Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N(C[C@@H](C1C=CC=C(Cl)C=1)O)CCC1C=CC(O[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=CC=1)=O)(C)(C)C.[OH-].[Na+]>C(O)C>[C:20]([OH:22])(=[O:21])[C:19]1[CH:24]=[CH:25][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(Oc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]benzoate (183 mg) in ethanol (1.2 ml) was added 1N aqueous sodium hydroxide solution (0.6 ml), and the mixture was stirred at 40° C. for 3 hours. The solvent was removed by evaporation, and the aqueous solution was acidified with 1N aqueous hydrochloride solution and extracted with ethyl acetate (30 ml×2). The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in tetrahydrofuran (2.0 ml) was added 4N hydrochloride in 1,4-dioxane (1.0 ml), and the mixture was stirred at room temperature for 12 hours. The resulting solid was collected by filtration and dried to give 4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-phenoxy]benzoic acid hydrochloride (127 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.Cl.[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12][NH2:13].C(N(CC)CC)C.[C:22]([S-:24])#[N:23].[K+].II>CC#N>[C:2]([C:3]1[S:24][C:22](=[NH:23])[N:13]([CH2:12][CH:11]=[C:10]([CH3:14])[CH3:9])[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)=CCN
Reactant: CC(C)(C)CC=O
Reactant: N#C[S-]
Agent: Cl
Agent: II
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)=CCn1cc(C(C)(C)C)sc1=N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3,3-Dimethylbutanal (0.95 g, 9.1 mmol), 3-methylbut-2-enyl-amine hydrochloride (1.1 g, 9.1 mmol), and triethylamine (1.3 mL, 9.1 mmol) were mixed in 9 mL of dry MeCN with 2 g of 4 Å (8-12 mesh beads) molecular sieves and stirred for 20 hours at room temperature. The reaction was filtered through Celite and washed with 8 mL of MeCN. KSCN (1.2 g, 12.3 mmol) was added and the mixture warmed to 50° C. Iodine (2.3 g, 9.1 mmol) was added and the reaction stirred at 50° C. for 6 hours. 20% Na2S2O5 was added, stirred for 30 minutes and the organic layer separated, dried with Na2SO4 and the solvent removed. The resulting solid was used without further purification. LC/MS m/z 225.3 (M+H)+.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[CH:10][C:9]=1[CH2:20][OH:21].CI.O>C1COCC1>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[C:10]([CH3:1])[C:9]=1[CH2:20][OH:21]
Reactant: COc1cc(CO)c(OC)c2ccccc12
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(CO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
n-Butyllithium (7.3 mL, 18.3 mmol, 2.5 M in hexanes) was added dropwise via syringe to a solution of 23a (1.00 g, 4.58 mmol) in THF (30 mL) at −78° C. under argon. The solution was slowly warmed to room temperature and stirred for 1 h. Methyl iodide (0.34 mL, 5.50 mmol) was added dropwise and the solution was stirred for 20 min. Water (8 mL) was added and the mixture was extracted with EtOAc (4×). The combined organic layers were dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (45:55 EtOAc:hexanes) afforded 23b (0.61 g, 57%) as a yellow solid; Rf=0.59 (45:55 EtOAc:hexanes); mp=116-117° C.; lit mp=118-121° C.25; 1H NMR (CDCl3): δ 8.07 (dd, 2H), 7.51 (m, 2H), 4.94 (s, 2H), 3.98 (s, 3H), 3.88 (s, 3H), 2.52 (s, 3H), 1.73 (bs, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: Nc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[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: COc1cccc2cc(C(=O)Nc3cccc(-c4cccc5[nH]ccc45)c3)c(=O)oc12
Temperature: 25 °C
Yield: 67.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-4-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.018 g of product in 70% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.C(O[CH:23](OCC)[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29](F)=[N:30][CH:31]=1)C.[CH2:36]([NH2:38])[CH3:37].O1CCCC1>>[CH2:36]([NH:38][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([O:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][N:10]=[C:9]3[NH:8][C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[N:30][CH:31]=1)[CH3:37]
Reactant: CCOC(COc1ccc(F)nc1)OCC
Reactant: CCN
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Solvent: C1CCOC1
Product: CCNCCOc1ccc(Oc2ccc3ncnc(Nc4cnc(C)cn4)c3c2)nc1

