Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:19][CH3:20].ClC1C=CC=CC=1Cl>O>[CH2:18]([N:21]1[C:1]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[C:10]([C:11](=[O:13])[N:25]2[CH2:24][CH2:23][CH2:22]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH3:20]
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CCCNCCCN
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCCN1CCCN2C(=O)c3ccccc3C12c1ccccc1

Procedure:
22.6 Parts of o-benzoyl-benzoic acid and 11.6 parts of N-propyl-1,3-propanediamine are haeted within 11/2 hours with 50 parts by volume of o-dichlorobenzene until the boiling point of the latter is attained. Almost the theoretical amount of reaction water is azeotropically distilled off. The clear solution is evaporated to dryness in vacuo, the oily residue is dissolved in ethyl acetate and crystallised by the dropwise addition of pentane. In this way, 1-propyl-10b-phenyl-1,3,4,10b-tetrahydro-pyrimido[2,1-a]isoindol-6(2H)-one is obtained of the formula ##STR19## M.P. 135°-137°. 1-Ethyl-10b-phenyl-1,3,4,10b-tetrahydro-pyrimido[2,1-a]isoindol -6(2H)-one is obtained in the same manner from o-benzoyl-benzoic acid and N-ethyl-1,3-propanediamine. M.P. 131°-133°.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH:20]1([CH2:19][O:18][C:3]2[C:2]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=3)=[CH:17][C:6]([C:7]([NH:9][C@@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[OH:16])=[O:8])=[CH:5][N:4]=2)[CH2:22][CH2:21]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 23, using 5-bromo-6-cyclopropylmethoxy-N-(trans-2-hydroxy-cyclohexyl)-nicotinamide and 4-trifluoromethoxyphenylboronic acid (commercially available) as starting materials. MS (m/e): 451.3 (MH+).
Reaction SMILES: Br.[OH:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[Si:23]([O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1cccc(-c2ncccc2O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccnc1-c1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To a stirred suspension of 3-(3-hydroxypyridin-2-yl)nitrobenzene hydrobromide (0.3 g) and imidazole (165 mg) in N,N-dimethylformamide (3 ml) was added tert-butyldimethylsilyl chloride (183 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 3-(3-tert-butyldimethylsilyloxypyridin-2-yl)nitrobenzene (332 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[ClH:21]>CO>[ClH:21].[ClH:21].[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:3][C:2]=1[CH3:1]
Reactant: COC(=O)CCCCCNc1ccc([N+](=O)[O-])c(C)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCCCCNc1ccc(N)c(C)c1

Procedure:
2.3 g of nitro derivative (14) prepared above and about 100 ml of methanol were introduced into a 200 ml autoclave (hydrogenator) equipped with a magnetic stirrer. The solution obtained was degassed with nitrogen. 0.4 g of palladium-on-charcoal (5% humidity, containing 50% water) was added thereto. The reaction mixture was stirred, while flushing once with hydrogen, and hydrogen was then introduced to a pressure of about 5 bar. After reaction for 4 hours, the reactor was flushed with nitrogen. The reaction mixture was filtered quickly through Celite under a gentle pressure of nitrogen. The filtrate was recovered into a precooled solution of methanol containing about 3 equivalents of hydrogen chloride gas. The filter cake was rinsed several times with methanol under a stream of nitrogen. The solution thus obtained was concentrated and then treated with ether. The product obtained, in the form of a pale pink paste, was stirred and then rinsed several times with acetonitrile and with ether under nitrogen. 2.1 g of expected product (15) were isolated in the form of a slightly pink-white powder.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NCc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-nitrobenzyl)isoindoline-1,3-dione (500 mg, 1.665 mmol) in tetrahydrofuran were added hydrazine monohydrate (333 mg, 6.661 mmol) and p-toluenesulfonic acid monohydrate (29 mg, 0.167 mmol). The reaction mixture was refluxed for 6 h, then cooled to room temperature, diluted with ethyl acetate. The mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to give (2-fluoro-4-nitrophenyl)methanamine (194 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O.Cl>C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][NH:10]1
Reactant: CCN(CC)c1cccc2nc3n(c12)CCN(C(=O)OC(C)(C)C)C3c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(CC)c1cccc2nc3n(c12)CCNC3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of tert-butyl 1-(2,4-dichlorophenyl)-6-(diethylamino)-3,4-dihydropyrazino[1,2-a]benzimidazole-2(1H)-carboxylate (244 mg, 0.499 mmol) and hydrochloric acid (4M, ethyl acetate solution, 5 mL) was stirred at room temperature for 1 h. The mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 40% ethyl acetate/n-hexane mixture to give a colorless amorphous solid (172 mg, 0.443 mmol, 89%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:26])[N:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][SH:32]>>[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][S:32][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[O:26])=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCC(C(F)(F)F)CC1
Reactant: COC(=O)CCS
Product: COC(=O)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCC(C(F)(F)F)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-trifluoromethyl-cyclohexyl)-urea (Example 204) and 3-mercaptopropionic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][N:14]([CH2:19][C:20]1[CH2:21][C:22]2[C:27]([C:28]=1[CH3:29])=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15](=[O:18])[CH:16]=[CH2:17].CCN(C(C)C)C(C)C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][N:14]([CH2:19][C:20]1[CH2:21][C:22]2[C:27]([C:28]=1[CH3:29])=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15](=[O:18])/[CH:16]=[CH:17]/[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C=CC(=O)N(C)CC1=C(C)c2ccccc2C1
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC1=C(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)Cc2ccccc21
Reaction time: 18 h
Yield: 38.3 %

