Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.[Ag]=O>[CH2:16]([O:4][CH2:3][C@@H:2]([C:5]([O:7][CH3:8])=[O:6])[NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C(CO)NC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=[Ag]
Solvent: ClCCl
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
A mixture of BOC-DL-Ser-OMe (434 mg, 2.0 mmol), benzyl bromide (513 mg, 3.0 mmol), and silver oxide (695 mg, 3.0 mmol) in dichloromethane (10 mL) at room temperature was stirred for 2 days, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 308 (M−H)−.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([O:14]CC)=[O:13])[N:6]=1>C(O)C.O>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([OH:14])=[O:13])[N:6]=1
Reactant: CCOC(=O)c1nc(C)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C)nc(C(=O)O)n1
Reaction time: 12 h

Procedure:
A solution of 11.5 g of sodium hydroxide in 156 ml of ethanol and 78 ml of water is added to a stirred solution of 51.5 g of ethyl 4-methoxy-6-methylpyrimidine-2-carboxylate in 280 ml of ethanol. Stirring is continued for 12 hours at room temperature, and the sodium salt of the carboxylic acid, which has precipitated, is filtered off with suction. The sodium salt is transferred to a solution of 17.3 g of acetyl chloride in 220 ml of methanol, and the sodium chloride, which has precipitated, is filtered off with suction. The methanolic solution is evaporated on a rotary evaporator. This gives 30.9 g of 4-methoxy-6-methylpyrimidine-2-carboxylic acid of melting point 140°-141° C. as the residue.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH2:26])[CH:20]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH3:26])[CH:20]=2)[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1)c1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(c1cccc(-c2cccc(C(C)(C)C)c2O)c1)c1ccccn1
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A solution of 12 (0.13 g, 0.31 mmol) in methanol (10 mL) and ethyl acetate (30 mL) was treated with 20% palladium on activated carbon (50% wet, 0.05 g) and was hydrogenated at 10 psi in a Parr shaker for 2 hr. The catalyst was filtered out and washed with ethyl acetate. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (25 g) with 5% ethyl acetate in hexane (3 L). Pure B1 (0.08 g, 80%) was isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][CH2:12][Cl:13].[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[Cl:13][CH2:12][CH2:11][CH2:10][C:9]1[C:3]2[C:2](=[CH:7][C:6]([F:8])=[CH:5][CH:4]=2)[NH:1][N:15]=1
Reactant: O=N[O-]
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Fc1ccc2c(CCCCl)n[nH]c2c1
Temperature: -3 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a suspension of 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (500 mg, 2.3 mmol) in conc. HCl (3.2 mL) was added a solution of NaNO2 in H2O (0.7 mL) and stirred for 1 h at −6-0° C. A solution of SnCl2.2H2O (1.25 g, 5.51 mmol) in conc. HCl (1.7 mL) was added the reaction mixture and stirred for additional 1 h at 0° C. The reaction was quenched by addition of ice water and extracted with Et2O. The combined organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give a white solid. It was recrystalized to give pure 3-(3-chloropropyl)-6-fluoroindazole (420 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11](=O)[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:11]([CH3:12])[CH3:10]
Reactant: CC(C)=O
Reactant: Nc1cc(F)ccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)Nc1cc(F)ccc1Br
Temperature: 20 °C

