Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:42])[CH2:10][N:11]([C:21](=[O:41])[C@H:22]([CH3:40])[NH:23][P:24]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.[OH-].[Na+]>CC(C)=O.O>[CH2:26]([P:24]([NH:23][C@H:22]([C:21]([N:11]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:43])=[O:2])=[O:42])=[O:41])[CH3:40])([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN(C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1)C1Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)O)C1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Dibenzylphosphory-L-alanyl-N-(2-indanyl) glycyl-L-proline methylester (0.79 g, 1.2 m mole) was dissolved in acetone (5 ml), and sodium hydroxide (0.15 g, 3.8 m mole) in water (4 ml) solution was added thereto while cooling in the ice bath. The mixture was stirred for 1 hour. To the solution water (100 ml) was added, and thereafter it was washed with ethyl ether (50 ml). It was neutralized with 1N hydrochloric acid, and therefrom the desired product was extracted with ethyl acetate. Thus extracted solution was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily dibenzylphosphoryl-L-alanyl-N-(2-indanyl) glycyl-L-proline (0.77 g, yield: 99.7%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4]([Cl:16])[N:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:15][C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([Cl:16])[N:3]=[C:2]([NH2:1])[N:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2O)n1
Product: Nc1nc(Cl)cc(-c2cc(Cl)ccc2OCc2ccccc2)n1
Yield: 56 %

Procedure:
Following the method described in Example 72, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-chloro-phenol and bromomethyl-benzene provided 4-(2-benzyloxy-5-chloro-phenyl)-6-chloro-pyrimidin-2-ylamine (56% yield).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1I.C([Li])CCC.CN([CH:24]=[O:25])C.[NH4+].[Cl-]>C1COCC1>[I:1][C:2]1[N:3]=[C:4]([CH:24]=[O:25])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cnc(I)c1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)nc1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A solution of 4,5-diiodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (8.86 g, 19.68 mmol) in anhydrous THF (110 ml) under argon was cooled to −78° C. and was treated dropwise with n-butyllithium (13.5 ml, 21.65 mmol, 1.6M in hexane). After 10 minutes stirring at −78°° C. and 30 minutes at 45° C., the reaction mixture was cooled to −78° C. and treated at once with DMF (10 ml). The mixture was allowed to warm to room temperature and saturated NH4Cl (150 ml) was added. The aqueous layer was extracted 2 times with AcOEt. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed (silica, elution with hexane/AcOEt=98:2) to provide the title compound (5.18 g, 75%) as a light yellow oil. MS: m/e=352.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH2:11]2)[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC1CCCO1.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([OH:9])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2CC2O1
Reactant: Br[Mg]c1ccccc1
Agent: I[Cu]I
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3 g, 16 mmol), was dissolved in 2-methyl-tetrahydrofuran (5 mL) and added dropwise to a solution of phenylmagnesium bromide (1.5 eq, 24.3 mL of a 1.0 M solution) and copper iodide (0.05 eq) at 0° C. The reaction was allowed to warm to room temperature and stir for 18 h. Reaction was cooled to 0° C. and quenched with sat. NH4Cl solution and extracted with EtOAc. Organic was washed with NaHCO3 and brine and dried over Na2SO4 and the solvent removed. Residue was purified by column chromatography on SiO2 (15-40% EtOAc/HEptane) which gave the title compound Ia as a yellow oil (3.59 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](OS(C1C=CC=CC=1)(=O)=O)[CH:7]=[CH:6]2)#[N:2].[CH2:23]([OH:29])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28]>CCCCCCC.CCOC(C)=O>[OH:29][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]2
Reactant: C#CCCCCO
Reactant: N#Cc1ccc2cc(OS(=O)(=O)c3ccccc3)ccc2c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cc(C#CCCCCO)ccc2c1