Procedure:
Using 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol, 5-(2,2-diethoxyethoxy)-2-fluoropyridine and 2 M ethylamine/tetrahydrofuran solution, and in the same manner as in Example 31 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (52 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:20]C(Cl)=O)(Cl)Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[NH:32][NH:33][CH2:34][C:35]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(OCC)C.C(N(CC)CC)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[NH:32][N:33]([C:17]([NH:11][C:10]3[CH:12]=[CH:13][C:7]([O:6][C:5]4[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:8][CH:9]=3)=[O:20])[CH2:34][C:35]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:29][CH:30]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Clc1ccc(C2=C(c3ccccc3)CNN2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Nc1ccc(Oc2ccc(Cl)cc2)cc1)N1CC(c2ccccc2)=C(c2ccc(Cl)cc2)N1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
To a stirred solution of 0.75 g (0.0034 mole) 4-(4-chlorophenoxy)aniline in 25 mL of toluene was added dropwise a solution of 0.43 mL (0.0036 mole) trichloromethylchloroformate in 20 mL of toluene. After complete addition, the mixture was heated at 85° C. for three hours. This mixture was cooled to room temperature and the solvent evaporated under reduced pressure to leave a residue. The residue was dissolved in 25 mL of diethyl ether. This solution was added dropwise to a stirred slurry of 1.0 g (0.0034 mole) of 3-(4-chlorophenyl)-4-phenylpyrazoline in diethyl ether. Three drops of triethylamine were added and the mixture was stirred at room temperature for two days. The solvent was evaporated from the mixture to yield 0.92 g of 3-(4-chlorophenyl)-N-[4-(4-chlorophenoxy)phenyl]-4-phenylpyrazoline-1-carboxamide (mp 158°-161° C.).
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][C:26]3[C:27](=[C:29](C#N)[C:30]([CH3:40])=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:32]=3F)[N:28]=2)=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].[CH2:43]([N:45](CC)CC)C>[Cl-].[Na+].O>[C:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2([C:43]#[N:45])[NH:28][C:27]3[CH:29]=[C:30]([CH3:40])[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:32]([N:9]4[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]4)[C:26]=3[O:25]2)=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCN(C(=O)c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Reactant: CCN(CC)CC
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N1CCN(C(=O)C2(C#N)Nc3cc(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3O2)CC1
Reaction time: 5 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (99 μl, 782 μmol) was added at 150° C. to a dimethyl sulfoxide (11 ml) solution of 2-[(4-acetylpiperazin-1-yl)carbonyl]-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-119) (265 mg, 652 μmol) and triethylamine (118 μl, 848 μmol), followed by stirring at the same temperature for 5 hours. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave a crude product of the entitled compound as a solid, and the solid was suspended and washed in diisopropyl ether to obtain the entitled compound (72 mg, 22%) as an amorphous substance.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:12])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1>O1CCCC1>[NH:16]1[CH:17]=[CH:18][C:14]([NH:13][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:12])=[N:15]1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1cc[nH]n1

Procedure:
E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.10 g) is reacted with 0.1756 gms of 3-aminopyrazole by refluxing in tetrahydrofuran (2.7 mL) for 48 hours to yield 0.11 gms of the named compound as a solid following concentration in vacuo, dilution with isopropanol and filtration.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:21][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc(CCc2ccccc2)c1
Reactant: CCCN
Product: CCCNC(=O)c1cccc(CCc2ccccc2)c1

