Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[O:11]1CCOCC1.C(=O)([O-])[O-].[Ca+2]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C1COCCO1
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(Br)cc(CO)c1

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-5-methylbenzene (40.0 g, 151 mmol), 1,4-dioxane (150 mL), water (150 mL) and calcium carbonate (37.9 g, 379 mmol) was heated for 16 h at reflux. The mixture was filtered and the filtrate was concentrated in vacuum, then diluted with CH2Cl2 (150 mL). The organic layer was washed with HCl (2N, 50 mL) and a solution of saturated sodium bicarbonate (50 mL), dried (Na2SO4) and concentrated in vacuum to give 25.0 g of crude product (3-bromo-5-methylphenyl)methanol.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[N:56]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[N:56]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1)=[O:50]
Reactant: COC(=O)c1cccc2c1nc(N)n2Cc1ccccc1
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1nc(NC(=O)c1cc3ccccc3cn1)n2Cc1ccccc1
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
To a solution of 0.031 g (0.18 mmol) of isoquinoline-3-carboxylic acid in DMF (1 mL) was added 0.085 g (0.22 mmol) of HBTU and 0.1 mL of DIEA. The mixture was stirred for 5 min, then added 0.04 g (0.18 mmol) of 2-amino-1-benzyl-1H-benzoimidazole-4-carboxylic acid methyl ester in one portion. The reaction mixture was stirred for 1 h. After usual workup, 45 mg (73%) of 1-benzyl-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester was isolated after purification by column chromatography eluting with DCM/methanol (v/v from 15:1 to 10:1). LCMS: 437 (M+1)+; 1H NMR (DMSO-d6, 400 MHz): δ 12.8 (s, 1H), 9.41 (s, 1H), 8.92 (s, 1H), 8.20 (d, 1H), 8.14 (d, 1H), 7.84 (t, 1H), 7.77 (m, 3H), 7.51 (d, 2H), 7.32 (m, 4H), 5.63 (s, 2H), 3.99 (s, 3H) ppm.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:38][C:39]2[CH:46]=[CH:45][C:42]([CH3:43])=[CH:41][CH:40]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: Cc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cc1
Yield: 74.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-methylbenzyl chloride (0.42 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)o1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(N)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (135 mg, 0.258 mmol) and ammonium hydroxide (5 mL), the title compound was obtained as an off-white solid (75 mg, 58%). 1H-NMR (DMSO-d6): δ ppm 10.74 (br s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.45-7.61 (m, 4H), 7.28-7.37 (m, 1H), 6.63-7.26 (m, 1H), 6.62 (d, J=5.6 Hz, 1H), 1.40 (s, 9H); MS: 504 [M+H]+.
Reaction SMILES: C(Cl)(=O)C.[CH:5]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:12][C@@:13]([NH:26][NH2:27])([C:23]([OH:25])=[O:24])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:22])=[C:19]([OH:21])[CH:20]=1>C(OCC)(=O)C>[OH:21][C:19]1[CH:20]=[C:15]([CH2:14][C@@:13]([NH:26][NH2:27])([CH3:12])[C:23]([O:25][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:24])[CH:16]=[CH:17][C:18]=1[OH:22]
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)O
Reactant: OC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OC1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Acetyl chloride (1 mL) was slowly added to cyclohexanol (5 mL) at 0° C. After stirring at 0° C. for 10 min, carbidopa (294 mg, 1.5 mmol) was added slowly as solid. The resulting mixture was warmed to 50° C. for 16 h. After cooling to room temperature, ethyl acetate (40 mL) was added and product was extracted with water (4×5 mL), then the aqueous phase was lyophilized to give the crude product. HPLC of the crude product afforded 50 mg of the title compound as an oil. 1H NMR (CD3OD): δ 1.46 (s, 3H), 1.52–1.80 (m, 10H), 2.92 (dd, J=13.6 Hz, 2H,), 4.85 (m, 1H), 6.49 (d, J=7.6 Hz, 1H), 6.59 (s, 1H), 6.68 (d, J=7.6 Hz, 1H). MS (ESI) m/z 309.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[CH2:10][N:11]([C:16](=[O:36])[C@H:17]([CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])[N:18]([N+:26]([O-:28])=[O:27])C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:38].C(OCC)(=O)C.C(OCC)C>C(OCC)(=O)C>[ClH:38].[CH2:1]([O:8][C:9](=[O:37])[CH2:10][N:11]([C:16](=[O:36])[C@H:17]([CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])[NH:18][N+:26]([O-:28])=[O:27])[CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CC(=O)OCc1ccccc1)C(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCN(CC(=O)OCc1ccccc1)C(=O)[C@H](CCCNC(=N)N)N[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred solution of 26.0 g of NG -nitro-N2 -(tertbutoxycarbonyl)-L-arginyl-N-butylglycine benzyl ester in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0° C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. This was filtered and washed with dry ethyl ether to give 20.8 g of NG -nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:3]=1.C([Li])CCC.[CH:28](N1CCOCC1)=[O:29].Cl>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:28]=[O:29])=[CH:3][C:4]=1[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1
Reactant: O=CN1CCOCC1
Reactant: COc1ccc(Br)cc1COCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1COCc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.4 g of 4-bromo-1-methoxy-2-({[4-(trifluoromethyl)benzyl]oxy}methyl)benzene was dissolved in 15 ml tetrahydrofuran and cooled at −78° C., and 3.0 ml n-butyl lithium (1.5 M solution in pentane) was added. After stirring the reaction mixture at −78° C. for 30 minutes, 0.45 ml N-formyl morpholine was added, and the mixture was stirred at −78° C. for 1 hour. 1N hydrochloric acid was added to the reaction solution, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 0.42 g of 4-methoxy-3-({[4-(trifluoromethyl)benzyl]oxy}methyl)benzaldehyde was obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13]/[C:12]/2=[N:25]\[C:26]#[N:27]>CO>[NH2:27][C:26]1[N:3]([CH3:2])[O:4][C:12]2([C:11]3[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=3)[O:15][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)[N:25]=1
Reactant: CNO
Reactant: N#C/N=C1\CC(c2ccccc2)Oc2ccc(O)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(O)cc32)N=C1N
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
To a solution of methylhydroxylamine HCl salt (28 mg, 0.326 mmol) in anhydrous MeOH (8 mL) was added NaOMe (25 wt. % in MeOH, 15.83 mg, 0.294 mmol), followed by (E)-N-(6-hydroxy-2-phenylchroman-4-ylidene)cyanamide (86 mg, 0.326 mmol). After stirred 10 minutes, the solvent was removed in vacuum. The residue was dissolved in DCM (15 mL) and filtered, and the solvent was removed in vacuum to give the crude product, which was purified by preparative TLC to give 3′-amino-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-6-ol (20 mg, 20%). 1HNMR (CDCl3): 7.30-7.51 (m, 5H), 6.95 (s, 1H), 6.69 (m, 2H), 5.15 (t, 3H), 2.98 (s, 3H), 2.28 (d, 2H), 1.17 (s, 1H).
Reaction SMILES: C(#N)C.N(OC(C)(C)C)=O.N[C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:16]=1.C(Cl)(Cl)[Cl:24].CCCCCC>[Cu](Cl)Cl>[Cl:24][C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:16]=1
Reactant: ClC(Cl)Cl
Reactant: CCCCCCc1csc(N)n1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCCCCC
Product: CCCCCCc1csc(Cl)n1
Reaction time: 2 h

