Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([C:22]([O:24]CC)=[O:23])[N:14]=[C:13]3[CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[NH:41][N:40]=[N:39][N:38]=1.[OH-].[K+].C(O)C.Cl>O>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([OH:19])=[O:18])=[C:15]([C:22]([OH:24])=[O:23])[N:14]=[C:13]3[CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[NH:41][N:40]=[N:39][N:38]=1
Reactant: CCCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(C(=O)O)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
A mixture of the product of Example 18 (117 mg), potassium hydroxide (31.6 mg), ethanol (1.14 ml) and water (253 μl) were stirred at room temperature for 18 h prior to acidification to pH 4 (2N HCl). The resultant mixture was extracted into ethyl acetate (3×10 ml) and the combined organic phases dried and concentrated in vacuo to afford the title compound (73 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13]CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][O:22]S(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[B-](CC)(CC)[CH2:29]C.Cl.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:21][O:22][CH3:29])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1COS(C)(=O)=O
Reactant: CC[B-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC1CC(O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
The 4-benzyloxy-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester (234.14 mg, 0.65 mmol) was taken up in anhydrous THF under argon and cooled to 0EC. Super-Hydride (1.0M, 0.98 mmol, 0.98 mL) was added via a syringe over 10 min. The solution was stirred for 1 h at 0EC, the TLC indicated that no starting material remained. The reaction mixture was slowly poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (4:1 hexane-ethyl acetate) Yield 168.57 mg. 1H NMR (CDCl3, 300 MHz): δ 1.22 (d, J=9.0 Hz, 3H), 1.44 (s, 9H), 1.65-1.77 (m, 1H), 2.13-2.24 (m, 1H), 3.45 (dd, J=7, 12 Hz, 1H), 3.61 (d, J=7 Hz, 1H), 3.94-4.04 (m, 1H), 4.50 (s, 2H), 7.27-7.39 (m, 5H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[Cl:7][C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:4][CH3:1])=[CH:20][CH:19]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:9]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reaction time: 0.67 h
Yield: 115.3 %

Procedure:
Cesium carbonate (0.860 mL, 10.74 mmol) was added to a mixture of 4-chloro-6-methyl-1,3,5-triazin-2-amine (1.10 g, 7.61 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.10 mL, 8.11 mmol) in DMF (8.0 mL) at rt. After 40 min, more 1-(chloromethyl)-4-methoxybenzene (1.10 mL, 8.11 mmol) was added. After another 1 h, more cesium carbonate (0.860 mL, 10.74 mmol) was added. After another 30 min, the mixture was diluted with EtOAc (30 mL) and filtered through a pad of Celite® (diatomaceous earth). The filtrate was transferred to a separatory funnel, diluted with more EtOAc, and washed with water (3×20 mL). The organic layer was dried over Na2SO4 and concentrated. The resulting slurry was filtered and washed with 1:1 hexane-EtOAc. The filtrate was purified by chromatography on silica using 5 to 100% DCM in hexane to give the product as a soft white solid (1.8 g). LCMS (ES, pos.): cacld for C20H21ClN4O2: 384.1. found: 385.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=8.12 Hz, 4H); 6.81-6.95 (m, 4H); 4.74 (s, 2H); 4.69 (s, 2H); 3.81 (s, 6H); 2.45 (s, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=2)O1.Br[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH2:26][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1cc(CBr)ccn1
Reactant: CCOC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cc2ccnc(OC)c2)c2ccccc2n1
Temperature: 85 °C

Procedure:
In a microwave vial containing ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate (K4) (0.23 g, 0.69 mmol), 4-(bromomethyl)-2-methoxypyridine (M3) (0.17 g, 0.83 mmol), and palladium tetrakis (0.52 g, 0.45 mmol) was, added 4.0 mL toluene, 2.8 mL, ethanol, and 1.0 mL 2.0 M aqueous Na2CO3. The resulting solution was heated to 85° C. for 30 minutes, filtered through Celite, and washed with excess ethyl acetate. The filtrate was washed twice with water, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford ethyl 4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxylate (M4) that gave a mass ion (ES+) of 323.3 for M+H+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[S:6][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[N:3][N:4]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(-c2nnc(N)s2)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-c2nnc(NS(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 29.1 %

