Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:15])[CH:3]=1.[Br:16][C:17]1[CH:22]=[C:21](Br)[CH:20]=[C:19]([Br:24])[N:18]=1.ClCCl.C(N(CC)CC)C>O.CN1CCCC1=O>[Br:16][C:17]1[CH:22]=[C:21]([S:1][C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:15])[CH:3]=2)[CH:20]=[C:19]([Br:24])[N:18]=1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: Brc1cc(Br)nc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)COc1ccc(Sc2cc(Br)nc(Br)c2)cc1C
Temperature: 80 °C

Procedure:
A mixture of ethyl (4-mercapto-2-methylphenoxy)acetate (1.0 g, 4.4 mmol), 2,4,6-tribromopyridine (1.26 g, 4 mmol; prepared as described in Chem. Ber. 1989, 122, 489), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium complex with dichloromethane (0.163 g, 0.20 mmol), triethylamine (1.23 mL, 8.8 mmol) and N-methylpyrrolidinone (12 mL) was heated under nitrogen at 80° C. for 3 h. The reaction mixture was then poured into water (60 mL) and extracted with ethyl acetate (3×70 mL). The combined organic layers were dried with anhydrous magnesium sulfate and evaporated in vacuo. Column chromatography of the crude product (silica gel Fluka 60, hexanes/ethyl acetate 98:2-80:20) afforded ethyl [4-(2,6-dibromopyridine-4-ylsulfanyl)-2-methylphenoxy]acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[OH:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1O
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1O)c1ccncc1
Temperature: 80 °C
Yield: 72.7 %

Procedure:
A mixture of 1.30 g of 2-amino-5-trifluoromethylphenol, 0.9 g of isonicotinic acid, 1.83 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for three hours. The mixture was cooled to room temperature, and then water was poured. Precipitated solid was filtered and washed with water, and then dried under reduced pressure to give 1.5 g of N-(2-hydroxy-4-trifluoromethylphenyl)isonicotinamide.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH2:25]Cl)=[CH:23][CH:24]=1)=[O:19]>CN(C)C=O>[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH2:25][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:14][CH:13]=2)=[CH:23][CH:24]=1)=[O:19]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Temperature: 5 °C
Reaction time: 2.5 h
Yield: 47491.2 %

Procedure:
N,N-Dimethylformamide (400 mL) was added to sodium hydride (60% dispersion; ˜16 g, 0.4 mol) which had been washed with hexanes. The mixture was cooled to ˜5° C., and then a solution of 4-phenylphenol (73.12 g, 0.43 mmol) in N,N-dimethylformamide (150 mL) was added. The mixture was allowed to stir at room temperature for 2.5 h, and then a solution of 5-chloromethylfuran-2-carboxylic acid methyl ester (25 g, 0.14 mmol) in N,N-dimethylformamide (100 mL) was added. The reaction mixture was heated at ˜105° C. for 2 h, and then it was allowed to cool, evaporated under reduced pressure, and water was added. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated brine, dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 75L purification system, eluting with 0-10% methylene chloride/toluene to give 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid methyl ester (20.5 g, 46%).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:24])[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1)=[O:4].O[Li].O>C1COCC1.O.CO>[CH2:17]([N:7]1[CH2:8][CH:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:5]([CH3:24])([C:3]([OH:4])=[O:2])[CH2:6]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C(=O)O)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Yield: 97.5 %