Procedure:
2-bromo-5-fluoroaniline E-1.7″″″ (2.00 g; 10.53 mmol) is suspended in 20 ml DCM and propan-2-one (1.55 ml; 21.05) is added and the reaction mixture is stirred for 16 at 20° C. Afterwards sodium triacetoxyborohydride (4.69 g; 21.05 mmol) is added and the reaction mixture is stirred for 48 h at 20° C. The reaction mixture is poured into water and extracted with DCM. The combined organic layer is dried over MgSO4 the solid materials are filtered off and HCl in dioxane is added until the pH value is below 2. The solvents are concentrated under reduced pressure. The crude product is purified using reversed phase chromatography (Method: prep. HPLC1). Product containing fractions are combined and extracted with DCM. To the organic layer HCl in dioxane is added until the pH value is below 2. The solvents are concentrated under reduced pressure.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH2:3]([O:10][CH2:11][CH:12]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[O:13][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Dried tetrahydrofuran (600 ml) was added to 60% sodium hydride (5.8 g), and the solution cooled to 5° C. A solution (100 ml) of 1-O-benzyl-3-O-t-butyldimethylsilylglycerol (35.9 g) in tetrahydrofuran was added thereto, and the resultant mixture stirred at the same temperature for 2 hours. Then, ethyl bromoacetate (24.3 g) was added dropwise thereto, and the mixture stirred at the same temperature for 2 hours and then room temperature overnight. Upon concentrating the reaction mixture under reduced pressure, water was added to the residue, and the mixture was acidified with 5% hydrochloric acid. After extracting the aqueous layer with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. Upon concentrating thereof under reduced pressure, the residue was purified on a silica gel column (eluent: n-hexane/ethyl acetate=6/1) to obtain the desired product (28.7 g) as oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]=[O:20])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:14]([CH:19]=[O:20])[CH:13]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCOc1ccc(Br)cc1C=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Ethyl 5-bromopentanoate (28.6 g) was added to a suspension of 4-bromo-2-formylphenol (25.0 g) and potassium carbonate (18.9 g) in DMF (100 ml), and the resulting solution was stirred at 50° C. overnight under a nitrogen atmosphere. The solution was allowed to cool. Water was added and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain yellow oil of ethyl 5-(4-bromo-2-formylphenoxy)pentanoate (40.9 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]([CH2:16][CH2:17][S:18][CH3:19])[C:13]([OH:15])=[O:14].[OH:20]O>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]([CH2:16][CH2:17][S:18]([CH3:19])=[O:20])[C:13]([OH:15])=[O:14]
Reactant: OO
Reactant: CSCC[C@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Solvent: CO
Product: CS(=O)CC[C@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(1,3-dioxoisoindolin-2-yl)-4-(methylthio)butanoic acid (87.124 g, 312 mmol) from preparation 54 in methanol (750 ml) was added hydrogen peroxide (pre-cooled to −30° C.; 38.9 g, 343 mmol) in methanol (250 ml) at −20° C. The reaction mixture was stirred at −20° C. overnight (by use of a cryostat) then warmed to rt over a further 24 hours then to 30° C. for 5 h, LCMS suggesting 95% conversion. The reaction mixture was evaporated under vacuum to give the title compound as a mixture of diastereoisomers that were progressed directly in preparation 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2ncccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc2c(c1)CCCN2
Yield: 89 %

Procedure:
A mixture of 6-methoxyquinoline (69 μL, 0.5 mmol), ammonium formate (0.32 g, 5.0 mmol), and 10% Pd/C (0.05 g) in anhydrous MeOH (5 mL) was microwaved for 900 s at 100° C. The mixture was filtered and 2M HCl in Et2O (1.5 mL) was added. The product was redissolved in H20/DCM and the aqueous layer basified with 0.1M aq. NaOH (pH 8). After extracting three times with DCM, the organic layer was concentrated to give the product in 89% yield. The product was used without further purification. LC/MS (10-99%) M/Z: M+1 obs=164.0; tR=0.40 min.
Reaction SMILES: F[C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:11]1[NH:12][N:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:10][C:9]1[C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: c1cn[nH]n1
Reactant: Cc1cccc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C#N)c1-n1nccn1
Temperature: 120 °C
Yield: 27.5 %

Procedure:
To a mixture of 2-fluoro-3-methylbenzonitrile (4.0 g, 29.6 mmol) and 2H-1,2,3-triazole (2.04 g, 29.6 mmol) in DMF (80 mL) was added potassium carbonate (8.26 g, 59.2 mmol). The resulting mixture was heated to 120° C. for 2 h. The mixture was cooled, diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (SiO2, ethyl acetate/hexanes, gradient 0-50%) to yield the title compound (1.5 g, 26%). MS (ESI) mass calcd. for C10H8N4, 184.2; m/z found, 185.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.95 (s, 2H), 7.66 (d, J=7.7, 0.7 Hz, 1H), 7.59 (d, J=7.8, 0.6 Hz, 1H), 7.50 (dd, J=9.8, 5.7 Hz, 1H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].I[CH2:25][CH2:26][F:27]>O1CCCC1>[F:27][CH2:26][CH2:25][N:21]1[CH2:20][CH2:19][N:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:23][CH2:22]1
Reactant: FCCI
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (intermediate 8120, 18.03 g, 56.10 mmol and 2.23 g, 6.96 mmol from separate batches) in tetrahydrofuran was added 1-Iodo-2-fluoroethane (7.38 mL, 90.79 mmol). The reaction was stirred at 85° C. overnight. The solution was transferred to a sealed tube. Upon addition of 1-Iodo-2-fluoroethane (7.38 mL, 90.79 mmol), the reaction was stirred at 85° C. for an additional 5 hours. The solvent was removed in vacuo and the residue was taken up in water and extracted with dichloromethane (×3), dried with magnesium sulfate, filtered and concentrated. Purification by flash chromatography provided 1-(2-fluoroethyl)-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (15.94 g, 43.50 mmol, 69%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (qd, J=11.9, 3.7 Hz, 2 H) 1.79 (d, J=10.8 Hz, 2 H) 2.32-2.42 (m, J=7.0, 3.7 Hz, 9 H) 2.52 (dt, JHF=28.6 Hz, J=4.9 Hz 2 H) 2.86-2.95 (m, 2H) 3.85 (s, 3 H) 3.99 (d, J=13.4 Hz, 2 H) 4.46 (dt, JHF=47.8 Hz J=4.9 Hz 2 H), 6.45 (d, J=2.4 Hz, 1 H) 6.54 (dd, J=9.5, 2.6 Hz, 1 H) 7.82 (d, J=9.3 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:29])[O:22][CH2:21][CH2:20]1>>[F:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:28]=1[CH:19]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=3[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=1)[CH2:20][CH2:21][O:22]2
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Reactant: Fc1cccc2c1C(Cl)CCO2
Product: Cc1nc2c(OC3CCOc4cccc(F)c43)cc(C(=O)N(C)C)cc2n1C
Yield: 35 %

