Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[CH3:36]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:36])[CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: Cn1cc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: Cn1cc(Cc2cn(C)c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4(1H)-pyrimidinone (71 mg, 0.109 mmol) in DCM (1.5 mL) was added DIPEA (0.038 mL, 0.217 mmol) and MeI (10.18 μL, 0.163 mmol). The mixture was stirred at room temp overnight. Purification via MDAP then afforded the title compound (34 mg, 60.3% yield). LCMS: rt=3.35 min, [M+H+]=519
Reaction SMILES: [Cl:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Br[C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:22][C:20]1[CH:21]=[CH:14][C:15]([C:16]#[N:17])=[C:18]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)[CH:19]=1
Reactant: N#Cc1ccc(Cl)cc1Br
Reactant: COc1cc(B(O)O)c(Cl)cn1
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(Cl)cn1

Procedure:
5.36 g (purity 91%, 26.03 mmol) of 5-chloro-2-methoxypyridin-4-ylboronic acid and 5.12 g (23.66 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. After work-up, the crude product was then purified by flash chromatography (silica gel 60, cyclohexane/dichloromethane mixtures). Yield: 4.11 g (purity 91%, 52% of theory)
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37](O)=[O:38])=[C:35]([F:45])[CH:34]=1.COC[CH2:49][S:50]([NH2:53])(=[O:52])=[O:51].CS(N)(=O)=O>>[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:38])=[C:35]([F:45])[CH:34]=1
Reactant: O=C(O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 72 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.090 g, 72%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (br s, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.84 (d, J=13.2 Hz, 1H), 4.42-4.35 (m, 1H), 3.30 (s, 3H), 2.38-2.34 (m, 1H), 2.30-2.24 (m, 1H), 2.00-1.94 (m, 1H), 1.86-1.77 (m, 1H), 1.59-1.32 (m, 4H), 1.25-1.04 (m, 3H), 0.88-0.79 (m, 2H), 0.66-0.59 (m, 2H); MS (ES−) m/z 368.1 (M+1).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[N+:10]([C:13]1[CH:14]=[C:15]([NH2:22])[C:16](=[CH:20][CH:21]=1)[C:17]([OH:19])=[O:18])([O-:12])=[O:11].N1C=CC=CC=1>ClCCl>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:22][C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[CH:14]=1)([O-:12])=[O:11]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc([N+](=O)[O-])ccc1C(=O)O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2,2,2-trichloroethylchloroformate (Troc-Cl) (1.66 mL, 12.1 mmol) in dry dichloromethane (25 mL) was added drop wise to a solution of 4-nitroanthranilic acid 144 (2 g, 11 mmol) and pyridine (1.78 mL, 22 mmol) in dichloromethane (25 ml) at 0° C. The solution was allowed to stir at 25° C. for 5 hours. The reaction mixture was washed with dilute HCl (1N, 2×50 mL), water (1×50 mL), brine (1×25 mL) and dried over MgSO4. Removal of excess solvent by rotary evaporation under reduced pressure afforded the crude product which was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH:15]([C:17]3[CH:18]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[C:22]4[C:26]#[N:27])[CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:34]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:34][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH:15]([C:17]2[CH:18]=[C:19]([C:28]([F:29])([F:30])[F:31])[CH:20]=[C:21]3[C:25]=2[NH:24][N:23]=[C:22]3[C:26]#[N:27])[CH3:16])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc2c(C#N)n[nH]c12
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(C(F)(F)F)cc2c(C#N)n[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-7-(1-((4-Phenylpiperidin-4-yl)methoxy)ethyl)-5-(trifluoromethyl)-1H-indazole-3-carbonitrile (24 mg, 0.06 mmol) and formaldehyde (37 wt. % solution in water, 77 μL) were combined in acetonitrile (2 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (18 g, 0.28 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated and the compound purified by flash chromatography on silica gel (1% aq. methanolic ammonia/8% methanol/methylene chloride) to afford 15 mg (59%). 1H-NMR (CDCl3, 500 MHz) δ 8.05 (s, 1H), 7.37-7.40 (m, 2H), 7.31-7.34 (m, 2H), 7.22-7.23 (m, 2H), 4.66 (q, J=6.7 Hz, 1H), 3.36-3.43 (m, 2H), 3.34 (q, J=9.2 Hz, 1H), 3.17 (d, J=9.2 Hz, 1H), 2.73-2.84 (m, 2H), 2.59 (s, 3H), 2.53-2.58 (m, 2H), 2.13-2.29 (m, 2H), 1.59 (m, 3H). Mass spec.: 442.48 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:16](=[O:17])[O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23][OH:24]>>[CH3:23][O:24][C:16]([C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][OH:15])=[O:17]