Procedure:
To 200 mL of acetonitrile was added 9.7 mL (81 mmol) of t-butyl nitrite and 8.75 g (65.1 mmol) of copper(II) chloride, and 10 mL of acetonitrile containing 10.0 g (54.3 mmol) of 2-amino-4-hexylthiazole (Helvetica Chemica Acta XXXII, Fasciculus I, 35 (1949)) dissolved therein was added to this portion-wise while cooling with ice under an argon atmosphere and the temperature thereof was returned to room temperature and the mixture was stirred for 2 hours. Then, the resultant reaction mixed liquid was poured into 100 ml of chloroform/hexane mixed liquid, and the precipitate was removed by filtration. The filtrate was washed with 100 ml of a 20 wt % hydrochloric acid aqueous solution three times, then, extracted with chloroform. The resultant extraction liquid was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, and purified by silica gel column chromatography (development solvent:chloroform/hexane=1/1 (volumetric ratio)), to obtain the intended 2-chloro-4-hexylthiazole.
Reaction SMILES: C([O:5][C:6](=[O:45])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH:42]([CH3:44])[CH3:43])[C:33]=4[C:34]=3[CH3:35])=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[Cl:40][C:37]1[CH:38]=[CH:39][C:32]2[O:31][C:30]([C:28]([NH:27][C:24]3[CH:23]=[CH:22][C:21]([C:18]4[CH:17]=[CH:16][C:15]([S:12]([NH:11][C@@H:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:45])=[O:5])(=[O:13])=[O:14])=[CH:20][CH:19]=4)=[CH:26][CH:25]=3)=[O:29])=[C:34]([CH3:35])[C:33]=2[C:36]=1[O:41][CH:42]([CH3:44])[CH3:43]
Reactant: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc3)cc2)oc2ccc(Cl)c(OC(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2ccc(Cl)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 9 h
Yield: 82 %