Procedure:
A mixture of 7.7 g (22.4 mmol) rac-(3R,4R)-1-Benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidine-3-carboxylic acid methyl ester and 1.41 g (22.4 mmol) LiOH.H2O in 80 mL THF, 80 mL water and 8 mL methanol was heated to reflux over night. The organic solvents were removed under vacuum and the pH was adjusted to 4-5 by addition of HCl aq. (1N). The mixture was extracted with ethyl acetate/THF (2:1) and the combined organic layers were washed with brine, dried with Na2SO4, filtered off and evaporated to dryness. The residue was dried to yield 7.2 g (97%) of the title compound as light brown foam. MS m/e: 328.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.O>CN(C)C=O>[O:9]1[CH:10]=[CH:11][C:7]([C:4]2[N:3]=[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]3)[S:6][N:5]=2)=[CH:8]1
Reactant: Clc1nc(-c2ccoc2)ns1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccoc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of 5-chloro-3-(3-furyl)-1,2,4-thiadiazole (2.98 g, 16.0 mmol) and 1-(tert-butoxycarbonyl)-piperazine (2.97 g, 16.0 mmol) in dimethylformamide (30 ml) was added triethylamine (8.9 ml, 63.9 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 3.30 g (61.4%) of tert-butyl 4-[3-(3-furyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxylate as a solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:35](=[O:37])[C@@H:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nc2ccccc2o1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2o1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
A solution of triphenylphosphine (274 mg, 1.04 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (211 mg, 1.18 mmol). The resulting brownish-purple mixture was stirred at 0° C. for 5 min until the reaction mixture became homogeneous. The reaction mixture was then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 3, 200 mg, 0.70 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzoxazole (140 mg, 1.04 mmol) and pyridine (0.17 mL, 2.09 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 80/20 hexanes/ethyl acetate) afforded N-benzooxazol-2-yl-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (234 mg, 83%) as a light yellow foam: [α]23589=−33.1° (c=0.169, chloroform); EI-HRMS m/e calcd for C21H20Cl2N2O2 (M+) 402.0902, found 402.0901.
Reaction SMILES: C(OC(NCCSCC(=C=O)[C@@H](C(O)=O)NOC(C)(C)C)=O)C1C=CC=CC=1.C1C2C(=CC=CC=2)C[C@@H](C(OCC)=O)N1.[CH2:44]([O:51][C:52]([NH:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][C@@H:60]([C:69]([N:71]1[C@H:80]([C:81]([O:83][CH2:84][CH3:85])=[O:82])[CH2:79][C:78]2[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=2)[CH2:72]1)=[O:70])[NH:61]C(OC(C)(C)C)=O)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.FC(F)(F)C([O-])=O>>[CH2:44]([O:51][C:52]([NH:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][C@@H:60]([C:69]([N:71]1[C@H:80]([C:81]([O:83][CH2:84][CH3:85])=[O:82])[CH2:79][C:78]2[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=2)[CH2:72]1)=[O:70])[NH2:61])=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2CN1C(=O)[C@H](CCSCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)(C)ON[C@H](C(=O)O)C(=C=O)CSCCNC(=O)OCc1ccccc1
Agent: CCOC(=O)[C@@H]1Cc2ccccc2CN1
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)[C@@H]1Cc2ccccc2CN1C(=O)[C@@H](N)CCSCCNC(=O)OCc1ccccc1

Procedure:
S-(2-Benzyloxycarbonylaminoethyl)-N-tert-butoxy-carbonyl-L-homocysteine (2.14 g., 0.00518 mole) and ethyl 1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (1.12 g., 0.00545 mole) were coupled via the procedure described in Example 5 to give 2.24 g. (72%) of ethyl N-[S-(2-benzyloxycarbonylaminoethyl)-N-tert-butoxycarbonyl-L-homocysteinyl]-1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (1); an oil. Compound 1 (1.10 g., 0.00183 mole) was stirred for 50 minutes at room temperature with 25 ml of trifluoroacetate acid. Concentration in vacuo gave ethyl N-[S-(2-benzyloxycarbonylaminoethyl)-L-homocysteinyl]1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (2) as a crude orange oil. This intermediate (2) was reductively alkylated with 2-oxo-4-phenylbutyric acid (3.00 g., 0.0068 mole) according to the procedure described in Example 5. After chromatography on an LH-20 column with methanol, 0.30 g. (25%) of ethyl N-[S-(2-benzyloxycarbonylaminoethyl)-N-(1-carboxy-3-phenylpropyl)-L-homocysteinyl]-1,2,3,4-tetrahydroisoquinoline-3-(S)-carboxylate (3) was obtained; a colorless oil.
Reaction SMILES: [CH2:1]([C@@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[C@@H:4]([CH3:7])[CH2:5]O)[CH3:2].[BrH:22].O>ClCCl>[Br:22][CH2:5][C@H:4]([CH3:7])[C@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:1][CH3:2]
Reactant: Br
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CO
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CBr
Yield: 86.4 %

