Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[C@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(-c2ccccc2)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -74 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A stirred solution of (S)-4-benzyl-3-(3-(biphenyl-4-yl)propanoyl)oxazolidin-2-one (intermediate 12: 5.01 g, 13.00 mmol) in THF (180 mL) is cooled to −73.8° C., and 1M THF solution of sodium hexamethyldisilylamide (14.30 mL, 14.30 mmol) is added during 5 minutes. After 30 minutes, a solution of tert-butyl bromoacetate (2.495 mL, 16.90 mmol) in THF (20 mL) is added dropwise during 5 minutes. The solution is stirred at −74° C. for 1 hour, and the reaction is quenched with saturated aqueous NH4Cl (100 mL), and warmed up to ambient temperature. The precipitated solid is filtered off and washed with ethyl acetate (50 mL). The organic phase is separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The obtained residue is suspended in MeOH (70 mL) and then filtered to collect the solid (5.9 g) as a mixture of the desired product and the starting material. The mixture is purified by flash column chromatography on 120 g of silica gel (heptane/EtOAc=90:10 to 50:50) to give (R)-tert-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(biphenyl-4-ylmethyl)-4-oxobutanoate (2.40 g, 37%). HPLC retention time=1.74 minutes (condition B); MS=499.4 (m+); 443.4 (m-tBu+1; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (s, 9 H) 2.42 (dd, J=16.67, 4.04 Hz, 1 H) 2.71 (ddd, J=16.55, 13.26, 9.60 Hz, 2 H) 2.87 (dd, J=16.93, 10.86 Hz, 1 H) 3.04 (dd, J=13.14, 6.32 Hz, 1 H) 3.32 (dd, J=13.39, 3.03 Hz, 1 H) 3.92 (t, J=8.34 Hz, 1 H) 4.07 (dd, J=8.97, 2.15 Hz, 1 H) 4.48-4.58 (m, 2 H) 7.20-7.30 (m, 3 H) 7.30-7.36 (m, 5 H) 7.42 (t, J=7.58 Hz, 2 H) 7.52 (d, J=8.1 Hz, 2 H) 7.56 (d, J=7.8 Hz, 2 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[NH2:26])=[CH:15][CH:14]=1>C(O)C>[CH3:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[C:20]2/[CH:21]([N:26]3[CH2:4][CH2:3][CH2:2]3)[CH2:22][CH2:23][CH2:24][CH2:25]/2)=[CH:17][CH:18]=1
Reactant: BrCCCBr
Reactant: Cc1ccc(C=C2CCCCC2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(/C=C2\CCCCC2N2CCC2)cc1

Procedure:
A mixture of N-[2-[4-methylphenyl)methylene]cyclohexyl]amine, from step C above, 0.64 g (3.2 mmol) with 1.28 g (6.4 mmol) of 1,3-dibromopropane and 0.88 g (6.4 mmol) of potassium carbonate in 20 ml of ethanol as refluxed 18 hr, evaporated and the residue was taken up in a water/diethyl ether mixture. The aqueous layer was separated and saturated with solid potassium hydroxide and extracted with diethyl ether. The ether extract was washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated. The residue, 0.67 g, was chromatographed using a HPLC Merck C silica gel column using a 3% methanol in chloroform solution containing 0.5% ammonium hydroxide mixture as eluent. Elution with 620 ml of this eluting mixture gave mixtures of products containing the N-allyl derivative of the starting N-[2-[(4-methylphenyl)methylene]cyclohexyl]amine. Elution of the column contents with 5% methanol in chloroform containing 0.5% ammonium hydroxide (240 ml) gave no product. The next 540 ml gave 180 mg of (±)-(E)-1-[2-[(4-methylphenyl)methylene]cyclohexyl]-azetidine. GC analyses (3% SE 30) 100% at 4.99 min, UV λmax(ε)247(15,300). HR mass spectrum Found 241.1844, Calcd. for C17H23N 241.1830. The NMR spectrum was also consistent for this named product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH:17]([C:14]1([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15]1)=[O:18]
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccc3ccccc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=CC1(c2ccc3ccccc3c2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[(Benzyloxy)carbonyl]-4-(2-naphthyl)piperidine-4-carboxylic acid To a solution of 1.60 g (3.59 mmol) of Intermediate 9 in 10 mL of anhydrous dichloromethane was added 10 mL of trifluoroacetic acid. The resulting mixture was stirred at ambient temperature for 2 h and then all volatiles were removed in vacuo. The resulting residue was dissolved in 15 mL of anhydrous toluene and all volatiles were again removed in vacuo to afford the title compound as a white solid. LC/MS 390.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33][S:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:6][CH:7]=1)(=[O:36])=[O:35]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1Cl
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3cccc(Cl)c3Cl)cc2)c2ccc3c(c2N1)CCCC3
Yield: 91.8 %