Reactant: CO
Reactant: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Agent: O=S(=O)(O)O
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)nc1CCO
Temperature: 55 °C
Reaction time: 15 h

Procedure:
Dissolve 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (500 g, 1882 mmol) in MeOH (5 L) and add concentrated sulfuric acid (31 mL). Stir the solution at 55° C. for 15 h, then warm to 66° C. and continue stirring for an additional 4.5 h. Cool the solution to 45° C. and concentrate in vacuo to one half of the volume. Continue to cool the slurry to 20° C. Isolate the precipitate by filtration and wash the solid with cold MeOH. Dry the solid (420.5 g) under vacuum overnight. Concentrate the filtrate to about 600 mL, filter, and wash with cold MeOH to obtain more solid (40.7 g). Purify the crude materials by flash chromatography, using 10% EtOAc/CH2Cl2 as eluent, to give a total of (442 g, 80%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.88 (dt, J=8.8, 4.7 Hz, 2H), 7.43 (dt, J=8.7, 4.3 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 3.90 (s, 3H), 3.43 (t, J=5.6 Hz, 2H), 3.32 (bs, 1H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8](=[O:10])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(O)CC1CCCCC1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CC1CCCCC1

Procedure:
Following General Procedure B′ above, and using cyclohexylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 92° C.-93° C. The reaction was monitored by tlc on silica gel (Rf=0.39 in 1:3 EtOAc:hexane) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[S:24]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=1)(=[O:26])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1C)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 14 %

Procedure:
To a solution of N-butyl-N-[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl)amine (58 mg, 0.19 mmol) in anhydrous CH2Cl2 (5 mL) was added ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (83 mg, 0.28 mmol) and triethylamine (0.052 mL, 0.38 mmol). The resulting solution was stirred 20 h at room temperature under nitrogen. The reaction was diluted with CH2Cl2 (50 mL), and the organic solution washed with aq. sat. NaHCO3 (10 mL) and brine (10 mL). The organic extract was separated by hydrophobic frit and evaporated. Purification by mass directed autoprep afforded the title compound as a colourless oil (15 mg).
Reaction SMILES: CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH2:26])[CH2:20]2.C1CCN2C(=NCCC2)CC1.[CH3:38][CH:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40]>C(Cl)Cl.Cl>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH:26][S:41]([CH:39]([CH3:40])[CH3:38])(=[O:43])=[O:42])[CH2:20]2
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Br)cc2C1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
(R)-5-bromo-2,3-dihydro-1H-inden-2-amine((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (7.88 mmol, 3.5 g) was suspended in DCM (40 mL) and DBU (23.63 mmol, 3.53 mL, 3.60 g) was added. The mixture was purged with nitrogen and cooled in an ice bath before dropwise addition of propane-2-sulfonyl chloride (15.75 mmol, 1.760 mL, 2.246 g). Stirring was continued at 0° C. for 1 h before allowing to come to room temperature. The mixture was diluted with DCM (100 mL) and 1N HCl (100 mL) and the phases mixed and separated. The aqueous phase was further extracted with DCM (2×100 mL) before combined organics were washed with brine. Concentration gave a light yellow oil which was purified on silica eluting with 75% DCM/heptane then neat DCM. Desired fractions were collected and concentrated to give (R)—N-(5-bromo-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide as a colourless oil (2.18 g, 87%). 1H NMR (400 MHz, CDCl3) δ 1.39 (d, 6H) 2.88 (m, 2H) 3.17 (sept, 1H) 3.28 (m, 2H) 4.27 (m, 2H) 7.08 (d, 1H) 7.30 (d, 1H) 7.35 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