Procedure:
A mixture of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.096 g, 0.42 mmole), from Preparation 15, and N-methyl-N-(3-methyl-1H-inden-2-ylmethyl)acrylamide (0.141 g, 0.62 mmole) in propionitrile (10 mL) was treated with (i-Pr)2NEt (0.15 mL, 0.08 mmole), palladium acetate (0.014 g, 0.062 mmole), and (O-tolyl)3P (0.025 g, 0.08 mmole), and the resulting mixture was heated at gentle reflux. After 18 hr, the reaction was cooled, filtered through celite®, and concentrated. Flash chromatography on silica gel (2% MeOH/CH2Cl2) gave the title compound (0.06 g, 41%) as a glassy solid: MS (ES) n/e 374.2 (M+H)+. Anal. Calcd for C23H23N3O2 1.25H2O: C, 69.76; H, 6.41; N, 10.61. Found: C, 69.86; H, 6.67; N, 10.51.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][CH2:8][N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CC([O-])(C)C.[Na+].I[C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:12]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:33]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:34]=3)[CH:11]=2)[C:6]([CH3:15])([CH3:16])[CH2:7][CH2:8]1)([CH3:13])[CH3:14]
Reactant: CC(C)N1CCC(C)(C)c2ccc(N)cc21
Reactant: CCOC(=O)c1ccccc1I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2ccc3c(c2)N(C(C)C)CCC3(C)C)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 41.4 %