Procedure:
A slurry of 0.52 g (1.7 mmol) of 4-(5-amino-1,3,4-thiadiazol-2-yl]-2,6-bis(1,1-dimethylethyl)phenol and 0.26 g (2.58 mmol) of triethylamine in 6 ml of toluene is treated with 0.30 g (2.58 mmol) of methane sulfonylchloride and warmed at 95°-105° C. for 21 hours under Nitrogen atmosphere. The reaction is cooled to room temperature and poured onto cold aqueous 1N NaOH (100 ml) and extracted with t-butylmethyl ether (3×20 ml). The aqueous layer is acidified with aqueous 1N HCl and filtered to give a yellow solid. Recrystallization from absolute ethanol gives 0.19 g (0.65 g, theor., 29%) of N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]methanesulfonamide as a solid: mp 293°-294° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10](=O)[N:11](C)[C:12]=2C(O)=O)[C:7]1=[O:23].C(Cl)(=O)C(Cl)=O.CC(N=NC(C#N)(C)C)(C#N)C.[N+]1([O-])C(S)=CC=CC=1.[Br:54]C(Cl)(Cl)Cl>ClCCl.CN(C=O)C.ClC(Cl)C>[Br:54][C:12]1[N:11]=[CH:10][C:9]([O:21][CH3:22])=[C:8]2[C:13]=1[CH2:14][CH2:15][N:6]([CH2:5][C:4]1[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=1)[C:7]2=[O:23]
Reactant: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: ClC(Cl)(Cl)Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(Cl)C(=O)Cl
Agent: [O-][n+]1ccccc1S
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cnc(Br)c2c1C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (3.5 g, 9.59 mmol; Example 12, step 12) in anhydrous dichloromethane (60 mL) and anhydrous DMF (0.45 mL) at room temperature was treated with oxalyl chloride (1.7 mL, 19.2 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum. A solution of the residue and AIBN (0.47 g, 2.88 mmol) in anhydrous dichloromethane (30 mL) was added portionwise to a solution of 2-pyridinethiol-N-oxide (2.4 g, 19.2 mmol) in a mixture of bromotrichloromethane (90 mL) and dichloroethane (30 mL) at 100° C. over a period of 20 minutes (Barton et al, Tetrahedron Lett., 5939, 1985). The mixture was heated at the same temperature for 20 minutes, cooled to room temperature, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in dichloromethane. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=[O:16].[CH3:18][N:19]1[CH2:24]CNC[CH2:20]1.CNC>>[CH3:18][N:19]1[CH2:24][CH2:1][N:2]([CH2:3][CH2:4][CH2:5][C:6]2[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[NH:8][C:7]=2[CH:15]=[O:16])[CH2:17][CH2:20]1
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Reactant: CN1CCNCC1
Agent: CNC
Product: CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1

Procedure:
3-[3-(4-Methylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde was prepared following the procedure described for 3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde as described for Example 1 above but substituting 1-methylpiperazine in step 2 above for dimethylamine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[N:3]=[N:2]1.S(Cl)([Cl:14])=O>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11])[N:3]=[N:2]1
Reactant: O=C(O)CCCc1c[nH]nn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCCc1c[nH]nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 4-(1H-1,2,3-triazol-4-yl)butanoic acid (Example 17, step 4) (0.088 g, 0.57 mmol) in DCM (5 mL) at RT under nitrogen was added thionyl chloride (0.499 mL, 6.84 mmol) and the reaction mixture stirred at RT for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the crude title product.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=2)[C:5](=[O:13])[C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:15])=[CH:3]1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.C(O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:27]#[C:26][CH2:25][OH:28])=[CH:9][CH:10]=2)[C:5](=[O:13])[C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:15])=[CH:3]1
Reactant: C#CCO
Reactant: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CCO
Product: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Amino-N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.25 g) from Preparation No. 57, copper (I) iodide (32 mg), and bis(triphenylphosphine)palladium (II) chloride (19 mg) are suspended in diethylamine (8 mL). Propargyl alcohol (39 μL) is added and the mixture is allowed to stir at room temperature for 16 h. The mixture is diluted with ethanol and then concentrated in vacuo. The crude solid is triturated with dichloromethane and recrystallized in acetic acid to affording 76 mg of the title compound as a beige solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][CH2:11][CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CS(C)=O>[C:13]1([CH:12]2[CH2:11][CH2:10][NH:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:19]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC(CCNCc1ccccc1F)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(C2CCNCc3ccccc3O2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 40.9 %