Procedure:
The product of Example 32 (2.6 g, 9 mmol) was dissolved in dichloromethane, and the mixture was cooled in an ice-water bath, then 48% hydrobromic acid (0.54 mL, 10 mmol) was added dropwise, after the addition was complete, it was reacted at room temperature for 16 hours. After that, water was added therein for separating, the aqueous phase was extracted with dichloromethane three times, then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound 2.7 g, yield: 87%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][C:12]([CH3:15])([OH:14])[CH2:11][CH:10]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:14][C:12]1([CH3:15])[CH2:13][CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH:10]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1cccnc1C1CC(C)(O)CC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CC(C)(O)CC(c2ncccc2C)N1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of meso-2′β,6′β-[3,4′,3″-trimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridin-4′-ol (0.2499 g, 0.84 mmol) in DMF (9 mL) was added 2-(4-bromo-butyl)-isoindole-1,3-dione (0.2605 g, 0.92 mmol), KI (0.0142 g, 0.08 mmol), and DIPEA (0.29 mL, 1.68 mmol), and stirred at 60° C. for 24 hours. The mixture was concentrated, and saturated NaHCO3 (30 mL) was added and extracted with CH2Cl2 (3×35 mL). The combined organic extracts were washed with brine (2×20 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2—MeOH—NH4OH) provided 0.3144 g (75%) of meso-2′β,6′β-[2-[4-(4′-hydroxy-3,4′,3″-trimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′yl)-butyl]-isoindole-1,3-dione as a white solid. 1H NMR (CDCl3) δ 0.48 (s, 1H), 0.86 (s, 2H), 1.42 (s, 3H), 1.68-1.72 (m, 2H), 2.18-2.38 (m, 6H), 2.45 (s, 6H), 3.15 (t, 2H, J=6.0 Hz), 4.13 (d, 2H, J=12.0 Hz), 6.94-7.03 (m, 2H), 7.25-7.34 (m, 2H), 7.67-7.70 (m, 2H), 7.75-7.78 (m, 2H), 8.32-8.34 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]2)=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.B.C1COCC1.Cl.O>C1COCC1>[CH2:20]([N:17]1[CH2:18][CH2:19][N:14]([CH2:12][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=2)[CH2:15][CH2:16]1)[CH3:21]
Reactant: CCN1CCN(C(=O)c2cc(N)cc(C(F)(F)F)c2)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCN(Cc2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (3-amino-5-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (14.6 g, 48.5 mmol) in THF (120 ml) under N2-atmosphere, a 1 M solution of BH3.THF (145.5 ml) is added dropwise (exothermic). The mixture is stirred for 14 h at rt and then 5 h at 65° C. After cooling to rt, HCl conc./H2O 1:1 (250 ml) Is added and the mixture stirred for 15 h. The suspension is filtered, the filtrate extracted 3 times with AcOEt. The organic phases are washed twice with 1 N HCl and then discarded. The combined acidic phases are made basic by addition of saturated Na2CO3 solution and extracted 3 times with AcOEt. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; AcOEt/EtOH/NH3 95:5:1→90:10:1) followed by extraction between 3 portions of AcOEt, 3 portions of water and finally brine, drying (Na2SO4) and concentration yields the title compound as an oil: MS: [M+1]+=288; 1H-NMR (CDCl3): 6.94 (s, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 3.82 (sb, H2N), 3.46 (s, 2H), 2.51 (m, 8H), 2.44 (q, 2H), 1.10 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:47][C:48]1[CH:61]=[CH:60][C:51]2[NH:52][C:53]([C@@H:55]([NH2:59])[CH2:56][O:57][CH3:58])=[N:54][C:50]=2[CH:49]=1.ClCl>CN(C)C=O.ClCCl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:59][C@H:55]([C:53]1[NH:52][C:51]2[CH:60]=[CH:61][C:48]([Cl:47])=[CH:49][C:50]=2[N:54]=1)[CH2:56][O:57][CH3:58])=[O:7]
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 74 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, N-methylmorpholine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine in N,N-dimethylformamide. Yield: 74%; Rf value: 0.38 (silica gel; dichloromethane/methanol=95:5); C23H23ClN4O3 (438.92); mass spectrum: (M+H)+=439/441 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([C:14]([O:16]CC)=[O:15])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH3:2].O[Li].O.CO.Cl>C1COCC1.O>[CH2:1]([O:3][C:4]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1c(OCC)ccc2cccnc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOc1ccc2cccnc2c1C(=O)O
Temperature: 67 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
To the title compound of Step C (1.3 g, 5.4 mmol) in THF (22 mL) and H2O (11 mL) was added LiOH hydrate (675 mg, 16.5 mmol) and MeOH. The mixture was heated at 67° C. for 12 h. Additional LiOH hydrate (675 mg, 16.5 mmol) was added and the heating was continued at 70° C. for 1 day. Additional LiOH hydrate (1.4 g, 33 mmol) was added and the heating was continued at 75° C. for 1 day. The reaction was allowed to cool to room temperature, acidified to pH=3 with 1 N HCl(aq) and concentrated. Purification via prep HPLC gave the title compound (1 g, 84%). MS (ESI) mass calcd. for C12H11NO3, 217.1. m/z found 218.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[O:23][CH2:24][CH2:25][CH3:26])/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[N:6][C:5]=2[N:4]([CH2:27][CH2:28][CH3:29])[N:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[O:23][CH2:24][CH2:25][CH3:26])/[CH:15]=[CH:16]/[C:17]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:18])=[N:6][C:5]=2[N:4]([CH2:27][CH2:28][CH3:29])[N:3]=1
Reactant: C1COCCN1
Reactant: CCCOc1ccc(/C=C/C(=O)O)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCOc1ccc(/C=C/C(=O)N2CCOCC2)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.6 %