Procedure:
7-Amino-1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (Compound 33, 130 mg, 0.5954 mmol) was placed into the round bottom flask charged with argon and Pd2 (dab)3 (1.363 mg, 0.25 mol %), and BINAP (2.78 mg, 0.75 mol %) were added, followed by addition of NaOtBu (80.11 mg, 0.8335 mmol), ethyl iodobenzoate (230 mg, 0.8335 mmol) and toluene (3 mL). The resulting mixture was stirred at 80° C. for 3 days, cooled to room temperature, and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.30) to give the title compound (90.3 mg, 41%) as a solid: PNMR (300 MHz, CDCl3): δ1.20 (d, 6 H, J=6.6 Hz), 1.28 (s, 6 H), 1.38 (t, 3 H, J=7.1 Hz), 1.71 (t, 2 H, J=6.0 Hz), 3.19 (t, 2 H, J=6.0 Hz), 4.02 (sp, 1 H, J=6.6 Hz), 4.34 (q, 2 H, J=7.1 Hz), 5.92 (s, 1 H), 6.43 (dd, 1 H, J=8.1, 2.1 Hz), 6.50 (d, 1 H, J=2.1 Hz), 6.97 (d, 2 H, J=8.7 Hz), 7.14 (d, 1 H, J=8.1 Hz), 7.90 (d, 2 H, J=8.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[NH3:33]>O1CCOCC1>[NH2:33][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=1
Reactant: N
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCOCC1
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
(S)-4-Amino-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (108 mg, 0.237 mmol) in dioxane (3 mL) was combined with 0.5 M ammonia in dioxane (1.419 mL, 0.710 mmol) to give a yellow solution, which was stirred overnight at 60° C. The product was purified by LC/MS using a 5-30% CH3CN gradient in H2O with 0.035% formic acid. The pure fractions were combined and lyophilized to give a formic acid salt of the title compound as a white solid (14 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.59 (m, 3 H), 2.74-2.87 (m, 2 H), 3.03-3.17 (m, 2 H), 3.70-3.99 (m, 8 H), 5.76-5.91 (m, 1 H), 6.52-6.69 (m, 1H), 7.45-7.48 (br s, 2 H), 7.52-7.62 (m, 1 H), 7.75-7.79 (br s, 2 H), 7.82-7.91 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394.4; found 394.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[H-].[Na+].[CH3:22][S:23]([NH2:26])(=[O:25])=[O:24]>CN(C=O)C.C(Cl)Cl.Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
In a 100 ml, round-bottomed flask, 1-(4-bromo-phenyl)-cyclopropanecarboxylic acid (4 g, 16.6 mmol) was combined with DCM (15 mL) and 3 drops of DMF to give a white suspension. To this was added drop wise a clear solution of oxalyl chloride (6.96 g, 4.8 mL, 54.8 mmol) dissolved in DCM (6 mL). After 10 min, the mixture became clear and the reaction was stirred at room temperature for 2 hr. The reaction was concentrated, dried from toluene and hexanes, and stored in a freezer overnight. In a 200 mL round-bottomed flask, NaH (60% mineral dispersion, 876 mg, 36.5 mmol) was washed with hexanes and the resulting solid was diluted with DMF (6 mL) to give a white suspension. The suspension was cooled in an ice bath and methanesulfonamide (3.16 g, 33.2 mmol) dissolved in DMF (6 mL) was added drop wise under nitrogen. After addition (5 min) the ice bath was removed and the reaction was warmed to room temperature overnight. The reaction was cooled in an ice bath, the acid chloride previously prepared and dissolved in DMF (6 mL) was added drop wise, and the reaction was warmed to room temperature overnight. The reaction was diluted with 0.2 N HCl (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with brine, combined, dried over MgSO4, and concentrated. The crude material was dissolved in minimal DCM and purified by flash chromatography (silica gel, 0% to 60% EtOAc in hexanes, 0.5% AcOH). The appropriate fractions were combined, concentrated, and dried from DCM/hexanes yielding N-[1-(4-bromo-phenyl)-cyclopropanecarbonyl]-methanesulfonamide (2.74 g, 51.9% yield) as a white solid. LC/MS calcd. for C11H12BrNO3S (m/e) 317/319, obsd. 318/320 (M+H, ES+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:29]=[CH:30][C:31]6[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=6)[N:27]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: OB(O)c1ccc2ccccc2n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6ccccc6n5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and quinoline-2-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=0.86 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)O[C:10](=[O:11])[C:5]=2[CH:4]=1.[CH:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH3:16]>CN(C=O)C>[NH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([CH:15]([CH2:17][CH3:18])[CH3:16])=[CH:20][CH:21]=1)=[O:11]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2cc(OC)ccc2N)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a flask (100 mL) with magnetic stirrer was added 6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (1.55 g, 8.00 mmol), 4-sec-butylaniline (1.19 mL, 8.0 mmol) and anhydrous DMF (10 mL). The reaction mixture was stirred at 115° C. for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel (230-400 mesh) using hexane/ethyl acetate=1:1 to give 2-amino-N-(4-sec-butyl-phenyl)-5-methoxy-benzamide. Yield: 0.90 g (37%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:29]1([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:4]2[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[CH2:6][CH2:5]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClC(c1ccccc1)c1ccccn1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccn2)CC1
Temperature: 50 °C
Yield: 23.4 %

