Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:5][N:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH2:39])=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH:39][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][CH2:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Reactant: COc1cc(CNc2ccccc2C(=O)O)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(CNc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-benzoic acid (Step A, 516 mg, 2.0 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol), TBTU (0.706 g, 2.2 mmol), and DIEA (0.7 mL) in 30 mL of CH2Cl2 was stirred at RT for 2 h. The mixture was diluted with more CH2Cl2. The organic layer was washed with water, brine, and dried with MgSO4. The solution was filtered, condensed, and the residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2) to obtain the titled compound as oil. MS (ES+): 517.2 (M+H)+. Calc'd for C30H36N4O4-516.27.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26](I)=[N:27][NH:28][C:22]=2[CH:21]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:38]=2)[CH2:33][CH2:32]1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26]([C:40]3[CH:39]=[N:38][C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:42][CH:41]=3)=[N:27][NH:28][C:22]=2[CH:21]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3[nH]nc(I)c3cn2)c1F
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc(N5CCN(C)CC5)nc4)c3cn2)c1F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine. LCMS (M+H)+=467.2.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[C:6]([F:12])[CH:5]=1)=O.[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[F:12][C:6]1[CH:5]=[C:4]([C:2]2[CH:1]=[CH:16][C:15](=[O:19])[NH:14][N:13]=2)[CH:9]=[C:8]([F:10])[C:7]=1[F:11]
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1cc(F)c(F)c(F)c1
Product: O=c1ccc(-c2cc(F)c(F)c(F)c2)n[nH]1

Procedure:
20 g of 3,4,5-trifluoroacetophenone are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH-:15].[K+]>CC(O)(C)C.[Na+].[Cl-]>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:15]
Reactant: CCOC(=O)Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc(CC(=O)O)cc1

Procedure:
A mixture of ethyl 4-cyanobenzeneacetate (1.9 g) and freshly ground KOH (2.8 g) in 2-methylpropan-2-ol (20 ml) was heated under gentle reflux for 20 min. The resulting mixture was cooled, diluted with 50% saturated NaCl solution (50 ml), washed with CHCl3 (4×50 ml), and acidified with 2M hydrochloric acid (25 ml) to precipitate the title compound (1.65 g) as a fine white solid m.p. 226°-227°.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:19])[CH:11](Cl)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:22]([NH2:24])[CH3:23].[I-].[K+]>CCCCCC.C(OCC)(=O)C>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:19])[CH:11]([NH:24][CH2:22][CH3:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCN
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)C(Cl)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCNC(C(=O)Nc1cccc(C(F)(F)F)c1)c1ccccc1
Yield: 89 %

Procedure:
An ethanolic (200 mL) solution of N-(3-trifluoromethylphenyl)-2-chloro-2-phenylacetamide (200.0 grams, 0.06 mol) and 70% aqueous ethylamine (75 mL, excess) and potassium iodide (1.0 gram, catalytic) was stirred at room temperature. The reaction was followed by thin layer chromatography (3:1 hexane-ethyl acetate). The mixture was worked up by removing the ethanol and the excess ethyl amine in a rotary evaporator. The residue was redissolved in fresh ethanol and concentrated hydrochloric acid (excess) was added to convert the product to its hydrochloride salt. Water and other excess reagents were removed by azeotropic distillation in a rotary evaporator. The salt was washed with ethyl ether and dissolved in saturated sodium bicarbonte to regenerate the amine. The product was extracted into ethyl acetate and isolated to give the desired N-(3-trifluoromethylphenyl)-2-ethylamino-2-phenylacetamide (17.1 grams, 89% yield) whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.
Reaction SMILES: CN.[NH2:3][C:4]1[C:9]([C:10]2[O:11][C:12]3[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][C:7]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:6][N:5]=1.F[P-](F)(F)(F)(F)F.[CH3:47][N:48](C(=[O+]N1C2=NC=CC=C2N=N1)N(C)C)C>CO.CN(C=O)C>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:8][C:9]=1[C:10]1[O:11][C:12]2[C:18]([C:19](=[O:20])[NH:48][CH3:47])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: CN(C)C(=[O+]n1nnc2cccnc21)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5cccc(C(=O)O)c5o4)c3)cn2)CC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc2nc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.8 %