Procedure:
Using preparation method 1, 75C (226 mg, 1 mmol) was reacted with n-propylamine (90 μL, 65 mg, 1.1 mmol). No purification was necessary. White crystals were obtained (107 mg, 40%). NMR 1H (ppm, CDCl3): 7.96-7.89 (m, 2H), 7.56-7.12 (m, 7H), 6.03 (br. s, 1H), 3.42-3.38 (m, 2H), 3.04-2.87 (m, 4H), 1.63 (sext., J3=7.3 Hz, 2H), 0.98 (t, J3=7.4 Hz, 3H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=3)[C:34]([Cl:46])=[CH:33][C:32]=2[CH2:47][CH2:48][O:49][CH2:50][C:51]([F:54])([F:53])[F:52])[O:11][C@@H:10]1[CH2:55][O:56]CC1C=CC=CC=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[Cl:46][C:34]1[C:35]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=2)=[CH:36][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:55][OH:56])[O:11]2)=[C:32]([CH2:47][CH2:48][O:49][CH2:50][C:51]([F:54])([F:52])[F:53])[CH:33]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CCOCC(F)(F)F)cc2Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(CCOCC(F)(F)F)cc2Cl)cc1
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-5-(4-ethylbenzyl)-2-(2-(2,2,2-trifluoroethoxy)ethyl)phenyl)tetrahydro-2H-pyran (30 mg, 0.034 mmol) and 10% Pd/C (30 mg) in 6 mL of MeOH:THF (1:1) was stirred under H2 atmosphere (1 atm) for 2 h. The mixture was filtered, and the filtrate was concentrated to provide the crude product, which was purified by HPLC to yield 9 mg of title compound. 1H-NMR (CD3OD, 300 MHz) δ 7.40 (s, 1H), 7.27 (s, 1H), 7.10 (s, 4H), 4.44-4.41 (m, 1H), 4.06 (d, J=15.3 Hz, 1H), 4.00 (d, J=15.3 Hz, 1H), 3.95-3.79 (m, 5H), 3.67-3.61 (m, 1H), 3.48-3.46 (m, 2H), 3.39-3.36 (m, 2H), 3.15-3.05 (m, 1H), 2.98-2.91 (m, 1H), 2.58 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H); MS ESI (m/z) 519 (M+1)+, calc. 518.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:19][CH2:20][O:21][CH3:22])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2s1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1c(=O)sc2ccc(Br)cc21
Reaction time: 24 h

Procedure:
5-Bromobenzo[d]thiazol-2(3H)-one (1 g) and potassium carbonate (1.502 g) were stirred in DMF (7 mL) at room temperature and 1-bromo-2-methoxyethane (0.408 mL) was added. The mixture was stirred for 24 h. The mixture was poured onto water and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried over sodium sulfate and evaporated. Purification by flash silica chromatography eluting with 10% ethyl acetate in isohexane afforded the sub-titled compound as a colourless solid (0.73 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[CH2:22]([Mg]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:19])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:16][CH:17]=2)[C:9]=1[CH3:10]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(C=O)cc2)c1C
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)nn(Cc2ccc(C(O)Cc3ccccc3)cc2)c1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
[1-(4-Formyl-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 15.1.1, 500 mg, 1.8 mmol) was dissolved in 5 ml tetrahydrofuran, cooled to −78° C., and benzyl magnesium chloride (1.92 ml, 2 M solution in tetrahydrofuran) was added to the solution. After 30 min at this temperature, the mixture was warmed to room temperature within 12 h, and ice and 4 N aqueous HCl was added to the solution. After dilution with ethyl acetate, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 98:2).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][O:15][C:16](=[O:34])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1>>[CH3:14][O:15][C:16](=[O:34])[CH2:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[C:21]([F:24])=[CH:22][CH:23]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-trifluoromethyl-benzaldehyde and [4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester; the isolated product was further purified by preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][N:15](C)[C:16](C1SC=NC=1)=O>>[CH3:13][O:14][N:15]([CH3:16])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CON(C)C(=O)c1cncs1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared by substituting thiazole-5-carboxylic acid with 4-nitrobenzoic acid then following the procedure described for the preparation of N-methoxy-N-methylthiazole-5-carboxamide (Intermediate 11: step a).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:24][CH:23]([CH3:25])[CH2:22][CH:21]([CH3:26])[CH2:20]3)=[O:18])[CH:14]=[C:13]([CH2:27][S:28][CH3:29])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=O.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40]>>[CH3:43][N:42]([CH3:44])[S:39]([C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[CH2:31][NH:30][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:20][CH:21]([CH3:26])[CH2:22][CH:23]([CH3:25])[CH2:24]3)=[O:18])[CH:14]=[C:13]([CH2:27][S:28][CH3:29])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:2])(=[O:41])=[O:40]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Reactant: COC(=O)c1nc2n(CC(=O)N3CC(C)CC(C)C3)cc(CSC)n2c(=O)c1O
Product: CSCc1cn(CC(=O)N2CC(C)CC(C)C2)c2nc(C(=O)NCc3ccc(F)cc3S(=O)(=O)N(C)C)c(O)c(=O)n12
Yield: 84.7 %