Procedure:
This product was prepared from benzenesulfonic acid 6-cyano-naphthalen-2-yl ester and hex-5-yn-1-ol following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 6:4; yield (90 mg, 72%); 1H NMR δ (CDCl3): 8.2 (s, 1H), 7.93 (s, 1H), 7.88-7.76 (m, 2H), 7.65-7.52 (m, 2H), 3.73 (t, J=7.20 Hz, 2H), 2.50 (t, J=7.22 Hz, 2H), 1.87-1.68 (br m, 5H); LCMS m/z: 249.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: ClCCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: O=C1CCc2ccc(OCCCCCl)cc21
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Mixture of 6-hydroxyindan-1-one of the formula (11) (20 gm, 0.135 mol), potassium carbonate (40 gm, 0.289 mol), 1,4-dichlorobutane (80 ml, 0.73 mol) and tetrabutyl ammonium bromide (2 g) was stirred for 1-3 hrs at 95° C. then distilled off excess 1,4-dichloro butane, diluted with water (80 ml). The aqueous layer was extracted with ethyl acetate, and the extract was washed with water, dried and evaporated off under reduced pressure to dryness. The evaporation residue is purified by crystallization using isopropyl ether as a solvent gave 29.5 gm of novel 6-(4-CHLORO BUTOXY)-INDAN-1-ONE of the formula (3).
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].[Cl:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1>CO>[Cl:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[CH:17]([NH2:7])[CH3:18])=[CH:13][CH:12]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)C(C)Oc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)C(C)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.3 %

Procedure:
82 g of ammonium acetate and 6.7 g of sodium cyanoborohydride were added to a solution containing 21 g of 3-(4-chlorophenoxy)-2-butanone dissolved in 500 ml of methanol, and the reaction mixture was stirred for 20 hours at room temperature. After the reaction mixture was concentrated under reduced pressure, 180 ml of concentrated hydrochloric acid, 100 ml of water, and 300 ml of diethyl ether were added to the residue. The obtained water layer was alkalified using a 5% aqueous solution of sodium hydroxide, and then the organic substances were extracted with 500 ml of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. A fraction possessing a low boiling point was removed from the obtained oily products to afford 18 g (yield 86%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[N:16][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:66]([C@@H:68]1[CH2:77][C@H:76]([NH2:78])[C:75]2[C:70](=[CH:71][CH:72]=[C:73]([C:79]([F:82])([F:81])[F:80])[CH:74]=2)[NH:69]1)[CH3:67].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[N:14][C:15]([NH:78][C@@H:76]2[C:75]3[C:70](=[CH:71][CH:72]=[C:73]([C:79]([F:82])([F:80])[F:81])[CH:74]=3)[NH:69][C@H:68]([CH2:66][CH3:67])[CH2:77]2)=[N:16][CH:17]=1)=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCCCOc1cnc(Cl)nc1
Reactant: CC[C@@H]1C[C@H](N)c2cc(C(F)(F)F)ccc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](Nc2ncc(OCCCCC(=O)OC(C)(C)C)cn2)c2cc(C(F)(F)F)ccc2N1
Temperature: 50 °C

Procedure:
5-(2-Chloropyrimidine-5-yloxy)-pentanoic acid tert-butyl ester (464 mg), palladium acetate (26 mg), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (81 mg) were dissolved in toluene (0.5 ml) and the mixture was stirred under nitrogen atmosphere at 50° C. for an hour. The reaction mixture was cooled to room temperature, thereto was added the compound obtained in Example 4 (1) dissolved in toluene (9.5 ml) and stirred at room temperature for 15 minutes. Then, sodium tert-butoxide (310 mg) was added and the mixture was stirred at room temperature for 4 days. Water and ethyl acetate was added to the mixture and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=49:1→17:3→4:1) to give the titled compound (537 mg). MS (m/z): 495 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:2]=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2cccnc12
Reaction time: 4 h
Yield: 48.8 %

Procedure:
To a solution of 4-chloro-8-nitroquinoline (Intermediate-11, step-2, 150 mg, 0.71 mmol) in EtOAc (3 mL) was added 10% Pd on C (75 mg) and the suspension was hydrogenated in a Parr apparatus for 4 h at 20 psi. Then the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography using 10% EtOAc in CHCl3 to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.71 (d, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.47-7.43 (m, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.86 (d, J=7.2 Hz, 1H), 5.90 (s, 2H).
Reaction SMILES: Cl.C([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)C1C=CC=CC=1.[C@@H:17]1([C:26]([OH:28])=O)[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([OH:25])=O>CCOC(C)=O>[C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23]([C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[C:26]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[C:10]([OH:9])=[O:16])=[O:28])=[O:25])([OH:16])=[O:9]
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)C1CCCN1C(=O)[C@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]1C(=O)O
Yield: 90.5 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 700 mg (4.1 mmol) trans-cyclohexane-1,2-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.36 g (62%) of the title compound as a colorless oil. MS m/e (%): 547 (M+H+, 100).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:28][NH2:29]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH2:2][NH:29][CH3:28])[CH:27]=[CH:26][CH:25]=2)[S:8]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(Cc2cccc(CBr)c2)c2ccccc2N1c1ccccc1F
Reactant: CN
Product: CNCc1cccc(CN2c3ccccc3N(c3ccccc3F)S2(=O)=O)c1
Yield: 71 %