Procedure:
To 160 mg of (S)-2-{4′-[(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester was added 3 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 9 h. When the reaction was done, the solvents were removed under vacuum and the residue was triturated with acetonitrile. The mixture was freeze-dried to yield 120 mg (77% yield) of (S)-2-{4′-[(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 1.3 (d, J=6.1 Hz, 6 H) 1.9 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 4.7 (m, 1 H) 7.5 (d, J=8.8 Hz, 1 H) 7.6 (m, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.3 Hz, 1 H) 10.6 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Sc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 305 was used, starting from 4-fluoro-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 381 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:24]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[CH:3]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(N)c1
Reactant: O=C1CCCC(=O)O1
Solvent: CN(C)C=O
Product: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(NC(=O)CCCC(=O)O)c1

Procedure:
In analogy to Example 70.4-6, from the methyl (RS)-(3-amino-4-methoxy-phenyl)-(4-cyano-phenylamino)-acetate described in Example 70.3, glutaric anhydride and Hüinig's base in DMF there was obtained (RS)-4-{5-[(4-cyano-phenylamino)-methoxycarbonyl-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid, which was subsequently converted via (RS)-4-{5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid into (RS)-(E)- and/or -(Z)-4-(5-{carboxy-[4-(N-hydroxycarbamimidoyl)-phenylamino]-methyl}-2-methoxy-phenylcarbamoyl)-butyric acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[CH2:26]([NH2:28])[CH3:27]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][NH:28][CH2:26][CH3:27])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (5-chloro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]=2[CH:2]=1)=O.[F:12][C:13]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1)([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15]>C1COCC1>[F:12][C:13]([C:22]1[CH:28]=[CH:27][C:25]([N:26]2[C:7](=[O:9])[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][C:3]=3[C:10]2=[O:11])=[C:24]([CH3:29])[CH:23]=1)([C:18]([F:19])([F:20])[F:21])[C:14]([F:17])([F:16])[F:15]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Reactant: O=C1OC(=O)c2cnccc21
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N1C(=O)c2ccncc2C1=O
Reaction time: 3 h

Procedure:
In 10 ml of THF were dissolved 1.50 g of pyridine-3,4-dicarboxylic acid anhydride and 2.75 g of 4-(heptafluoro-2-propyl)-2-methylaniline, and the reaction was carried out at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and 20 ml of trifluoroacetic anhydride was added to the resulting residue, and the reaction was carried out with refluxing for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain crude N-[4-(heptafluoro-2-propyl)-2-methylphenyl]pyridine-3,4-dicarboximide quantitatively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[N:23]=[CH:22][N:21]=2)=[C:17]([F:44])[CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:44][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[S:13])[CH:43]=[CH:42][C:18]=1[O:19][C:20]1[CH:25]=[C:24]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][CH:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:33][CH2:34]2)=[O:28])[N:23]=[CH:22][N:21]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)ncn3)CC2)CC1
Reaction time: 3.5 h
Yield: 46 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 2.0 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyrimidine (98 mg) and (+)-10-camphorsulfonic acid (79 mg) in ethanol (2.0 ml) at room temperature, the mixture was stirred for 3.5 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3) to provide the title compound (65.2 mg, 46%) as white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2.[H-].[Na+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1cccc2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4cccnc34)ncn2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 100-mL round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.30 g, 1.2 mmol) and 8-hydroxyquinoline (0.17 g, 1.2 mmol, Aldrich) in DMF (5 mL), was added NaH (56 mg, 1.4 mmol, 60% in mineral oil, Aldrich) at room temperature and the mixture was then stirred at room temperature for 48 h. After the solvent was removed in vacuum, EtOAc (25 mL) was added to the residue, and the mixture was washed with water (2×15 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Silica gel chromatography (4:1 hexanes/EtOAc) afforded the title compound as a white solid. Mp: 155–157° C. MS (ESI, pos. ion) m/z: 368 (M+1). Anal. Calcd for C20H12F3N3O: C, 65.40; H, 3.29; N, 11.44. Found: C, 65.29; H, 3.25; N, 11.41.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>CO>[ClH:30].[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=2)=[CH:20][C:21]=1[CH3:26]
Reactant: Cc1cc(-c2cn(CCO)c(C3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(-c2cn(CCO)c(C3CCNCC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[4-(4-Fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1600.00 mg; 3.97 mmol; 1.00 eq.) in methanol 10 ml added 4.0M HCl in dioxane (9.91 ml; 39.65 mmol; 10.00 eq.), the reaction mixture was stirred at RT for 3 hrs, lc-ms showed clean desired, removed off solvent, got white solid as title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1.C(OCC)(=[O:30])C>>[CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:30])[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CCOC(C)=O
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccc(I)cc3)ccc2O1
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3ccc(I)cc3)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 21, from 3,4-dihydro-2,2-dimethyl-6(4-iodobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-[3,4-dihydro-2,2-dimethyl-6-(4-iodobenzoyl)-2H-1-benzopyran-4-yl]pyridine N-oxide of melting point 171°-173° C. (from ethyl acetate).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.054 g, 0.00014 mol), 2-(dimethylamino)acetic acid (0.0018 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-(dimethylamino)-1-ethanone (0.031 g, 0.00007 mol).