Procedure:
By using 5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (32 mg, 0.100 mmol) obtained in Example 55, and (2,3-dichlorophenyl)methanesulfonyl chloride (31 mg, 0.119 mmol), the title compound (50 mg, yield 92%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C(O)C1CNC1
Product: O=C(O)C1CN(C(=O)c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (104 mg, 0.266 mmol) and azetidine-3-carboxylic acid (32 mg, 0.320 mmol). MS (ESI) m/z: Calculated: 473.1; Observed: 474.1 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])=[C:10]([CH2:36][CH:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)[CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(CC2CCCCC2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid ethyl ester (0.54 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.95 (dd, 1H, J=7.8 Hz, J=1.0 Hz) 7.64-7.69 (m, 3H), 7.50-7.54 (m, 1H), 7.46 (t, 2H, J=7.6 Hz), 7.37-7.39 (m, 1H), 6.77 (d, 1H, J=8.3 Hz), 6.66 (d, 1H, J=3.4 Hz), 6.62 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 4.17 (t, 2H, J=6.4 Hz), 3.03 (t, 2H, J=6.4 Hz), 2.41 (s, 3H), 1.62-1.65 (m, 5H), 1.52 (s, 6H), 1.44 (s, 2H), 1.15-1.19 (m, 4H), 0.85-0.91 (m, 2H), MS (ES) m/e 554.2 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[C:32]1([S:29]([NH:28][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([OH:38])=[O:5])(=[O:31])=[O:30])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h

Procedure:
40.1 mg of (2S)-2-benzenesulfonylamino-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-propionic acid tert-butyl ester were dissolved in trifluoroacetic acid/water (95/5) and stirred for 2 hours. The solvent was removed in vacuo, and the residue was dissolved in acetic acid/water and lyophilized. Yield 24 mg. MS (ES+): m/e=489.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.CON(C)[C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1)=[O:16]>C1COCC1.[Ni].Cl>[CH3:22][N:20]1[CH:21]=[C:17]([C:15]([C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[O:16])[CH:18]=[N:19]1
Reactant: CON(C)C(=O)c1cnn(C)c1
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: [Ni]
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cc(C(=O)c2ccc(C(F)(F)F)nc2)cn1
Temperature: -78 °C
Yield: 34.1 %

Procedure:
A solution of 5-bromo-2-(trifluoromethyl)pyridine (3.80 g, 16.82 mmol) in THF (24 ml) was cooled at −18° C. A solution of isopropylmagnesium chloride lithium chloride complex in THF (17.97 ml, 14.02 mmol, 0.78 molar) was added dropwise over a period of 30 minutes. The reaction was then cooled at −78° C. kept there for 1½ hour. The reaction was allowed to reach −3° C. before being cooled to −10° C. A solution of N-methoxy-N,1-dimethyl-1H-pyrazole-4-carboxamide (2.372 g, 14.02 mmol) in THF (8 ml) was added dropwise over a period of 5 minutes. The reaction was allowed to warm to room temperature and stirred over night. Cooled to 0° C. and a 2 Ni HCl solution (150 mL) was added slowly. The crude mixture was extracted with AcOEt (3×150 mL), the combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by comlumn chromatography to yield (1-methyl-1H-pyrazol-4-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone 1.22 g (34%) as a light yellow solid.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:19]=[CH:18][C:11]2[C:12]([CH2:16]O)=[CH:13][CH2:14][O:15][C:10]=2[CH:9]=1.S(Cl)([Cl:22])=O>C(OCC)C>[F:7][C:8]1[CH:19]=[CH:18][C:11]2[C:12]([CH2:16][Cl:22])=[CH:13][CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1=CCOc2cc(F)ccc21
Solvent: c1ccncc1
Solvent: CCOCC
Product: Fc1ccc2c(c1)OCC=C2CCl
Reaction time: 2 h