Procedure:
A mixture of 5.2 parts of 1,3-dihydro-1-[3-(1-piperzinyl)propyl]-2H-benzimidazol-2-one, 5.28 parts of 2-(chlorophenylmethyl)pyridine hydrochloride, 5.3 parts of sodium carbonate and 90 parts of N,N-dimethylformamide is stirred and heated overnight at 50° C. The reaction mixture is cooled and poured onto ice-water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 2 parts (23.4%) of 1,3-dihydro-1-[3-{4-[phenyl(2-pyridinyl)methyl]-1-piperazinyl}propyl]-2H-benzimidazol-2-one; mp. 141.7° C.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[C:27]([O:32][CH3:33])[C:28]=1[N+:29]([O-])=O)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[NH2:29][C:28]1[C:27]([O:32][CH3:33])=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=1[F:13]
Reactant: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])c(OC)c1)OCC
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOP(=O)(Cc1cc(F)c(N)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Compound 102A (2-Amino-5-fluoro-N-methylbenzamide) with Diethyl (3-fluoro-5-methoxy-4-nitrobenzyl)phosphonate (Compound 146B). 1H NMR (CDCl3, 400 MHz): δ=1.27 (t, J=7.07 Hz, 6 H), 2.99-3.08 (m, 2H), 3.87 (s, 3 H), 4.00-4.06 (m, 4 H), 6.59 (s, 1 H), 6.63 (dt, J=10.74, 2.21 Hz, 1 H). MS (ES+): m/z 292.06 [MH+] (TOF, polar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14](C(F)(F)F)([C:18]([F:21])([F:20])[F:19])[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30][N:31](C)[CH:32]=O>>[CH3:30][N:31]([CH3:32])[C:15](=[O:16])[CH:14]([O:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F
Temperature: 100 °C

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid (2.06 g.) in dimethylformamide (10 ml.) is added dropwise at 0° C. under argon to a stirred suspension of sodium hydride (216 mg. of a 60% dispersion in oil from which the oil has been washed with light petroleum) in dimethylformamide (15 ml.). The mixture is heated at 100° C. for 18 hours, cooled, and evaporated in vacuo. The residue is mixed with water and the solid obtained (1.8 g.) is washed with water and dried, then chromatographed in toluene on a column of silica (60 g.). The column is washed with toluene (900 ml.) until no more material is eluted, and then with ether. The ether is evaporated and the solid (0.4 g.) is crystallised from light petroleum to give (±)-N,N-dimethyl-2-[4-(4-chlorophenyl)-benzyloxy]-3,3,3-trifluoropropionamide, m.p. 103°-107° C. (212 mg.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](C=O)[CH:5]=[CH:4][C:3]=1[F:10].[CH:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])OCC>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[C:3]([F:10])=[CH:4][CH:5]=[C:6]([CH:11]([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])[N:7]=1
Reactant: O=Cc1ccc(F)c(Cl)n1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(OCC)c1ccc(F)c(Cl)n1
Yield: 81.3 %

Procedure:
To a mixed solution of a commercially available product of 6-chloro-5-fluoropyridine-2-carbaldehyde (820 mg, 5.14 mmol) and ethanol (10.0 mL) were added triethyl orthoformate (2.56 mL, 15.4 mmol) and pyridinium p-toluenesulfonate (64.6 mg, 0.257 mmol) at room temperature. The resultant mixture was stirred at 80° C. for 5 hours. The reaction mixture was concentrated under a reduced pressure, water was added to the residue, and the resultant solution was extracted with ethyl acetate two times. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, to give a crude product (977 mg) of the title compound. The product was used in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7](Br)[C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.O.O.O.O.C1(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=O)C=2C=CC=1>C(#N)C.CC(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 67.3 %

Procedure:
21.6 g (0.05 mole) of crude 1,4-bis-(4-chlorophenoxy)-1-bromo-3,3-dimethyl-butan-2-one were stirred under reflux with 14 g (0.2 mole) of imidazole in 100 ml of acetonitrile for 17 hours. The mixture was then concentrated by distilling off the solvent under reduced pressure. The residue was taken up in 400 ml of methylene chloride and the mixture was extracted by shaking three times with 800 ml of water each time, dried over sodium sulphate and concentrated. The residue was taken up in 100 ml of acetone, and 9 g (0.05 mole) of 1,5-naphthalenedisulphonic acid tetrahydrate in 50 ml of acetone were added dropwise. The precipitate formed was filtered off and suspended in 200 ml of methylene chloride. 400 ml of saturated sodium bicarbonate solution ere added, the mixture was stirred for 30 minutes and the organic phase was separated off. After distilling off the solvent, 14.1 g (67% of theory) of 1,4-bis-(4-chlorophenoxy)- 3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one were obtained as an oil.