Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([CH2:37][OH:38])=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([CH2:37][OH:38])=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
To 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [990 mg, 1.63 mmol, Intermediate (77)] in acetonitrile (20 mL) were added polymer supported DIEA (3.83 mmol/g, 850 mg, 3.26 mmol) and piperidine (0.32 mL, 3.26 mmol). The mixture was stirred gently at 60° C. for 4 hours. The PS-DIEA was filtered and the solvent was removed. The residue was chromatographed through silica gel (dichloromethane/1.0M ammonia in methanol, 95/05) to produce 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-indole-1-carboxylic acid tert-butyl ester [730 mg, 74%, Intermediate (78)] as a white foam. LC/MS: 611.2 (M+H), RT=3.05 minutes.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:28])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)=[CH:23][CH:22]=2)[O:17]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Yield: 90 %

Procedure:
Alkylation of 2-Chloromethyl-quinoline with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A for Example 2A to give 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-quinoline in 90% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.2 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 1 H) 7.6 (dd, J=11.4, 8.6Hz, 3 H) 7.7 (m, 1 H) 7.8 (dd, J=8.1, 1.5 Hz, 1 H) 7.9 (d, J=8.6 Hz, 1 H) 8.3 (d, J=8.6 Hz, 1 H).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO.O>[OH:17][N:16]=[CH:1][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C=Cc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C=Cc1ccc(C=NO)cc1
Reaction time: 8 h

Procedure:
4.0 g of methyl 4-formylcinnamate are dissolved in 40 ml methanol and then 1.6 g hydroxylamine-hydrochloride and 1.9 g sodium acetate are added. The mixture is stirred overnight and then diluted with 300 ml water. The precipitate is filtered by suction, dried in vacuo and crystallized from ethyl acetate/petrolether. This gives 3.56 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6]([C:18]([OH:20])=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[C:28]#[N:29]>CN(C)C=O.ClCCl>[C:28]([C:23]1[CH:24]=[N:25][N:26]([CH3:27])[C:22]=1[NH:21][C:18]([C:6]1[C:7]2[S:11][C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20])#[N:29]
Reactant: COc1ccc(C(=O)O)c2sc(N3CCOCC3)nc12
Reactant: Cn1ncc(C#N)c1N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCOCC3)nc12
Yield: 11.4 %

Procedure:
Starting with 4-methoxy-2-(morpholin-4-yl)benzothiazole-7-carboxylic acid (0.13 g) oxalyl chloride (0.10 ml), dichloromethane (10 ml) and dimethylformamide (1 drop), followed by 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (0.11 g), sodium hexamethyldisilylamine (1.0M in tetrahydrofuran, 0.88 ml) and dichloromethane (10 ml). Purification by flash chromatography (eluent ethyl acetate) yielded the title compound as an off-white solid (0.02 g). TLC Rf 0.45 (ethyl acetate); Mpt 299-300° C.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:15]([N-]C(C)C)(C)C.[Li+]>>[Cl:1][C:2]1[N:12]=[C:11]([Cl:13])[C:10]([F:14])=[C:9]([CH3:15])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)c1c(Cl)nc(Cl)c(F)c1C

Procedure:
Ethyl 2,6-dichloro-5-fluoronicotinate (Chem. Pharm. Bull. 35(6), 2280 (1987)) was treated with lithium diisopropylamide and quenched with methyl iodide to give, upon work-up, ethyl 2,6-dichloro-5-fluoro-4-methylnicotinate. This material was hydrolyzed to give the corresponding acid which was elaborated in the usual manner to give 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid. 7-chloro-1-cyclopropyl-5-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was synthesized in the same manner.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)=[CH:25][C:23]=4[CH:24]=3)=[O:17])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:44][N+:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[C:3]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ncccc4O)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4c(O)ccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.3 %

