Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(=NO)C(C)=NO.[BH4-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH:15]=[C:16]1[S:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].C(O)(=O)C>O.[OH-].[Na+].C1COCC1.CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:15][CH:16]1[S:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCC3CCCCC3)c(Cl)c2)S1
Agent: CC(=NO)C(C)=NO
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCCC3CCCCC3)c(Cl)c2)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To the suspension containing CoCl2.6H2O (3.83 mg, 0.014 mmol) and dimethylglyoxime (63.56 mg, 0.54 mmol) in 10 ml of water, 4 drops of 1.0N NaOH and NaBH4 (355.43 mg, 9.24 mmol) were subsequently added. The mixture was cooled to 0° C., and 5-(3-chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione (1 g, 2.72 mmol) in 15 ml of THF-DMF (2:1) was added thereto over 20 minutes. The mixture was stirred at room temperature for 18 hours, to which acetic acid was then added until the pH thereof reached about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on silica gel to afford 5-(3-chloro-4-(2-cyclohexylethoxy)benzyl)thiazolidine-2,4-dione (Derivative 120 of the above formula) as white solid (0.8 g, yield: 79%).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:10]([NH:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:14]=1)=[O:11].[S:32]1[CH:36]=[C:35]([CH:37]=O)[N:34]=[CH:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>ClCCCl>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:9]([NH:8][CH2:37][C:35]2[N:34]=[CH:33][S:32][CH:36]=2)[C:10]([NH:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:14]=2)=[O:11])=[CH:30][CH:29]=1
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)Nc1cc(-c2ccncc2)no1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2ccncc2)no1)[C@H](Cc1ccc(Cl)cc1)NCc1cscn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 6.7 %

Procedure:
To a 20 ml vial were added (S)-2-amino-3-(4-chlorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5-yl)propanamide 3.1.C (50 mg, 0.15 mmole), thiazole-4-carbaldehyde (20 mg, 0.18 mmole), sodium triacetoxyborohydride (62 mg, 0.29 mmole), 5 ml of DCE, and DIEA (97 μl, 0.15 mmole). The reaction was stirred at 70° C. for 12 hours. The reaction was then partitioned between 10 ml of water and 20 ml of DCM and the solvent was removed by rotary evaporation. The crude was purified using reverse phase preparative HPLC to give 5.55 mg of (S)-3-(4-chlorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5-yl)-2-(thiazol-4-ylmethylamino)propanamide TFA salt 3.1 as a clear film (5.6 mg, 9% yield). LCMS ESI (pos.) m/e: 440.1 (M+1): 1H NMR (500 MHz, MeOH) δ ppm 9.01 (d, J=1.71 Hz, 1H), 8.76-8.78 (m, 2H), 8.19 (d, J=6.60 Hz, 2H), 7.69 (dd, J=13.82, 8.68 Hz, 1H), 7.24 (d, J=1.96 Hz, 1H), 7.13 (d, J=8.31 Hz, 2H), 6.99 (d, J=8.31 Hz, 2H), 4.35-4.45 (s, 1H), 4.26 (m, 2H), 3.34 (dd, J=8.56, 5.87 Hz, 1H), 3.17 (dd, J=13.69, 5.87 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][CH:34]=[C:33](F)[C:4]=1[O:5][C:6]1[C:14]2[N:13]=[C:12]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)[NH:11][C:10]=2[CH:9]=[C:8]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:7]=1)#[N:2].[F:38]C1C=C(F)C=CC=1C#N>>[C:1]([C:3]1[CH:36]=[CH:35][C:34]([F:38])=[CH:33][C:4]=1[O:5][C:6]1[C:14]2[N:13]=[C:12]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)[NH:11][C:10]=2[CH:9]=[C:8]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:7]=1)#[N:2]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(Oc3c(F)cccc3C#N)c3nc(-c4cnccn4)[nH]c3c2)cn1
Reactant: N#Cc1ccc(F)cc1F
Product: CCS(=O)(=O)c1ccc(Oc2cc(Oc3cc(F)ccc3C#N)c3nc(-c4cnccn4)[nH]c3c2)cn1

Procedure:
