Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCCC.C1COCC1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(O)[CH2:21][CH3:22].C(O)(C)C.S(=O)(=O)(O)O>O>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH3:22]
Reactant: CCC(O)(c1ccccc1)c1ccccc1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CC=C(c1ccccc1)c1ccccc1C
Temperature: 25 °C
Yield: 93.9 %

Procedure:
TLC: rf=0.50 (SiO2; n-heptane/THF=7:3). 1-(2-Methylphenyl)-1-phenyl-1-propanol (10.4 g, 46 mmol) was dissolved into isopropanol (100 ml) and a 4 N sulphuric acid solution (50 ml) was added. The reaction mixture was heated at reflux temperature for 18 h and cooled to room temperature. Water (300 ml) was added and the mixture was extracted with dichloromethane (2×200 ml). The combined organic extracts was washed with a diluted sodium bicarbonate solution, dried (Na2SO4) and the solvent evaporated in vacuo to give 9.0 g (91%) of 1-(2-methylphenyl)-1-phenyl-1-propene. To a solution of 1-(2-methylphenyl)-1-phenyl-1-propene (9.0 g, 43 mmol) in carbon-tetrachloride (40 ml), N-bromosuccinimide (7.7 g, 43 mmol) and benzoylperoxide (0.1 g) were added. The reaction mixture was heated at reflux temperature for 18 h. The cooled reaction mixture was filtered through silica gel and the solvent evaporated in vacuo to give 9.3 g (76 %) of 3-bromo-1 (2-methylphenyl)-1-phenyl-1-propene.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)(O)=O.[CH2:17]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH3:15][C:11]([S:10][C:7]1[S:8][CH:9]=[C:5]([CH2:4][CH2:1][NH:26][C:25]2[CH:27]=[CH:28][C:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=2)[N:6]=1)([CH3:16])[C:12]([OH:14])=[O:13]
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Reactant: CCCCCc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCCCCc1ccc(NCCc2csc(SC(C)(C)C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An operation similar to that of Example 520-1 was performed using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin synthesized in Example 461-4 and 4-amylaniline (0.098 g) as starting materials. To the obtained resin were added tetrahydrofuran (2.0 mL) and 1 mol/L borane-tetrahydrofuran complex (2.0 mL), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the reaction mixture, washed once with tetrahydrofuran, twice with tetrahydrofuran/methanol=1:1 solution, and twice with methanol. Then, a solution (4.0 mL) of tetrahydrofuran-methanol-piperidine (1:1:2) was added to the resin, and the mixture was stirred at room temperature overnight. After completion of the reaction, the resin was collected by filtration, washed four times with tetrahydrofuran and twice with methanol, and vacuum dried to give the title pale-yellow resin (0.30 g).
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:3][CH2:4][N:5]([C:35]([C:37]2[S:41][C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[N:39][C:38]=2[CH3:48])=[O:36])[C:6]2[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:25][C:26]([O:28]CC)=[O:27])C(=O)C(F)(F)F)[CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[F:49][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:35]([C:37]2[S:41][C:40]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[N:39][C:38]=2[CH3:48])=[O:36])[C:6]2[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:25][C:26]([OH:28])=[O:27])[CH2:14][CH2:13]1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)C(F)(F)F)C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(NCC(=O)O)CC2)c2ccccc21
Temperature: 40 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