Procedure:
In an analogous manner to general procedure V, 1-[3(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.08 g, 0.18 mmol) was treated with methylamine (10 mL) to provide 0.05 g (71%) of 1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methyl}phenyl)-N-methylmethanamine. HRMS: calcd for C21H20FN3O2S+H+, 398.13330; found (ESI, [M+H]+), 398.1337; HPLC purity 95.4% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:17]([CH:30]([OH:32])[CH3:31])=[N:16][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])(C(C)(C)C)(C)C.Cl>C(O)C.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:18]2[C:19]3[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:34])[N:14]([CH3:33])[C:15]=3[N:16]=[C:17]2[CH:30]([OH:32])[CH3:31])=[CH:28][CH:27]=1
Reactant: CC(O)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(O)c1nc2c(c(=O)n(CCCO)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
Step 2 1-(3-((tert-butyldimethysilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.052 g, 0.10 mmoL) was dissolved in ethanol (2 mL) and 6N aqueous HCl (0.5 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (25 mL) and extracted with DCM (3×25 mL). The combined organic extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to a golden oil. The oil was purified using a 2000 micron preparative TLC plate eluted with 50% ethyl acetate/hexanes. Target band was extracted with ethyl acetate and the solvent was removed under reduced pressure to give 7-(4-chlorobenzyl)-8-(1-hydroxyethyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.012 g, 29% yield) as a clear oil. LCMS retention time=2.429 min and 96% purity, LCMS MH+ 393. 1H NMR (CDCl3) δ 7.25 (dd, 4H, J=8 Hz and 64 Hz), 5.65 (dd, J=12 Hz and 40 Hz), 4.91-4.97 (m, 1H), 4.19 (t, 2H, J=4 Hz), 3.61 (s, 3H), 3.51-3.55 (m, 2H), 2.52 (d, 1H, J=4 Hz), 1.87-1.93 (m, 2H), 1.57 (d, 3H, J=4 Hz).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:9].O=O>CO>[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:4]1(=[O:9])[CH:5]=[CH:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: O=S(=O)(O)O
Agent: O=O
Solvent: CO
Solvent: Oc1ccccc1
Product: O=C1C=CC(=O)C=C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Twenty milligrams of the inactive complex obtained as described in Example 1, 100 milligrams of phenol and one cubic centimeter of methanol were added to a 1/2 ounce bottle. The complex was insoluble in the methanol. Two microliter portions of concentrated sulfuric acid were added until 10 microliters were in the bottle. The insoluble complex went into solution with the methanol and acid when the mixture was heated with steam at 100° C. An oxidation was run with the solution formed by charging 100 microliters of said solution into a micro reactor, heating to 65° C., and charging 500 pounds per square inch gauge oxygen pressure. After oxidizing for 60 minutes, 29.6 percent conversion of phenol to benzoquinone was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]1([C:14](=O)[NH2:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]1([C:14]#[N:15])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
To a 0° C. solution of (1-carbamoyl-cyclopropyl)-carbamic acid benzyl ester (1.8 g, 7.7 mmol) in DMF (20 mL) was added cyanuric chloride in one portion. The reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water (3×50 mL), brine and dried with MgSO4. The mixture was filtered and concentrated. The resulting crude residue was dissolved in 30% EtOAc in hexanes (90 mL) and filtered through a plug of silica gel. The filtrate was concentrated to give (1-cyano-cyclopropyl)-carbamic acid benzyl ester (1.4 g, 6.5 mmol) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(OC)c(-c3c(F)cnn3C)c2)cc1
Yield: 29 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-methoxyphenylisocyanate, in a similar manner as described in Example 1.68. Additionally the residue was washed with CH2Cl2, providing 18 mg (29% yield) of Compound 87: LCMS m/z (%)=371 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.06 (s, 1H), 7.95 (s, 1H), 7.63 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.49 (d, J=2.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.37 (d, JH,F=4.4 Hz, 1H), 7.11 (d, J=9.2 Hz, 1H), 6.85 (d, J=9.2 Hz, 2H), 3.82 (s, 3H), 3.75 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.41 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-])=O.C1(=O)OC(=O)C=C1>O1CCOCC1.[Pd]>[C:13]([OH:15])(=[O:14])[C:6]1[C:7](=[CH:11][CH:12]=[CH:4][CH:5]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Agent: O=C1C=CC(=O)O1
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
84.5 g (0.4 mol) of 4-nitrophthalic acid are hydrogenated in 720 ml of dioxane, in the presence of 4 g of a palladium/charcoal catalyst containing 5% by weight of palladium, at 25° C. 47.02 g (0.48 mol) of maleic anhydride are added to the filtered reaction solution. After a reaction time of 12 hours, the 4-(maleinamidyl)-phthalic acid which has precipitated is filtered off and washed with 50 ml of dioxane. After drying at 80° C./15 mm Hg for 12 hours, 101.6 g (91% of theory) of 4-maleinamidyl)-phthalic acid are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[O:16].Cl>C1COCC1.O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(=O)C(CC(=O)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A solution of Meldrum's acid (5.0 g, 35 mmol) in anhydrous THF (25 mL) was added cautiously to a stirred suspension of sodium hydride (95%, 960 mg, 38 mmol) in anhydrous THF (25 mL). The resulting solution was stirred at room temperature for 1 hr. A solution of 2,4′-dibromoacetophenone (11.6 g, 42 mmol) in anhydrous THF (25 mL) was added dropwise, and the resultant solution was stirred at room temperature for 16-24 hrs (TLC control). The reaction mixture was poured into water (50 mL), acidified to pH 2-3 with 0.5N hydrochloric acid and extracted with ethyl acetate (3×50 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Trituration and filtration from MeOH afforded the title compound as a white solid (6.56 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][CH:8]=[C:7]([CH2:12][O:13][CH3:14])[N:6]=1)=[O:4].[C:15](=[O:22])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[NH2:16].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:18]([O:17][C:15]([NH:16][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([CH2:12][O:13][CH3:14])=[CH:8][CH:9]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(N)=O
Reactant: COCc1ccc(Br)c(C(=O)OC)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCc1ccc(NC(=O)OC(C)(C)C)c(C(=O)OC)n1
Temperature: 100 °C
Yield: 56.2 %