Procedure:
The title compound was prepared as a pale brown solid in 35% yield (69 mg) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (120 mg, 0.51 mmol, WO 2004054984) and 4-chloro-5-fluorochromane (100 mg, 0.54 mmol, STEP 2) by the same manner in STEP 1 of Example 1:
Reaction SMILES: C(C([OH:13])(CC=C)C)C1C=CC=CC=1.C(=O)([O-])O[C:16]1([CH3:25])[CH2:21][CH2:20][CH:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1>>[CH:16]1([CH3:25])[CH2:21][CH2:20][CH:19]([CH:22]([CH3:24])[CH3:23])[CH:18]([OH:13])[CH2:17]1
Reactant: CC(C)C1CCC(C)(OC(=O)[O-])CC1
Reactant: C=CCC(C)(O)Cc1ccccc1
Product: CC1CCC(C(C)C)C(O)C1
Yield: 18 %

Procedure:
The method of Grignard and Chambret, Compt. rend. 182, 299(1926) was used to prepare 2-benzylpent-4-en-2-ol. The alcohol was converted to the 1-menthyl carbonate by a procedure like that of Example 4. Distillation of the extracted product through an 8-inch Vigreux column gave fractions boiling 25°-110°/0.04-0.6 mm, all having strong OH absorption in the infra-red. The residue was distilled through a short path and the fraction boiling 165°-6°/0.6-0.7 mm showed the following IR absorptions: no OH, strong carbonate (1750 and 1255 cm-1), vinyl (1655, 978, 913 cm-1), monosubstituted aromatic (750 shoulder, 697 cm-1). NMR analysis indicated 80% of the expected mixed ester, a yield of 18.0% from the alcohol. This product had very little odor, but on heating produced a menthol odor.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][C:10]=1[Cl:22])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[C:10]([Cl:22])=[CH:11][C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:13]([CH:15]=[CH2:16])[CH:14]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)c(Cl)cc1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc(CN)c(Cl)cc1NS(C)(=O)=O
Reaction time: 12 h
Yield: 129.7 %

Procedure:
To a dried 25 ml round bottom flask was added (2-chloro-4-methanesulfonylamino-5-vinyl-benzyl)-carbamic acid t-butyl ester (103.9 mg, 0.29 mmol) and diluted with methylenechloride. To the solution were added 5-6 drops of CF3COOH and stirred for 12 hours. After confirming the completion of the reaction with TLC, the resulting solution was concentrated under reduced pressure using toluene to yield a brownish syrup (98.1 mg, 130.74%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]1[CH:26]=[C:27](O)[C:28](=[CH:30][CH:31]=1)[OH:29].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:24][C:25]1[CH:26]=[CH:27][C:28]2[O:29][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[O:23][C:30]=2[CH:31]=1
Reactant: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Oc1ccc(F)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(C2(C3CCNCC3)Oc3ccc(F)cc3O2)cc1
Yield: 33.4 %

Procedure:
A solution of 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 284) (638 mg, 2.00 mmol), 4-fluorocatechol (512 mg, 4.00 mmol) and p-TsOH.H2O (760 mg, 4.00 mmol) in xylene (20 mL) was heated at reflux using a Dean-Stark apparatus to remove water for 52 hours. Standard work-up and purification gave 4-[5-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pale yellow oil (220 mg, 33%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][NH2:21])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: Clc1ccc2nc(Cl)cc(-c3ccccc3)c2c1
Solvent: O
Product: NNc1cc(-c2ccccc2)c2cc(Cl)ccc2n1