Procedure:
Following the same procedure for Example 187 but using 1-[2-(3,5-dimethyl-piperidin-1-yl)-2-oxo-ethyl]-6-hydroxy-3-methylsulfanylmethyl-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester Example 191 and 2-aminomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, the title product was obtained in 84.7% yield as a yellowish amorphous solid.
Reaction SMILES: O[C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.FC(F)(F)C(O)=O.C(Cl)Cl.CO.[H][H]>[Pd]>[C:18]1([C@@H:2]2[CH2:6][NH:5][C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@@H]1CC(O)(c2ccccc2)CN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](c2ccccc2)CN1

Procedure:
1-tert-Butyl 2-methyl (2S)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxylate (0.32 g, 0.0010 mol) was treated with trifluoroacetic acid (1.00 mL, 0.0130 mol) and methylene chloride (1.00 mL, 0.0156 mol) at rt for 4 h. The solvents were evaporated and the residue was dissolved in methanol (5.0 mL, 0.12 mol). Palladium (50.0 mg, 0.000470 mol) was added under nitrogen and the resulting mixture was hydrogenized with a hydrogen-gas-filled-balloon for 3 h. The mixture was filtered and the filtrate was concentrated to give the desired product, which was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6].[NH:24]1C=CN=[CH:25]1>>[N:2]1([CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH3:16])[C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:6])[CH:1]=[CH:25][N:24]=[CH:23]1
Reactant: CN(C)CCC(=O)c1c(-c2ccccc2)n(C)c2ccccc12
Reactant: c1c[nH]cn1
Product: Cn1c(-c2ccccc2)c(C(=O)CCn2ccnc2)c2ccccc21

Procedure:
3-(Dimethylamino)-1-(1-methyl-2-phenyl-1H-indol-3-yl)-1-propanone was converted to the methiodide (5.50 g) which was then reacted with imidazole (5.50 g) to give a solid which was crystallised from ethyl acetate to give the title compound (2.91 g), m.p. 159°-162°; λmax (EtOH) 251 nm (ε19,470), λmax 307 nm (ε13,800).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([CH:33]=[O:34])([OH:32])[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11].[BH4-].[Na+].Cl.C(OCC)(=O)C>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:32])([CH2:33][OH:34])[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:22][CH:23]=2)[CH:14]=[N:13]1)[CH3:11]
Reactant: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(C=O)c1ccc(F)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
2-[(1R,2S)-2-(2,4-Difluorophenyl)-2-formyl-2-hydroxy-1-methylethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (300 mg) was dissolved in 9 ml of methanol, to which 74 mg of sodium borohydride was added at 0° C. The mixture was stirred with ice cooling for 30 minutes. To the reaction solution was added 1 ml of 1N-hydrochloric acid and 50 ml of ethyl acetate, and then the organic layer was washed with 10 ml of water and 10 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=1:1) to give 165 mg of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoro-propoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as colorless prisms.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:17]3=[N:18][N:19]([CH2:27][C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[C:20]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[C:16]3[C:15](=[O:38])[N:14]([CH3:39])[C:13]2=[O:40])=[CH:7][CH:6]=1)(=O)C.[Li+].[OH-]>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:17]3=[N:18][N:19]([CH2:27][C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[C:20]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[C:16]3[C:15](=[O:38])[N:14]([CH3:39])[C:13]2=[O:40])=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(Cn2c(=O)n(C)c(=O)c3c(-c4ccncc4)n(Cc4cccc5ccccc45)nc32)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc2n(Cc2ccc(O)cc2)c1=O

Procedure:
This compound was synthesized by the hydrolysis of 4-{[5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-3-pyridin-4-yl-2,4,5,6-tetrahydro-7H-pyrazolo[3,4-d]pyrimidin-7-yl]methyl}phenyl acetate with 0.5N LiOH at room temperature for six hours. Mass: 489.80 (M+H).