Procedure:
A 2M solution of methylamine in methanol (0.535 ml) was added to a mixture of 2-[2-amino-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazole-7-carboxylic acid (270 mg) and bis(dimethylamino)methylene-(triazolo[5,4-b]pyridin-3-yl)oxonium hexafluorophosphate (285 mg) dissolved in DMF (1 ml). The resulting solution was heated at 25° C. for 1 day. A 2N solution of methylamine (0.535 ml) in methanol was added and the mixture was stirred at 25° C. in a sealed tube for 3 days. The mixture was evaporated to dryness and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 20 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-[7-(methylcarbamoyl)-1,3-benzoxazol-2-yl]-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (210 mg) as a pale yellow solid. NMR Spectrum: (DMSOd6) 1.43 (s, 9H), 1.80 (dd, 1H), 1.85 (dd, 1H), 2.01-2.11 (m, 2H), 2.94 (bs, 2H), 2.96 (d, 3H), 4.00-4.13 (m, 2H), 4.36-4.46 (m, 1H), 7.51 (dd, 1H), 7.65 (bs, 2H), 7.82 (dd, 1H), 7.93 (s, 1H), 7.98 (dd, 1H), 8.30 (s, 1H), 8.43 (q, 1H), 8.54 (d, 1H), 8.57 (d, 1H); Mass spectrum: M+H+ 518.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[CH:20]=1)(=[O:17])[CH3:16]>>[C:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:20]=1)(=[O:17])[CH3:16]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CC(=O)Oc1cccc(CO)c1
Product: CC(=O)Oc1cccc(COc2ccnn2-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-(hydroxymethyl)phenyl acetate according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.24 (3H, s), 5.17 (2H, s), 5.66 (1H, d, J=1.6 Hz), 7.01-7.03 (1H, m), 7.14 (1H, s), 7.20-7.22 (1H, m), 7.32-7.36 (2H, m), 7.49 (1H, d, J=1.6 Hz), 7.97 (1H, s), 8.63 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H14N4O3, 335; Found, 335.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:18][N:19](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Temperature: 150 °C
Yield: 31 %

Procedure:
Compound 113 (530 mg, 1.8 mmol) was dissolved in dry DMF (17 mL) under N2.Zn(CN)2 (416 mg, 3.6 mmol) and Pd(PPh3)4 (200 mg, 0.18 mmol) was added. The reaction mixture was stirred and heated at 150° C. in a microwave instrument (CEM Discover®) for 20 min and the reaction mixture was then concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexanes (20˜80%) to yield 114 (540 mg, 31%) as a white solid. MS (APCI, negative): m/z 245 [M−H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([CH3:10])[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.[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=1
Reactant: CC(C)C[Mg]Br
Reactant: Cc1cc(C=O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(O)CC(C)C)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-Dimethyl-4′-trifluoromethyl-biphenyl-4-carbaldehyde (1.0 g, 3.6 mmol) in THF (10 mL) at 0° C. is added isobutyl magnesium bromide (2M, 2.2 mL). After stirring at room temperature for 2 hours, it is quenched with saturated ammonium chloride, extracted with EtOAc. The organic is concentrated to give the titled compound as colorless oil: 0.47 g (39%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[N:10]=1)[C:5]([NH2:7])=O.CSC.Cl.[OH-].[Na+]>C1COCC1>[NH2:7][CH2:5][C:4]1[CH:8]=[C:9]([NH2:11])[N:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: NC(=O)c1cc(N)nc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1cc(N)nc(N)c1
Yield: 36.5 %

Procedure:
To a refluxing suspension of 0.5 g (3.29 mmol) 2,6-diamino-isonicotinamide in 3 ml THF was added dropwise 0.455 ml (4.8 mmol) boran-dimethylsulfide-complex and the mixture was refluxed for 4 d. After cooling to room temperature 0.548 ml 6N HCl was added and the mixture was neutralized with 2N NaOH. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica eluting with DCM:MeOH:NH3aq. 100:100:1 to yield 166 mg (36%) of the title compound as yellow solid.
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[CH:26]=[C:25]([Br:27])[C:24]([NH2:28])=[C:23]([CH3:29])[C:22]=1[CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C([O-])(=O)C.[K+]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[C:22]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:23]2[C:24](=[C:25]([Br:27])[CH:26]=1)[NH:28][N:1]=[CH:29]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c(N)c(C)c1COC(C)=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
Isoamyl nitrite (2.3 mL, 17 mmol), was added drop-wise to an ice cold solution of 2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic acid diethyl ester (7.14 g, 16 mmol) in 5% acetic acid in toluene (280 mL). Mixture stirred at 0° C. for 40 minutes. Potassium acetate (4.00 g, 41 mmol) was added to the mixture. Mixture was slowly warmed to room temperature. Reaction was stirred at room temperature for 14 hours. Mixture was washed twice with water and once with brine. Organic was dried (magnesium sulfate) filtered and concentrated. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 77% yield as an amber oil. MS m/e (M+H)+=455.0, 457.0.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[C:9]1([CH3:8])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[NH:17][C:18]([N:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7])=[O:19]
Reactant: Cc1cc(C)c(N=C=O)c(C)c1
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: Cc1cc(C)c(NC(=O)N=C2CCCN2C)c(C)c1
Temperature: 25 °C

Procedure:
The hydrochoride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 L mole) is converted to free base (4.0 g.; 0.05 mole) by adding 10 ml. of 50% NaOH to an aqueous slurry (minimal amount of water) of the salt and benzene extraction. After drying over K2CO3, the benzene solution is stirred at room temperature and 8.06 g. (0.05 mole) of 2,4,6-trimethylphenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene is added. The reaction mixture is stirred at room temperature for 11/2 hours and then the solvent is evaporated in vacuo leaving an oily residue, which crystallizes on cooling. Recrystallizaton from acetone yields the pure product, 1-mesityl-3-(1-methyl-2-pyrrolidylidene)urea, m.p. = 121°-123° C.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[NH2:10][CH2:11][CH2:12][OH:13]>[OH-].[Na+]>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][NH:10][CH2:11][CH2:12][OH:13])[CH3:3]
Reactant: NCCO
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)CCNCCO
Temperature: 120 °C
Reaction time: 5 h
Yield: 43.1 %