Procedure:
1.22 g of pyridine are added to 28 g of 7-fluoro-4-hydroxymethyl-2H-1-benzopyrane in 50 ml of diethylether. The mixture is cooled to 5° and 2 g of thionylchloride in 10 ml diethylether slowly added dropwise. The reaction is continued for 30 minutes at 5°-10° and 2 hours at room temperature. The resulting mixture is poured onto ice-water, the organic phase separated and the aqueous phase extracted with a further 20 ml of diethyl ether. The combined ether solutions are dried over MgSO4 and concentrated by evaporation.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[Cl:1][C:14]1[C:10]([CH3:9])=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:12][C:13]=1[CH3:15]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-Chlorosuccinimide (1.77 g, 13.25 mmol) was added to a solution of ethyl 3,5-dimethyl-2-pyrrole carboxylate (2.11 g, 12.62 mmol) in chloroform (45 mL). The reaction mixture was stirred at room temperature for 24 h and then poured into 2 N NaOH. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude solid. The crude solid was dissolved in hot MeOH, cooled to room temperature, and the precipitate was collected by filtration (493 mg, 19%). MS (ES) MH+: 174 for C9H12ClNO2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=1.O1CCOCC1.C([O-])(O)=O.[Na+]>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.O>[NH2:20][C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)[CH:15]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=1
Reactant: Nc1nc(Cl)cc(Nc2ccccc2)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(Nc3ccccc3)nc(N)n2)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To (4-cyano-3-fluorophenyl)boronic acid (197 mg, 1.20 mmol) and 6-chloro-N4-phenyl-2,4-pyrimidinediamine (330 mg, 1.50 mmol) in a sealable flask were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL). The mixture was degassed with nitrogen gas for 10 minutes. Pd(Ph3P)4 (86 mg, 0.075 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto EtOAc and water. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was chromatographed on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH) to afford the title compound (366 mg). LC-MS (ES) m/z=306 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)nc[nH]1

Procedure:
6-[4-(3,4-Dichloro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3,4-dichlorobenzaldehyde. Mass spectrum (ES) MH+=339.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(F)c1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
2,3-Difluorophenol (4.55 g) was dissolved in DMF (25 mL) and was treated with powdered K2CO3 (6.0 grams) and the mixture was stirred at an ambient temperature for 10 minutes under nitrogen atmosphere. The mixture was treated with iodomethane (9.0 grams), and was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and was extracted with ether. The ether extract was washed with water, dried (Na2SO4) and concentrated to afford 3.8 grams of title compound as amber oil. 1HNMR(CDCl3): δ 6.97(m, 1H), 6.78(m, 2H), 3.90(s, 3H). Step 2: 2,3-Difluoro-4-methoxybenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1.NN>O1CCCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2cccc(F)c2)sc1Cl
Reaction time: 24 h