The entitled compound was obtained in the same method as in Example 438 (step 2) or in accordance with the method or by combining it with an ordinary method but using 4-hydroxy-6-(6-ethanesulfonyl-pyridin-3-yloxy)-2-pyrazin-2-yl-1H-benzimidazole obtained in Example 442 and 2,4-difluoro-benzonitrile.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([CH2:49][CH2:50][CH2:51][O:52][C:53](=[O:55])[CH3:54])[C:20]([O:22][C@H:23]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]4[CH2:48][CH2:47]4)[CH:35]=3)[CH2:24][C:25]3[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=3[Cl:33])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCOCC1>C(Cl)Cl>[C:53]([O:52][CH2:51][CH2:50][CH2:49][C@@H:19]([NH2:18])[C:20]([O:22][C@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[CH2:24][C:25]1[C:26]([Cl:33])=[CH:27][N+:28]([O-:32])=[CH:29][C:30]=1[Cl:31])=[O:21])(=[O:55])[CH3:54]
Reactant: CC(=O)OCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC(=O)OCCC[C@@H](N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of 4-((S)-2-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-acetoxypentanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)-3,5-dichloropyridine 1-oxide (284 mg, 0.355 mmol) dissolved in DCM (5.7 ml), morpholine (615 μl, 7.10 mmol) was added. The mixture was stirred at RT for 48 hours. The mixture was then diluted with DCM and washed twice with water. The organic phase was dried over Na2SO4 and the solvent was evaporated, to yield 205 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH:30]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CN1CCNC(C(=O)O)C1
Product: CCOC(=O)C1=C(CN2CCN(C)CC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 58.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.5 g, 3 mmol) was reacted with 4-methylpiperazine-2-carboxylic acid (0.43 g, 3 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (1.00 g, 59%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14]CC3C=CC(OC)=CC=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:5]=[CH:6][CH:7]=1.[N:31]1[C:40]2[C:35](=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.[Na+].O.S(C1C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=CC=1)([O-])(=O)=O.[Na+].[Na+].C(NC(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[OH:14][C:12]1[C:11](=[O:24])[CH:10]=[C:9]([CH:25]([OH:30])[C:26]([F:29])([F:27])[F:28])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:36]3[CH:37]=[CH:38][CH:39]=[C:40]4[C:35]=3[CH:34]=[CH:33][CH:32]=[N:31]4)[CH:3]=2)[CH:13]=1
Reactant: OB(O)c1cccc2ncccc12
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(O)C(F)(F)F)cc2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=c1cc(C(O)C(F)(F)F)n(-c2cccc(-c3cccc4ncccc34)c2)cc1O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To a mixture of 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (400 mg, 0.826 mmol), quinolin-5-ylboronic acid (171 mg, 0.991 mmol), tris(3-sulfonatophenyl)phosphine hydrate sodium salt (79 mg, 0.124 mmol) and palladium(II)acetate (9.27 mg, 0.041 mmol), under nitrogen, were added DMF (6 mL), diisopropylamine (0.353 mL, 2.478 mmol) and water (1 mL). The reaction mixture was stirred at 60° C. under nitrogen for 1.5 h. After cooling to room temperature the reaction mixture was partitioned between half-saturated aqueous NH4Cl and EtOAc. Layers were separated and the aqueous solution was extracted with EtOAc (3×). Combined organic solutions were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2-TFA (1:1, 6 mL), allowed to stand at room temperature for 10 min and then concentrated. Purification was done by preparative HPLC (5-95% CH3CN/H2O over 20 min, 0.05% added TFA, C18 OBD Sunfire 30×150 mm). The desired fractions were loaded onto a Strata-X—C cation exchange column. After washing the column with water and MeOH, the column was eluted with 5% NH4OH in MeOH to give 5-hydroxy-1-[3-(quinolin-5-yl)phenyl]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one as tan solid (277 mg, 81%). 1H NMR (DMSO-d6, 400 MHz) □ 8.97-8.96 (m, 1H), 8.27 (dd, J=28.8, 8.4 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.87 (t, J=7.5 Hz, 1H), 7.81-7.69 (m, 2H), 7.63-7.53 (m, 4H), 7.28 (br m, 1H), 6.54 (d, J=12.1 Hz, 1H), 4.84-4.73 (m, 1H). HRMS Calc (M+H)+ 413.1035. Found 413.1102.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14]O)[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(O)C#C.S(Cl)([Cl:24])=O>>[Cl:24][CH2:14][C:12]1[O:11][N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=2)[CH:13]=1