To a solution of 240 mg of ethyl (Z)-[(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)-(trifluoroacetyl)amino]acetate in 5 ml of ethanol was added a solution of 100 mg of potassium carbonate in 4 ml of water, and the mixture was stirred at 40° C. for 18 hours. After evaporation of the solvent, 1N hydrochloric acid was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, and the solvent was evaporated therefrom. The resulting residue was crystallized from diethyl ether to give 40 mg of (Z)-[(1-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}-4-piperidyl)amino]acetic acid as a pale yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[CH:18][C:17]=3[F:30])=[C:12]([C:31]([F:34])([F:33])[F:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C2C(CO)=C(C(F)(F)F)SN=2)=CC=1)C.FC1C=C(CC(C)C(OCC)=O)C=CC=1O.[Li+].[OH-]>O.O1CCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[CH:18][C:17]=3[F:30])=[C:12]([C:31]([F:32])([F:34])[F:33])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C(C)Cc1ccc(OCc2c(-c3ccc(CC)cc3)nsc2C(F)(F)F)c(F)c1
Agent: CCOC(=O)C(C)Cc1ccc(O)c(F)c1
Agent: CCc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CC(C)C(=O)O)cc2F)cc1
Reaction time: 0.12 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3-fluorophenyl)-2-methylpropanoate (74 mg, 0.15 mmol, 1.00 equiv) (prepared according to the procedure of Example 1 step 5 by coupling (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and ethyl 3-(3-fluoro-4-hydroxy phenyl)-2-methylpropanoate), tetrahydrofuran (1.5 mL). This was followed by the addition of a solution of LiOH (74 mg, 3.09 mmol, 20.69 equiv) in water (1.5 mL) dropwise with stirring. The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. Hydrogen chloride (2N) was employed to adjust the pH to 1. The solids were collected by filtration. The crude product (35 mg) was purified by Prep-HPLC with the following conditions (1# water 2767-16): Column, SunFire Prep C18 Sum, 19*150 nm; mobile phase, water with 0.05% trifluoroacetic acid and CH3CN. (70% CH3CN up to 90% in 7.0 min, up to 100% in 2.0 min, down to 70% in 2.0 min); Detector, 254 nm. This resulted in 3.4 mg (5%) of 3-(4-((3-(4-ethylphenyl)-5-(trifluoro methyl)isothiazol-4-yl)methoxy)-3-fluorophenyl)-2-methylpropanoic acid as a white solid. 1H NMR (300 Hz, CD3OD): 7.64 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 6.92-7.03 (m, 3H), 5.14 (s, 2H), 2.89-2.97 (m, 1H), 2.62-2.75 (m, 4H), 1.27 (t, J=7.8 Hz, 3H), 1.16 (d, J=3.3 Hz, 3H). 19F NMR (300 Hz, CD3OD): δ−56.57, −76.95, −135.59. Mass spectrum (ESI, m/z): Calcd. for C24H21.5F5.5NO4S, 468.1 (M-0.5CF3COOH+H). found 468.1.
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC=CC=1OCC(O)=O.CC1C=CC=CC=1OCC(Cl)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1.[CH3:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH2:55][C:56]([N:58]=[C:59]=[S:60])=[O:57]>C1(C)C=CC=CC=1.C(O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][C:59]([NH:58][C:56](=[O:57])[CH2:55][O:54][C:53]2[CH:61]=[CH:62][CH:63]=[CH:64][C:52]=2[CH3:51])=[S:60])=[CH:46][CH:45]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1OCC(=O)N=C=S
Agent: Cc1ccccc1OCC(=O)Cl
Agent: Cc1ccccc1OCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)COc4ccccc4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-(2-methylphenoxy)acetic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-(2-methylphenoxy)ethanoyl isothiocyanate was prepared using the resultant 2-(2-methylphenoxy)ethanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(2-methylphenoxy)ethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (37 mg, yield 44%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:25]2[CH2:24][CH2:23][CH:22]([N:14]([CH3:13])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:27][CH2:26]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 4-fluoro-2-methoxy-1-nitrobenzene and tert-butyl methyl(piperidin-4-yl)carbamate. m/z 366.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH3:11].[C:12]1([CH2:18][SH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.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.CCN(C(C)C)C(C)C>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]>[CH2:18]([S:19][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1c(Br)cc(F)cc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Br)cc(F)cc1SCc1ccccc1