Procedure:
To a 250 mL round-bottomed flask was added 5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (7.8 g, 14.91 mmol) and hydrazine (14.50 ml, 298 mmol) in tetrahydrofuran (THF) (75 ml) and methanol (75 mL). After 24 h at RT, the precipitate was filtered, the filtrate was concentrated. The crude product was purified on a silica gel column [CHCl3/MeOH/NH4OH, 90:9:1] to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[C:11]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[C:18]1[C:17]([O:24][CH3:25])=[C:16]([O:26][CH3:27])[C:15]([O:28][CH3:29])=[C:14]([O:30][CH3:31])[C:13]=1[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[C:11]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[C:18]1[C:17]([O:24][CH3:25])=[C:16]([O:26][CH3:27])[C:15]([O:28][CH3:29])=[C:14]([O:30][CH3:31])[C:13]=1[N:12]2[CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(OC)c(OC)c2c(=O)c3ccc(OCc4ccccc4)c(OC)c3[nH]c2c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(OC)c(OC)c2c(c1OC)c(=O)c1ccc(OCc3ccccc3)c(OC)c1n2C
Temperature: 25 °C

Procedure:
A mixture of 6-benzyloxy-1,2,3,4,5-pentamethoxy-9-acridone (2.257 g, 5 mmol), K2CO3 (3.0 g) and methyl iodide (2.128 g, 15 mmol) in acetone (60 ml) was heated under reflux for 20 hours. After cooling to room temperature, the mixture was filtered and washed with acetone. The combined filtrate and washings are evaporated in vacuo to dryness. The residue was dissolved in chloroform (60 ml), and the solution is washed with water (30 ml×3), dried over sodium sulfate, and concentrated to dryness. The residue was crystallized from ethanol to give 6-benzyloxy-10-methyl-1,2,3,4,5-pentamethoxy-9-acridone, 2.007 g (89%), mp 127-8 ° C. 1H-NMR (CDCl3): δ3.70, 3.87, 3.91, 3.93, 3.98, and 4.10 (each 3H, s, 5×OMe, 1×NMe), 5.24 (2H, s, CH2), 6.96 (1H, d, J=9.05 Hz, H-7), 7.32- 7.48 (5H, m Ph), 8.01 (1H, d, J=9.05, H-8). Analyses: Calculated for C25H27NO7 : C, 66.21; H, 6.00; N, 3.09. Found: C, 65.99; H, 6.18; N, 3.11.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][NH2:17]>C1COCC1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][NH2:17]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: NN
Solvent: C1CCOC1
Product: COc1cc2ncnc(NN)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
To a suspension of 4-Chloro-6,7-dimethoxy-quinazoline (0.20 g, 0.89 mmol) in anhydrous THF (0.5 ml) was added hydrazine (1M in THF, 2.0 ml, 2.0 mmol). The mixture was stirred at room temperature for 16 hours whereupon a precipitate had formed which was removed by filtration and washed with cold THF to give the desired product (177 mg, 91%) as a sticky off white solid which was sufficiently pure to be used without any further purification. m/z (LC-MS, ESP): 221 [M+H]+, R/T=2.48 mins.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](N2CCOCC2)=[O:9])=[CH:4][C:3]=1[F:16].[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[CH3:17])=[CH:4][C:3]=1[F:16]
Reactant: O=C(c1ccc(Br)c(F)c1)N1CCOCC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
To a 0° C. solution containing 8.62 g of 4-[(4-bromo-3-fluorophenyl)carbonyl]morpholine (30 mmols) in 150 mL THF was added 15 mL of methylmagnesium bromide (45 mmols, 3M solution in Et2O). The reaction mixture was allowed to warm slowly to ambient temperature. After 18 h the reaction mixture was quenched with 20 mL saturated aqueous NH4Cl solution. The layers were separated, and the organic layer was dried over MgSO4, filtered through a frit, and concentrated. The crude product was purified by silica gel chromatography (120 g redisep column, silica 40 um, 60 A, 85 ml/min, A: EtOAc, B: hexanes, A: 8% for 14 min) to give 2.40 g (37%) of title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[H-].[Na+].Cl[CH2:19][C:20](=O)[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11]2[C:20]([CH3:21])=[CH:19][O:15][C:10]=2[CH2:9]1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (mp157-158° C.; 1.11 g) in DMF (20 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (15 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.35 g).