Procedure:
To a stirred solution of 3-bromo-6-methoxymethyl-pyridine-2-carboxylic acid methyl ester (933 mg, 3.59 mmol; intermediate A-3, step 6) and tert-butyl carbamate (504 mg, 4.3 mmol) at r.t. in dioxane (15 ml) under an argon atmosphere were added cesium carbonate (1.64 g, 5.02 mmol), Pd2(dba)3 (65.7 mg, 71.7 μmol) and Xantphos (62.3 mg, 108 μmol; CAS 161265-03-8). The mixture was degassed under vacuum and flushed with argon, then heated to 100° C. overnight. The mixture was cooled to r.t., diluted with CH2Cl2, and the solids were filtered off and washed with some CH2Cl2. The filtrate was concentrated. The crude product was purified by silica gel chromatography using a cyclohexane/EtOAc gradient to give the title compound (598 mg, 56%) as viscous light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH:13]1([C:16]2[CH:17]=[C:18]([CH3:28])[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[CH:17]=[C:18]([CH3:28])[C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:4]([C:3]4[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:2]=4[F:1])=[O:6])[CH2:26][CH2:27]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(I)cc1F
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2F)CC1
Yield: 95.8 %

Procedure:
Using 2-fluoro-4-iodobenzoic acid (399 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (381 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Preparation Example 160, the title compound (668.5 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Br)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
Then, 8.47 g of 4-bromo-2-trifluoromethylphenol, 5.34 g of potassium carbonate, 4.49 g of benzyl chloride and 100 ml of N,N-dimethylformamide were charged into a reaction vessel, and stirred under ice cooling. After 24 hours, the reaction solution was poured into ice-water and extracted three times with 50 ml of diethyl ether. The ether layers were combined, washed with an aqueous 10 % sodium hydroxide solution, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 9.38 g of 4-bromo-2-trifluoromethyl-1-benzyloxybenzene (yield, 81%).