Procedure:
To a suspension of N-[4-(3-hydroxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (400 mg) in tetrahydrofuran (30 ml) was added 3-chloroperbenzoic acid (70%, 0.32 g) at 0° C., and the mixture was stirred at room temperature for 15 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate, concentrated under reduced pressure and recrystallized from ethanol to give N-[4-(1-oxido-3-hydroxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 175) (262 mg) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][C:5]2=[O:13].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[O:16]=[C:17]1[C:10]2=[CH:11][C:2]([F:1])=[CH:3][C:4]3=[C:9]2[N:8]([CH:7]([CH3:12])[CH2:6][C:5]3=[O:13])[CH:24]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1CC(=O)c2cc(F)ccc2N1
Product: CCOC(=O)c1cn2c3c(cc(F)cc3c1=O)C(=O)CC2C
Temperature: 60 °C

Procedure:
A stirred mixture of 12 g (0.067 mole) of 6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline from example 4 and 14.8 g (0.070 mole) of diethyl ethoxymethylenemalonate was heated gradually to 160° to 180° C. while removing the ethanol generated by distillation. After 0.5 hour the mixture was cooled to 60° C., and 30 g of polyphosphoric acid was added. This mixture was heated gradually to 150° to 160° C. and maintained at 155° to 160° C. for 5 to 10 minutes. Following cooling, water was added, and the mixture was kneaded to produce an orange powder which was separated by filtration. Recrystallization from a mixture of 500 ml of 95% ethanol and 100 ml of glacial acetic acid gave a yellow product, ethyl 6,7-dihydro-1,7-dioxo-9-fluoro-5-methyl-1H,5H-benzo[ij]quinolizine-2-carboxylate, m.p. 262°-265° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([I:20])=[C:14]2[C:13]([CH:21]([CH3:23])[CH3:22])=[N:12]1)[C:6]#[N:7])=O.[CH3:24][NH:25][CH3:26]>C(O)(=O)C.CO>[CH3:24][N:25]([CH2:1][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([I:20])=[C:14]2[C:13]([CH:21]([CH3:23])[CH3:22])=[N:12]1)[C:6]#[N:7])[CH3:26]
Reactant: CNC
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2C=O)c2nccc(I)c12
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1nn(-c2ccc(C#N)cc2CN(C)C)c2nccc(I)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
Compound (125a) (0.500 g), 2-picoline-borane complex (0.166 g), and dimethylamine (0.216 mL) were dissolved in acetic acid (1.0 mL) and methanol (10 mL), followed by stirring at room temperature for 12 hr. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (0.213 g, 40%). This 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (1.6 mL), and a hydrogen peroxide solution (30 wt %) (0.060 mL) and a 4 mol % aqueous sodium hydroxide solution (0.132 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (0.144 g, 65%). According to Example 97(2), compound (126) (64%) was prepared as a white solid using 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O=[Pt]=O.CCO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Compound 4-3 (2.73 g, 7.76 mmol), EtOH/AcOH (1:1, 60 mL) and PtO2 (0.895 g) were shaken in a Parr apparatus (15 psig of hydrogen) for 10 hrs. The reaction mixture was filtered thru Celite®, washing with ethanol. The solution was concentrated, and the residue was diluted with dichloromethane and washed with saturated NaHCO3. The aqueous layer was again extracted with dichloromethane, and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash chromatography (gradient elution with 15-50% ethylacetate (0.1% TEA) in heptane. The desired product Compound 4-4 was isolated as thick colorless oil (2.55 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=2.3 Hz, 1H), 7.43 (d of d, J=8.5 and 2.3 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 4.22 (m, 2H), 3.91 (s, 3H), 3.52 (m, 1H), 2.82 (m, 2H), 2.8-1.5 (m, 4H), 1.48 (s, 9H); MS (ES+) m/z 253.8 (M-Boc+1); HRMS (FAB+) Calcd for C18H23ClNO4: 352.1316. Found: 352.1329.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]I.C(OCC)C.C(OCC)C.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])([CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: C[Mg]I
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1cccc(Br)c1
Reaction time: 0.33 h