Procedure:
1,3-Dibromo-5-fluoro-2-methoxy-benzene (14.2 g, 50 mmol), phenyl-methanethiol (5.86 ml, 50 mmol), Pd2 dba3 (1.145 g, 1.25 mmol, 2.5 mol-%), Xantphos (1.447 g, 2.5 mmol, 5 mol-%) and DIPEA (17.5 ml, 100 mmol) were dissolved in 130 ml dry, degassed 1,4-dioxane and heated to reflux for 3 hours. After cooling down the mixture was filtrated and evaporated. The remaining solid (22 g) was chromatographed on silica gel using n-heptane-MTBE as eluent. Yield: 12.42 g, 76%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:13]=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N:14]1[CH:15]=[C:16](B(O)O)[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12>>[N:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:13]=[CH:12][O:11][N:10]=3)[CH:5]=[CH:6][CH:7]=2)[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12
Reactant: Brc1cccc(Nc2ccon2)c1
Reactant: OB(O)c1cnc2ccccn12
Product: c1cc(Nc2ccon2)cc(-c2cnc3ccccn23)c1

Procedure:
Prepared using procedure outlined in Procedure H using (3-Bromo-phenyl)-isoxazol-3-yl-amine and imidazo[1,2-a]pyridine-3-ylboronic acid as the coupling partners.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:27]=1[NH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2ccc(C(F)(F)F)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 15 h

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 2.24 g, 6.63 mmol), 2-bromo-4-trifluoromethylaniline (3.18 g, 13.25 mmol), p-toluenesulfonic acid monohydrate (1.35 g, 7.09 mmol) and xylene (5.0 mL) was stirred at 130° C. for 15 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give crude ethyl 4-[2-{[2-bromo-4-(trifluoromethyl)phenyl]amino}-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate. The crude material (MS Calcd.: 573; Found: 574 (M+H)) was subjected for the next step without further purification. To a solution of the crude material in tetrahydrofuran (15.0 mL) was added lithium borohydride (193.0 mg, 8.86 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr and warmed to 60° C. and stirred for 19 hr. The reaction mixture was quenched with water at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give a mixture contained the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless powder (110.4 mg, 0.207 mmol, 3.1% (2 steps)).
Reaction SMILES: [F:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.Cl>C(O)C>[F:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1F
Agent: Cl
Solvent: CCO
Product: COc1cc([N+](=O)[O-])c(N)cc1F
Yield: 88 %

Procedure:
N-(5-Fluoro-4-methoxy-2-nitrophenyl)acetamide obtained in Reference Example 13 (5.7 g) was suspended in ethanol (20 ml), and 6N hydrochloric acid (100 ml) was added thereto. The mixture was refluxed for 30 minutes. The reaction mixture was ice-cooled, and the resulting precipitate was collected and washed with water to obtain the title compound as crystals (4.1 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])=[C:13]([C:24]([OH:26])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]2[C:35]3([CH2:41][O:42][C:31]=2[CH:30]=1)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])=[C:13]([C:24]([N:38]3[CH2:39][CH2:40][C:35]4([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=5[O:42][CH2:41]4)[CH2:36][CH2:37]3)=[O:26])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Reactant: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 75.5 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.363 mmol) obtained in step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.082 g, 0.399 mmol), the title compound (0.150 g, 75%) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:7][NH2:8].[Cl:14][C:15]1[C:16](=[O:25])[N:17]([CH2:22][CH2:23][CH3:24])[N:18]=[CH:19][C:20]=1Cl.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:14][C:15]1[C:16](=[O:25])[N:17]([CH2:22][CH2:23][CH3:24])[N:18]=[CH:19][C:20]=1[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([O:3][CH3:2])[CH:5]=1
Reactant: CCCn1ncc(Cl)c(Cl)c1=O
Reactant: COc1ccc(CN)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCn1ncc(NCc2ccc(OC)c(OC)c2)c(Cl)c1=O
Reaction time: 5 h