Reactant: OCc1cc(-c2cccc(C(F)(F)F)c2)no1
Reactant: O=S(Cl)Cl
Agent: C#CCO
Product: FC(F)(F)c1cccc(-c2cc(CCl)on2)c1

Procedure:
To 17.6 g (0.0724 ml) of 3-(m-trifluoromethylphenyl-5-isoxazole methanol (prepared as described in Example 1 except that propargyl alcohol was used instead of propargyl bromide) was added 50 ml of thionyl chloride dropwise under nitrogen. After complete addition of thionyl chloride, the reaction mixture was heated on a steam bath for 30 minutes, thereafter excess thionyl chloride was removed under reduced pressure. The residue was triturated with hexane and an oil precipitate resulted. After partial removal of hexane in a rotary evaporator under reduced pressure, the oil precipitate crystallized and was filtered to give a tan solid, mp 33°-36° C. The tan solid (6 g) was recrystallized from hexane to give 3.0 g of brown solid, mp 33°-37° C. which was Kugelrohr distilled (1 mm, 140° C.) to give 2.9 g of solid, mp, 36°-38° C. Combined filtrates were concentrated and the residue (14.8 g) was Kugelrohr distilled (1 mm, 140° C.) to give 13.6 g of yellow oil which crystallized upon standing, mp 29°-36.5° C.; total yield 16.5 g (87%).
Reaction SMILES: [ClH:1].C(OCC)C.[F:7][C:8]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:9]=1[CH2:10][O:11][C:12]1[C:13]2[N:14]([C:18]([C:22]([NH:24][CH:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1>>[ClH:1].[ClH:1].[NH2:27][CH2:26][CH:25]([NH:24][C:22]([C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:9]3[C:41]([F:45])=[CH:42][CH:43]=[CH:44][C:8]=3[F:7])[C:13]2=[N:20][C:19]=1[CH3:21])=[O:23])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CNC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
15.75 ml of a 2 M solution of hydrochloric acid in diethyl ether (31.5 mmol) were added to 370 mg of rac-tert-butyl {2-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-carbonyl)amino]-2-phenylethyl}carbamate (Example 80A, 0.69 mmol), and the mixture was stirred at RT for 3.5 h. The resulting precipitate was filtered off, washed with diethyl ether and dried under high vacuum. This gave 306 mg of the title compound (85% of theory, purity 98%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: NCCCN1CCOCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCN5CCOCC5)n4)cc3)cc12

Procedure:
Using 3-(morpholin-4-yl)-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>N1C=CC=CC=1.C(N(CC)CC)C>[S:18]1[C:19]2=[N:27][CH:26]=[CH:25][CH:24]=[C:20]2[C:21]([OH:22])=[N:15]1
Reactant: O=C(O)c1cccnc1S
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Oc1nsc2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diphenylphosphoryl azide (6.9 ml, 32 mmol) in pyridine (50 ml) and triethylamine (4.5 ml) is added, at 0° C., 2-mercaptonicotinic acid (5 g, 32 mmol) in portions. After 30 min, the ice cooling is removed and the mixture is stirred at 25° C. for a further 16 h. The solvent is distilled off under reduced pressure and the residue, a viscous oil, is admixed with methyl tert-butyl ether. While stirring, EtOAc/H2O is added and the mixture is stirred for another 15 min. The resulting pale yellow solid is filtered off with suction and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25]CC)=[O:24])=[C:16]3[N:15]=2)[C:12]([CH3:29])([CH3:28])[CH2:11][CH2:10]1.[OH-].[Na+].Cl>CO.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[C:16]3[N:15]=2)[C:12]([CH3:29])([CH3:28])[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1cnn2ccc(N3[C@@H](c4cc(F)ccc4F)CCC3(C)C)nc12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CC[C@H](c2cc(F)ccc2F)N1c1ccn2ncc(C(=O)O)c2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 97.2 %