Procedure:
In a nitrogen atmosphere with cooling with ice, 5.29 mL of 3′-bromoacetophenone was added to 25 mL of 2 M methylmagnesium iodide/diethyl ether solution and 100 mL of diethyl ether, and stirred for 20 minutes. Water and 2 N hydrochloric acid were added to the reaction liquid, extracted with ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain crude 2-(3-bromophenyl)propan-2-ol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[F:13][C:14]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:15]=1[CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:15]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:14]=2[F:13])[CH2:22][CH2:21]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: Fc1ccc(CN2CCNCC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a mixture of 2,3-dichloropyrido[3,4-b]pyrazine (8 g, 40.0 mmol) and 1-(2,4-difluorobenzyl)piperazine (8.49 g, 40.0 mmol) in DCM (100 mL) was added triethylamine (16.72 mL, 120 mmol) at room temperature. Then the mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with 30 mL of DCM, washed with brine twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 50:1 to 5:1 PE:EtOAc to give the title compound (12 g, 80%). ESI-MS m/z [M+H]+ 376.0.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19](Cl)=[O:20].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:20]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 2-naphthoyl chloride (1.906 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 8 hours. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 817 mg of the title compound (yield: 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12](O)[CH2:13][OH:14].O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:14][CH2:13][CH2:12][O:6]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: OCCO
Reactant: COc1ccc(C=O)cc1F
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCO2)cc1F
Yield: 92.5 %

Procedure:
A solution of 3-fluoro-4-methoxy-benzaldehyde (463 mg, 3 mmol), ethylene glycol (0.86 mL, 15 mmol) and PPTs (75 mg, 0.3 mmol) in toluene (15 mL) was heated at reflux with aceotropic removal of water for 6 hours. The solvent was evaporated and the residue was diluted with methylene chloride (20 mL), washed with water (2×10 mL) and dried (MgSO4). Concentration produced 2-(3-Fluoro-4-methoxy-phenyl)-[1,3]-dioxolane as a colorless oil (550 mg, 92%). 1H-NMR (CDCl3, 200.15 MHz): δ 7.24–7.15 (m, 2H), 6.92 (t, 1H, J=8.5), 5.71 (s, 1H), 4.10–3.98 (m, 4H), 3.86 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[CH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Reaction time: 4 h
Yield: 71.7 %

Procedure:
A mixture of 18.0 g (50.0 mmol) of 19, 1.8 g of 10% Pd on charcoal, and 180 mL of anhydrous ethanol was hydrogenated in a stainless steel autoclave at 20 atm constant pressure of hydrogen and 80° C. The reaction was carried out for ca. 4 hr, i.e. until hydrogen consumption was finished. The resulting mixture was filtered through glass frit, and the filtrate was evaporated to dryness. The product was isolated from the residue using flash-chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate from 50:1 to 2:1, vol.) to yield 13.1 g (73%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[S:32])[CH:19]([CH3:21])[CH3:20])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C(=S)Nc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 110 °C
Yield: 46.3 %

Procedure:
To N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)isobutyramide (50 mg, 0.16 mmol) in toluene (2 mL) at 110° C. was added Lawesson's reagent (35 mg, 0.09 mmol). The resulting solution was heated at 110° C. for 7 h. After cooling, the solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, then dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 13.8 mg (26%) of the title compound (LCMS RT=7.36 min, MH+331.2)
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>O.O1CCCC1>[ClH:24].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:3][C:4]2[CH:5]=[C:6]([NH:10][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[NH:12])[CH:7]=[CH:8][CH:9]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N=C(Nc1cccc(NC(=O)c2ccc(Cl)cc2)c1)N1CCCC1
Temperature: 0 °C
Reaction time: 65 h

Procedure:
A solution of the product of Example 1, step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. A solution of 4-chlorobenzoyl chloride, 0.96 g, 0.0053 moles, in 10 ml of tetrahydrofuran was added. A white solid developed after stirring for 65 hours, and was filtered. The filtered product was then taken up in 20 ml of isopropanol and 1 ml of concentrated hydrochloric acid was added. The mix was then brought to a volume of 500 ml with ether and crystals developed. The crystals were filtered and washed with 20 ml of ether (twice) and the product was dried in a vacuum oven, yielding N-(3-(((4-chlorophenyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 1.15 g, m.p. 247°-250° C.