Procedure:
A mixture comprising 1.52 g of 3,4-dimethoxybenzylamine hydrochloride prepared in Reference Example 1, 0.62 g of 4,5-dichloro-2-n-propyl-3(2H)pyridazinone, 1.66 g of potassium carbonate, 10 ml of 1,4-dioxane and 30 ml of water was refluxed under stirring for 5 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained, and the mixture was extracted with ethyl acetate. The extract was washed successively with 2% diluted hydrochloric acid, water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off to obtain a pale yellow oily substance. This substance was crystallized from diethyl ether-n-hexane to obtain 522 mg of the above identified compound having a melting point of from 139 to 140° C. as colorless crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:22]=1[NH:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55]O)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55][O:36][C:30]2[CH:29]=[C:28]3[C:33]([C:24]([NH:23][C:22]4[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:21]=4[F:20])=[N:25][CH:26]=[N:27]3)=[CH:32][C:31]=2[O:34][CH3:35])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
Triphenylphosphine (2.19 g, 8.36 mmol) was added to a suspension of 4-(2-fluoro-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (1 g, 3.34 mmol) in methylene chloride (10 ml) cooled at 0° C., followed by 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (1.08 g, 5.01 mmol), (prepared as described for the starting material in Example 1), and diethyl azodicarboxylate (1.31 ml, 8.36 mmol). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (2/98). After removal of the solvent by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline (327 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[NH2:8][C:6]1[CH:5]=[C:4]([OH:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)cc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)cc(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
3-Chloro-5-nitrophenol from Example 63A (3.00 g, 17.3 mmol) and zinc powder (5.65 g, 86.4 mmol) in ethanol (80 mL) were heated to 60° C., and a solution of ammonium chloride (1.85 g, 34.6 mmol) in water (16 mL) was added dropwise. The reaction was stirred for further 3 h at 60° C. It was then filtered through Celite®, and the solvent was removed in vacuo. The residue was dissolved in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with DCM, and the precipitate was collected by suction filtration to yield 1.97 g (77%) of the title compound as yellowish crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[C:8]([C:13]([OH:15])=O)=[CH:7]2.S(Cl)([Cl:18])=O>>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[C:8]([C:13]([Cl:18])=[O:15])=[CH:7]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Product: O=C(Cl)c1cc2cccc(O)c2oc1=O

Procedure:
A solution of 8-hydroxycoumarin-3-carboxylic acid (2.06 g) in 10 ml thionyl chloride was heated under reflux for three hours, and 8-hydroxycoumarin-3-carboxylic acid chloride was obtained by distilling off the excess thionyl chloride. This was added in small portions to a methylene chloride solution (100 ml) containing ampicillin trihydrate (4.1 g) and triethylamine (3.5 ml) over a period of forty minutes under stirring and cooling on ice.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:15]1(=[O:20])[N:14]([O:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:3])[C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(ON1C(=O)CCC1=O)c1ccc(B(O)O)cc1
Reaction time: 0.17 h

Procedure:
4-Carboxyphenyl-boronic acid (CPBA, Example 1, 0.25 g, 1.51 mmol) and N-hydroxysuccinimide (0.26 g, 2.26 mmol) were dissolved in 8.5 ml DMF using a magnetic stirrer. 20 ml of dichloromethane (CH2Cl2) was then added, and the solution was stirred for 10 minutes. N,N'-dicyclohexyl-carbodiimide (DCC, 0.93 g, 4.52 mmol) in 3 ml CH2Cl was then added. The solution was left to react under a nitrogen atmosphere overnight (approx. 12 hours) at ambient temperature, and then filtered to remove the insoluble urea byproduct (DCU). The title compound was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)=[O:10])=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[ClH:27]>O1CCOCC1>[ClH:27].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]2)=[O:10])=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(NC(=O)[C@H]2CCCCN2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(R)-tert-Butyl 2-[(4-amino-3-nitrophenyl)aminocarbonyl]piperidine-1-carboxylate (4.80 g, 13.2 mmol) was suspended in dioxane (100 mL) and hydrogen chloride (75 mL of a 4M solution in dioxane) was added. The resulting dark colored solution was stirred at room temperature for 3.5 hr resulting in a yellow/brown suspension. The solid was collected by filtration and briefly dried under high vacuum. The solid was suspended in water, the pH was adjusted to pH 8 with 1M sodium carbonate solution and the resulting suspension stirred for 15 minutes. The solid was collected and dried under high vacuum to give (R)—N-(4-amino-3-nitrophenyl)piperidine-2-carboxamide hydrochloride salt as an orange solid (2.08 g). This was treated with 1M sodium carbonate solution (200 mL) and extracted with EA (3×). The combined EA extracts were washed with brine, dried over magnesium sulfate, and concentrated to give (R)—N-(4-amino-3-nitrophenyl)piperidine-2-carboxamide as an orange foam (1.77 g).