-5-yl)-benzamide (example 178) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 516.2 (MH+).