Procedure:
In the manner given in Example 1, 2,6-dichloro-4-phenylquinoline is reacted at reflux with hydrazine hydrate to give 6-chloro-4-phenyl-2-hydrazinoquinoline.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CS(O[CH2:16][CH2:17][CH:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH3:19])(=O)=O>>[N:20]1([CH:18]([CH3:19])[CH2:17][CH2:16][NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(CCOS(C)(=O)=O)N1CCOCC1
Product: CC(CCNc1ccc([N+](=O)[O-])cc1)N1CCOCC1

Procedure:
In a manner similar to Preparation 2, react 4-nitrobenzenamine with 3-(morpholin-4-yl)-1-butanol methanesulfonate to obtain the title compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[OH:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([CH2:27][C:28](O)=[O:29])([CH2:20]3)[CH2:18]1)[CH2:24]2>>[OH:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([CH2:27][C:28]([NH:1][N:2]4[N:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[C:3]4=[O:15])=[O:29])([CH2:20]3)[CH2:18]1)[CH2:24]2
Reactant: O=C(O)CC12CC3CC(CC(O)(C3)C1)C2
Reactant: CC(C)c1nn(N)c(=O)c2ccccc12
Product: CC(C)c1nn(NC(=O)CC23CC4CC(CC(O)(C4)C2)C3)c(=O)c2ccccc12

Procedure:
The product of Example 1B and 2-(3-hydroxyadamantan-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.12 (s, 1H), 8.34 (dd, J=7.9, 1.3 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 8.00 (ddd, J=8.3, 7.1, 1.3 Hz, 1H), 7.89 (ddd, J=8.0, 7.1, 1.0 Hz, 1H), 3.61 (p, J=6.7 Hz, 1H), 2.08-2.11 (m, 4H), 1.36-1.63 (m, 13H), 1.26 (d, J=6.7 Hz, 6H); MS (ESI) m/z 396 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])[C:16]([F:20])=[CH:15][N:14]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,4-dimethoxyaniline (4.1 g, 24.6 mmol) was added to a solution of 2,4-dichloro-5-fluoropyrimidine (4.1 g, 24.6 mmol) in isopropanol (16 mL). N,N-Diisopropyl-ethylamine (6.30 g, 8.50 mL, 48.8 mmol) was added and the mixture was allowed to stir at room temperature for 24 h. The solution was partitioned between ethyl acetate and water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford an oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-10% methanol-methylenechloride) to afford (2-chloro-5-fluoro-pyrimidin-4-yl)-(2,4-dimethoxy-phenyl) amine. MS (MH+) 284; Calculated 283.69 for C12H11ClFN3O2.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:26]I>ClCCl.C(Cl)(Cl)Cl>[Br:25][C:21]1[CH:20]=[C:19]([N:18]2[CH:2]([CH2:3][I:26])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])[CH:24]=[CH:23][CH:22]=1
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Reactant: II
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine (0.14 g, 0.35 mmol) (from Example 17, Step E, supra) in dichloromethane (20 mL) was added I2 (0.23 g, 1.75 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with chloroform (100 mL) and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.01) as eluent to give the desired 4-(3-bromo-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as a pale yellow foam. (Yield 0.12 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CC)C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 5,6-dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (6.0 gm., 0.02 mole), ethyl bromoacetate (4.0 gm., 0.025 mole) and potassium carbonate (8.3 gm., 0.06 mole) in dimethylformamide (35 ml.) is heated at 50° C. and stirred for one hour. The mixture is cooled and poured into water (300 ml.). The solid product that separates is removed by filtration, then washed with water followed by benzene (10 ml.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>ClCCl.O>[Cl:8][CH2:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(CCCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of aniline (40 g, 0.429 mol) in dichloromethane (500 mL) cooled at 0° C., was added 3-chloropropanoyl chloride (49.1 mL, 0.515 mol) drop wise with constant stirring. Reaction mass was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (4×500 mL). The combined organic layer was washed with saturated sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.58-7.56 (d, J=8 Hz, 2H), 7.30-7.26 (t, J=8 Hz, 2H), 7.05-7.01 (t, J=7.6 Hz, 1H), 3.88-3.85 (t, J=6.4 Hz, 2H), 2.82-2.81 (t, J=6.0 Hz, 2H). MS (M+1): 184.1.