Procedure:
To a stirred solution of (E)-3-(3-methyl-4-oxo-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-n-propoxycinnamic acid (Example 13; 1.0 g, 0.0025 mol) and morpholine (0.21 g, 0.0025 mol) in dichloromethane at 0° C. was added, sequentially, N-methylmorpholine (0.5 g, 0.005 mol), 1-hydroxybenzotriazole hydrate (0.383 g, 0.0025 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.957 g, 0.005 mol). The reaction mixture was allowed to warm to room temperature, stirred for 20 hours and evaporated under vacuum, then the residue partitioned between water (30 ml) and dichloromethane (30 ml). The organic phase was removed and the aqueous phase extracted with more dichloromethane (2×30 ml); the combined organic solutions were then dried (Na2SO4 and the solvent removed under vacuum to give a white solid. Purification by column chromatography (SiO2, CH2Cl2 then 3% MeOH in CH2Cl2) and crystallisation from ethyl acetate-hexane-methanol afforded the title compound as white crystals (0.74 g, 63%), m.p. 156-157° C. Found: C, 64.60; H, 6.85; N, 15.16. C25H31N5O4 requires C, 64.50; H,, 6.71; N, 15.04%.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (550 mg, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:47]1[CH:48]=[N:49][CH:50]=[C:51]([N+:54]([O-:56])=[O:55])[C:52]=1[NH2:53]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CN(C=O)C>[NH2:53][C:52]1[C:51]([N+:54]([O-:56])=[O:55])=[CH:50][N:49]=[CH:48][C:47]=1[C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: CN(C)CCNc1cc(F)cc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCNc1cc(F)cc(-c2cncc([N+](=O)[O-])c2N)c1
Temperature: 95 °C
Yield: 54 %

Procedure:
A solution of N1-(3-bromo-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine (LXXV) (5 g, 19.15 mmol), bis(pinacolato)diboron (5.83 g, 22.98 mmol), KOAc (5.63 g, 57.45 mmol) and dry DMF (20 mL) was purged with argon. PdCl2(dppf)2 (938 mg, 1.15 mmol) was added to the reaction and purged again with argon. The solution was heated at 95° C. for 2 h. Once TLC showed the disappearance of (LXXV), the solution was cooled to room temperature. To this solution was added K3PO4 (6.09 g, 28.72 mmol), 3-bromo-5-nitropyridin-4-amine (LVIII) (4.17 g, 19.15 mmol), Pd(PPh3)4 (663 mg, 0.57 mmol) and water (4 mL). The solution was purged with argon and heated at 100° C. for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between DCM and water. The aqueous phase was filtered through Celite® and concentrated under vacuum. The residue was purified on a silica gel column (100% CHCl3→5:95 MeOH:CHCl3) to give N1-(3-(4-amino-5-nitropyridin-3-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine (LXXVII) as a yellow amorphous solid (3.30 g, 10.33 mmol, 54.0% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.18 (s, 6H), 2.44 (t, J=6.5 Hz, 2H), 3.12 (q, J=6 Hz, 2H), 6.01 (t, J=5 Hz, 1H), 6.35 (d, J=9 Hz, 1H), 6.43 (s, 1H), 6.48 (dt, J=10 Hz, J=2 Hz, 1H), 7.32 (brs, 2H), 8.10 (s, 1H), 9.01 (s, 1H); ESIMS found for C15H18FN5O2 m/z 320.3 (M+H).