To a solution of 2-fluoro-4-hydroxy-benzaldehyde (1.0 g, 7.1 mmol) in DMF (70 mL) was added benzylbromide (0.85 mL, 1.2 g, 7.1 mmol) and K2CO3 (1.1 g, 7.9 mmol) and the reaction mixture was stirred (rt, 12 h). The reaction mixture was treated with H2O (50 mL) and filtered to afford the title compound as a colorless solid (1.4 g, 85%). MS (ESI): mass calcd. for C14H11FO2, 230.1; m/z found, 231.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 10.21 (s, 1H), 7.82 (t, J=8.8, 1H), 7.48-7.32 (m, 5H), 6.85 (dd, J=8.8, 2.3, 1H), 6.71 (dd, J=12.3, 2.3, 1H), 5.11 (d, J=14.8, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][OH:28])[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][S:41]([CH3:40])(=[O:43])=[O:42])[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COS(C)(=O)=O)C3)C(C)C12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution, under argon, of 0.821 g of product from Example 56 and 3.4 ml of pyridine is added 148 microliter of methanesulfonyl chloride. The reaction is stirred at 0° C. for 2 hours, diluted with water and extracted with chloroform. The organic layer washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (Silica Gel; 80% ethyl acetate/hexane) to give 0.632 g of the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](=O)[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:20])[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: [BH3-]C#N
Reactant: CC(=O)Cc1ccc2occc2c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)Cc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 1 gm (5.7 mMol) 1-(benzofur-5-yl)-2-propanone, 8.9 gm (115 mMol) ammonium acetate, and 2.8 gm powdered 3A molecular sieves in 60 mL methanol was stirred at room temperature for 1 hour. To this mixture were then added 5.8 mL (5.8 mMol) sodium cyanoborohydride (1.0 M in tetrahydrofuran) and the mixture was stirred for an additional 5 hours at room temperature under a nitrogen atmosphere. The reaction mixture was then filtered over a pad of celite and the pad was rinsed with 200 mL methanol and 200 mL dichloromethane. The combined filtrates were concentrated under reduced pressure and the resultant residue was partitioned between 200 mL dichloromethane and 20 mL water. The mixture was washed with two 25 mL portions of 5 N sodium hydroxide. The combined aqueous extracts were extracted with three 100 mL portions of dichloromethane. All of the organic phases were combined, washed with 25 mL 0.1 N sodium hydroxide followed by 25 mL water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of dichloromethane containing 6% methanol to dichloromethane containing 9% methanol and 9% concentrated ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.498 gm (49%) of 1-(benzofur-5-yl)-2-aminopropane.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[CH:12]=1.O>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[CH:12]=1
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Reactant: COCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCCCOc1cc[n+]([O-])c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
6.77 g (0.065 mol) of 4-methoxybutanol was dissolved in 60 ml of dimethyl sulfoxide to obtain a solution. 2.6 g (0.065 mol) of 60% sodium hydride was added to this solution at a room temperature in a nitrogen atmosphere. The obtained mixture was heated to 60° C., stirred for one hour and cooled to a room temperature. A solution of 4.66 g (0.032 mol) of 4-chloro-2-methylpyridine 1-oxide in 20 ml of dimethyl sulfoxide was dropwise added to a resulting mixture. The obtained mixture was stirred at 40° C. for one hour. After the completion of the reaction, 5 ml of water was added to the mixture and the obtained mixture was evaporated to dryness to remove the solvent. 150 ml of water was added to the residue. The obtained mixture was extracted with 200 ml of chloroform four times. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain 5.06 g of the title compound as an oil.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:21])([F:20])[C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([C:15](=[NH:19])OCC)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C(O)C>[ClH:1].[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][N:26]=[C:15]([C:13]1[O:14][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:20])[F:21])[CH:5]=2)=[CH:11][CH:12]=1)[NH2:19]