Procedure:
(R)-ethyl 5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (136 mg, 0.340 mmol) was dissolved in MeOH (5.0 mL) and 1N NaOH (3.40 mL, 3.40 mmol) was added. The reaction was stirred at ambient temperature for 5 days and then heated at reflux for 4 hours. The reaction mixture was cooled, poured onto a mixture of brine (10 mL) and 2N HCl (5 mL) and extracted with DCM. The combined organic extracts were filtered through PS paper and concentrated to provide the title compound (123 mg, 97% yield) as a beige solid. MS (apci) m/z=373.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:18])[CH2:13][C@@H:12]1[CH3:19]>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:18])[CH2:13][C@@H:12]1[CH3:19])[NH2:8]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1C
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(N)cc2F)[C@@H](C)CN1C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a solution of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,4,5-trimethylpiperazine (0.10 g, 0.4 mmol) in 4 mL EtOH is added 0.04 g of 5% Pd/C. The atmosphere over the reaction is evacuated and replaced with H2 thrice and then fitted with a balloon filled with H2 gas. After stirring 12 h, the crude reaction mixture is filtered through Celite, rinsed with EtOH, concentrated in vacuo and chromatographed (silica gel, 10% MeOH in CH2Cl2) to give 0.027 g (0.12 mmol, 32%) of racemic-3-fluoro-4-(trans-2,4,5-trimethylpiperazin-1-yl)aniline as a yellow liquid. 1H NMR (300 MHz, CDCl3) δ 0.86 (d, J=6.0 Hz, 3H), 1.07 (d, J=6.0 Hz, 3H), 2.16 (t, J=10.8 Hz, 2H), 2.34 (s, 3H), 2.72 (t, 1H), 2.83-2.92 (m, 2H), 3.19 (br. s., 1H), 3.58 (br. s., 2H), 6.32-6.40 (m, 2H), 6.92-7.00 (m, 1H). LCMS-ESI (m/z): calcd for C13H20FN3, 237.1; [M+H]+ found, 238.2.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([O:6][CH:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[CH3:31])[C:9]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:5].[C:38](=O)([O:48]C1C=CC([N+]([O-])=O)=CC=1)[O:39][CH2:40][CH:41]1[CH:45]([CH3:46])[O:44][C:43](=[O:47])[O:42]1.O>CN(C=O)C>[CH3:1][N:2]([CH2:3][C:4]([O:6][CH:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[CH3:31])[C:9]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:5])[C:38]([O:39][CH2:40][C:41]1[O:42][C:43](=[O:47])[O:44][C:45]=1[CH3:46])=[O:48]
Reactant: CC1OC(=O)OC1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CN(C)C(=O)OCc3oc(=O)oc3C)c3cc(Cl)ccc32)c(C)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl methylaminoacetate (0.34 g, 0.65 mmol), and (5-methyl-1,3-dioxolane-2-one-4-yl)-methyl 4-nitrophenyl carbonate (0.22 g, 0.74 mmol) were dissolved in DMF (5 ml), and the mixture was stirred at room temperature over night. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium chloride solution, and then dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate) to obtain 0.44 g (43%) of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} [methyl-(5-methyl-2-oxo-1,3-dioxol-4-yl-methoxycarbonyl)-amino]acetate as amorphous.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][CH2:8][C:9]([CH2:11]Cl)=[CH2:10].[C:13]([C:16]1[CH:17]=[CH:18][C:19]([OH:24])=[C:20]([CH:23]=1)[CH:21]=[O:22])(=[O:15])[CH3:14].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O>[C:13]([C:16]1[CH:17]=[CH:18][C:19]([O:24][CH2:11][C:9]([CH2:8][Cl:7])=[CH2:10])=[C:20]([CH:23]=1)[CH:21]=[O:22])(=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc(O)c(C=O)c1
Reactant: C=C(CCl)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CCl)COc1ccc(C(C)=O)cc1C=O
Reaction time: 21 h
Yield: 52.7 %

Procedure:
6.02 g (16.31 mmol) of tetrabutylammonium iodide, 6.17 g (2.5 equivalents) of sodium carbonate and, finally, 6.7 ml (58.2 mmol) of 2-chloromethyl-3-chloro-1-propene are successively added to 3.82 g (23 mmol) of 5-acetyl-2-hydroxybenzaldehyde, prepared according to Tromelin, A. et al., Synthesis, (1985), 1074–1076, and then Laali, K. et al., Journal of Organic Chemistry, 58, (1993), 1385–1392, in solution in 250 ml of N,N-dimethylformamide. The medium is stirred for 21 hours. After addition of water and 1N hydrochloric acid, the solution is extracted with dichloromethane. The organic phase is subsequently washed, then dried and, finally, concentrated under vacuum. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 20/80) to give 3.06 g (52%) of 5-acetyl-2-{[2-(chloromethyl)-2-propenyl]oxy}benzaldehyde in the form of a yellow-white solid; 1H NMR (300 MHz, CDCl3): 10.49 (s, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.18 (dd, J=2.1 Hz and 8.7 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 5.46 and 5.41 (2s, 2H), 4.83 (s, 2H), 4.21 (s, 2H), 2.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([I:9])=[CH:4][N:3]=1.Br[CH2:11][C:12](=[CH2:22])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:14][CH2:13][C:12](=[CH2:11])[CH2:22][NH:8][C:6]1[C:5]([I:9])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: C=C(CBr)COCc1ccccc1
Product: C=C(CNc1cc(Cl)ncc1I)COCc1ccccc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
The title compound was prepared from 2-chloro-5-iodo-pyridin-4-yl-amine and (2-bromomethyl-allyloxymethyl)-benzene following a similar method to that described in Preparation 108. The reaction was stirred at 55° C. for 3 h. MS: [M+H]+=415.
Reaction SMILES: [NH:1]([C:8](=[O:28])[CH:9]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:50][C:51]1[CH:56]=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:54]=[CH:53][C:52]=1[OH:63]>CN(C=O)C>[OH:63][C:52]1[CH:53]=[CH:54][C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:56][C:51]=1[NH:50][C:23]([C:22]1[CH:21]=[CH:20][C:19]([CH:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:28])=[CH:27][CH:26]=1)=[O:25]
Reactant: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2ccccc2)ccc1O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a solution of 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoic acid (33 mg, 0.088 mmol) in DMF (1 mL) at room temperature was added EDCI (13 mg, 0.094 mmol) and HOBT (19 mg, 0.14 mmol). The solution was stirred for 30 min and 2-amino-4-phenylphenol (33 mg, 0.18 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h and purified directly by reverse phase HPLC (40% to 95% MeCN in water) to give 2-(4-{[(4-hydroxybiphenyl-3-yl)amino]carbonyl}phenyl)-N,N′-diphenylmalonamide (27 mg, 57%) as a white solid: 1H NMR (600 MHz, DMSO-d6) δ 10.27 (s br, 2H), 9.96 (s br, 1H), 9:58 (s br, 1H), 8.01-7.97 (m, 3H), 7.59-7.55 (m, 8H), 7.41 (t, J=7.9 Hz, 2H), 7.35-7.27 (m, 6H), 7.04 (t, J=7.0 Hz, 2H), 6.98 (d, J=8.2 Hz, 1H), 4.97 (s, 1H); ESIMS calcd 542.2 (M++H), found 542.1 (M++H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2)(C(C)(C)C)(C)C.N1C=CC=CC=1.F.C(=O)([O-])O.[Na+]>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2
Reactant: CC(C)C(O)(c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1)c1c[nH]cn1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 1-(6-tert-butyldimethylsilyloxynaphthalen-2-yl -1-(1H-imidazol-4-yl)-2-methylpropanol (1.60 g) in THF (10 mL) was added 70% aqueous solution of hydrogen fluoride-pyridine (3 ml) under ice cooling. The mixture was stirred for 30 min under ice cooling and for 2 h at room temperature. The mixture was neutralized with saturated solution of sodium hydrogencarbonate, extracted with dichloromethane and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent, dichloromethane:methanol=10:1→5:1) to give the titled compound (856 mg) as a colorless powder.