Procedure:
A mixture of 2-(diethylamino)ethylchloride hydrochloride (18 g, 0.11 mol) and 2-aminoethanol (19 mL, 0.32 mol) was stirred at 120° C. for 5 hours. After the reaction mixture was cooled to room temperature, a 1.0 mol/L aqueous solution of sodium hydroxide (40 mL) was added thereto, and the mixture was extracted with chloroform (100 mL×6). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was distilled to obtain N,N-diethyl-N′-(2-hydroxyethyl)ethylenediamine (7.6 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.Cl.[CH2:18]([N:20]([CH2:33][CH3:34])[CH2:21][CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][N:20]([CH2:33][CH3:34])[CH2:18][CH3:19])=[CH:32][CH:31]=3)[C:6]=2[CH:16]=1
Reactant: CCN(CC)CCOc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2oc(-c3ccccc3)cc2c1
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1

Procedure:
Acylation of 5-chloro-2-phenylbenzofuran with 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride as described in the procedure of Example 6 gives the title compound which is converted to the corresponding hydrochloride salt as described in the procedure of Example 1, m.p. 197°-199° (ethyl acetate).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[C:13]([O:20][CH3:21])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].Cl>C1COCC1.O>[C:23]([C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[C:13]([O:20][CH3:21])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(C(=O)O)c(Br)c(OC)c1OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)c(C(=O)OCc2ccccc2)c(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyllithium (1.7M solution in pentane, 15 mmol) is added to a solution of 2-bromo-3,4,5-trimethoxybenzoic acid 5 (5 mmol, synthesis described in Example 12) in 50 mL of THF, while maintaining the temperature of the mixture below −95° C. After the addition is completed, the mixture is allowed to warm to −78° C. After 30 minutes, benzyl chloroformate (5 mmol) is added in one portion, and the mixture is allowed to warm to 0° C. Water (50 mL) is added, and then the pH of the mixture is carefully adjusted to 3 using 0.1 M HCl. The mixture is extracted with ethyl acetate (5×100 mL). The organic phases are dried over anhydrous Na2SO4 and concentrated in vacuo. The mixture is purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([Cl:20])=[N:7][C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[N:9][C:10]=1[Cl:11].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](O)=[O:33].CCOC(C)=O>C1COCC1>[Cl:20][C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])=[C:10]([Cl:11])[N:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:32]([C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:33])=[CH:15][CH:14]=2)[N:7]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1Cl
Reactant: O=C(O)c1ccc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 669.2 %

Procedure:
A mixture of methyl[2-(4-aminobenzyl)-4,6-dichloropyrimidin-5-yl]acetate (0.073 g, 0.23 mmol), 2-naphthoic acid (0.048 g, 0.028 mmol), and WSCI (0.049 g, 0.026 mmol) in anhydrous THF (3 mL) was stirred at room temperature under Ar atmosphere for 10 hours. EtOAc (80 mL) was then introduced and the organic phase was washed sequentially with saturated NaHCO3, water, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained as a light orange oil was triturated with diisopropyl ether and the separated solids was collected by suction to give methyl {4,6-dichloro-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.090 g, 78% yield) as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:36])[N:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])=O)(C)(C)C>C(Cl)Cl>[CH2:29]([O:28][N:21]([C:20](=[O:36])[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (25 mL) was slowly dripped into a solution of (4) (7.10 g, 13.93 mmol) in CH2Cl2 (150 mL) which had been cooled to 0° C. The solution was stirred at 0° C. for 30 minutes and at room temperature for 15 minutes. Solvent and excess TFA were removed by rotary evaporation, and the concentrate was cooled to 0° C., treated with saturated NaHCO3 (150 mL) and extracted with CH2Cl2 (4×80 mL). After solvent removal, the crude oil was purified by silica gel column chromatography with 1:1 hexane/EtOAc as the eluant, generating 4.6 g (81%) of (5) as an oil: NMR δ 1.40-190 (m, 8H), 2.30 (t, 2H, J=6), 2.40 (t, 2H, J=6), 2.90 (t, 2H, J=6), 3.63 (t, 2H, J= 6), 4.63 (s, 2H), 4.75 (s, 2H), 4.93 (br s, 1H), 7.27 (s, 5H), 7.33 (s, 5H). Anal. (C24H31N3O3) C, H, N.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[C:31]([CH:39]=O)=[CH:32][C:33]2[O:37][CH2:36][O:35][C:34]=2[CH:38]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:31]3[C:30]([Br:29])=[CH:38][C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2c(cc1Br)OCO2
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc5c(cc4Br)OCO5)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 6-bromo benzo[1,3]dioxole-5-carbaldehyde. MS (ESI) m/z 591.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.Cl.[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Agent: Cl
Product: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)c(OC(C)C)c1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 6) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone hydrochloride (Oakwood Chemicals) in an analogous manner as described in example 8. LR-MS: 694.3 [(M+H)+].