Reactant: CCOC(=N)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CCO
Product: COC(CN=C(N)c1ccc(-c2cccc(C(F)(F)F)c2)o1)OC
Yield: 77.7 %

Procedure:
To a stirring mixture of 110 g (0.36 mole) of ethyl 5-(3-trifluoromethylphenyl)-2-furimidate hydrochloride and 1700 ml of absolute ethanol was added 38 g (0.36 mole) of aminoacetaldehyde dimethyl acetal with dissolution. The reaction solution was refluxed for 6 hours, the solvent was removed on the Calab evaporator, and the residual solid was washed in hexane and air dried to yield 106 g (78%) of N'-(2,2-dimethoxyethyl)-5-(3-trifluoromethylphenyl)-2-furamidine hydrochloride. A sample was recrystallized from acetonitrile and dried at room temperature to give a m.p. of 173°-174°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:20])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:11](=[O:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:23][N:24]([CH3:26])[CH3:25])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(Cc1ccc(C(=O)O)cc1)C(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 44 %

Procedure:
To a solution of 3-(4-carboxyphenyl)-1-phenyl-1,2-propanedione in 100 ml of dry dimethylformamide cooled in an ice-bath was added, with stirring, 56 ml of dimethylformamide dimethyl acetal. The reaction mixture was stirred at 0°-5° C for 10 min. and then it was poured onto 1.2 l of ice-water and acidified with 130 ml of 1N hydrochloric acid. After stirring for 5 min., 1.8 l of water was added and the precipitate was collected, washed with water and air-dried. The filter cake was dissolved in 1.7 l of methylene chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to about 200 ml. Ether (200 ml) was added and the solution was concentrated to about 300 ml and allowed to stand at room temperature for 2 days. The solid was collected, washed with methylene chloride-ether (1:9) and dried at 80° C for 3 hrs. to give 17.4 g (44%) of 2-(4-carboxyphenyl)-1-dimethylamino-4-phenyl-1-butene-3,4-dione as yellow crystals, m.p. 208°-209° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C)C=O>[CH2:16]([O:15][CH2:14][CH2:13][N:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCOCc1ccccc1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(CCOCc2ccccc2)c1C
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Ethyl 2-methyl-1H-pyrrole-3-carboxylate (10 g, 65.3 mmol) is dissolved in 100 mL of dimethylformamide under argon cooled to 0° C., and then 2-bromoethoxymethylbenzene (28.1 g, 130.6 mmol) is added all at once. The reaction mixture is placed under stirring. There is then added thereto, at 0° C., in three portions, NaH (1.72 g, 71.83 mmol) over a period of 15 minutes. The reaction mixture is stirred for 15 minutes at 0° C., and then for 15 hours at ambient temperature. It is then poured into an ice bath and then extracted 3 times with ethyl acetate. The organic phase is washed 3 times with saturated aqueous lithium chloride solution, dried over MgSO4, filtered and then evaporated to dryness. The residue thereby obtained is purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The expected compound is obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][N:7]([C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([F:21])=[CH:14][C:13]=3[CH3:22])[C:6](=[O:23])[N:5]([CH3:24])[C:4]=2[CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:18][C:16]1[C:15]([F:21])=[CH:14][C:13]([CH3:22])=[C:12]([N:7]2[CH2:8][C:9]3[CH:10]=[N:11][C:2]([Cl:1])=[CH:3][C:4]=3[N:5]([CH3:24])[C:6]2=[O:23])[CH:17]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1N1Cc2cnc(Cl)cc2N(C)C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(F)c(N)cc1N1Cc2cnc(Cl)cc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
Zn Dust (0.575 g, 8.80 mmol) was added to a suspension of 7-chloro-3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (0.309 g, 0.880 mmol) and NH4Cl (0.471 g, 8.80 mmol in MeOH/THF (1:1, 16 mL) and the mixture was stirred 1.5 h at RT. The mixture was filtered through Celite, rinsing forward with MeOH and the filtrates were concentrated, diluted with brine and extracted with THF (2×). The combined organics layers were washed with brine, dried (MgSO4), and concentrated to afford 3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (0.260 g, 92% yield). MS (ESI) m/z: 321.0 [M+H+].