Procedure:
A mixture of N-(2-fluorophenylmethyl)-3-hydroxy-3-phenylpropylamine (4.5 g, 17 mM), 50% sodium hydride dispersion (870 mg, 17 mM) and dimethylsulphoxide (200 ml) was stirred for 24 hours at 50° C. under argon. The mixture was cooled to ambient temperature, poured onto water (700 ml) and extracted with ether (3×200 ml). The combined ether layers were extracted with 1N hydrochloric acid (3×50 ml), the acid layer basified and extracted with ether (2×200 ml). The organic phase was dried and the solvent removed under reduced pressure. Recrystallisation from cyclohexane gave the title compound (1.7 g) m.p. 73°-4° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
Under argon, 4-hydroxyphenyl 4-nitrophenyl ketone (370 mg) obtained in Example 134 and 4-dimethylaminopyridine (204 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (340 mg) was added, and the mixture was then refluxed with heat for 23 hours. The reaction mixture was treated in the same manner as described in Example 130 to obtain 238 mg of the title compound (yield: 36%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:13]3[S:14][CH2:15][CH2:16][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O1CCOCC1.O.[Cl-].[NH4+]>O.C(OCC)(=O)C.[Zn]>[N:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:10]([C:6]3[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=3)=[N:11][N:12]3[CH2:16][CH2:15][S:14][C:13]=23)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
6-(3-Nitro-phenyl)-7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazole (150 mg, 0.463 mmol) was suspended in a 5:1 dioxane/water mixture (3 mL). Zinc powder (121 mg, 1.852 mmol, 4 eq) was added, followed by ammonium chloride (247 mg, 4.63 mmol, 10 eq) and the mixture was heated to 100° C. and stirred at the same temperature for 2 hours. The reaction mixture was then allowed to cool to room temperature and diluted with water and ethyl acetate. The aqueous phase was basified by adding solid Na2HPO4 and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried and concentrated to dryness. 100 mg of 3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenylamine were obtained as off-white solid (73%).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)O>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C@H:41]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:40]([OH:50])=[O:39])=[C:25]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)ccc2O)cc1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)ccc2O[C@H](Cc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 4-(2-benzyl-benzo[b]thiophene-3-yl)-4″-methoxy-[1,1′;3′,1″]terphenyl-4′-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 82-84° C.; MS m/e 645 (M−H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[N:24]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36]CN)=[CH:32][CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.C(O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][CH2:36][C:33]4[CH:32]=[CH:31][C:30]([CH2:29][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:35][CH:34]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCCc1ccc(CN2CCCC2)cc1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ncn1CCc1ccc(CN2CCCC2)cc1
Yield: 60.9 %

Procedure:
A mixture of methyl 5-(4-chlorophenyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylate (0.2 g), 2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethanamine dihydrochloride (0.17 g), N,N-diisopropylethylamine (0.20 g) and ethanol (4 ml) was heated under reflux overnight. The reaction mixture was allowed to cool, ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (168 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([N+:25]([O-])=O)[CH:24]=[C:19]4[CH:18]=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30]>C(O)(=O)C.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([NH2:25])[CH:24]=[C:19]4[CH:18]=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COc1cc(N2CCN(C(=O)Cn3ncc4cc([N+](=O)[O-])cnc43)CC2)ccc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3ncc4cc(N)cnc43)CC2)ccc1Cl
Temperature: 25 °C

Procedure:
1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-nitro-pyrazolo[3,4-b]pyridine-1-yl]ethanone (15 mg) is combined with 200 mg of iron powder in 2 mL of acetic acid at 100° C. for 30 min. After cooling to rt, the reaction solution was diluted with EtOAc and filtered. The filtrate was evaporated in vacuo and purified by HPLC to provide 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(5-amino-pyrazolo[3,4-b]pyridine-1-yl]-ethanone: HPLC retention time=1.46 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=414.2. found=415.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[NH2:12][CH2:13][C:14]([N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][CH2:13][C:14]([N:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:15])=[O:7]
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CN(C(=O)CNC(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
4-Dimethylaminopyridine (5 mg) and then N,N'-carbonyldiimidazole (1.78 g) are added to a solution of 3,4-dichlorobenzoic acid (1.91 g) in anhydrous 1,2-dichloroethane (50 cc). The solution obtained is stirred for 2 hours at a temperature in the region of 20° C., tert-butyl 2-(2-amino-N-phenylacetamido)acetate (2.64 g) is then added and the mixture is stirred for 3 hours at a temperature in the region of 20° C. The reaction mixture is then washed with water (3×75 cc), and the organic phase is separated, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on silica gel (0.04-0.063 mm; 250 g) contained in column 4.2 cm in diameter [eluant: dichloromethane/methanol (98:2 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 20-cc fractions. Fractions 7 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue is recrystallized in a mixture of cyclohexane and 2-propanol (80:20 by volume). tert-Butyl N-[N- (3,4-dichlorobenzoyl)glycyl]-N-phenylglycinate (1.5 g), m.p. 95° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[C:26]([Cl:28])[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([OH:25])=[C:11]([CH:24]=2)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:13])=[C:4]([Cl:29])[CH:3]=1.C[CH:31]([C:35](Cl)=[O:36])[C:32](Cl)=[O:33].C1C[O:41][CH2:40]C1>>[CH3:40][O:41][C:35](=[O:36])[CH2:31][C:32]([NH:1][C:2]1[CH:3]=[C:4]([Cl:29])[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([OH:25])=[C:11]([C:12](=[O:13])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:24]=2)=[C:26]([Cl:28])[CH:27]=1)=[O:33]
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: C1CCOC1
Reactant: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1O
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(NC(=O)CC(=O)OC)cc2Cl)ccc1O

Procedure:
To a solution of 5-(4-amino-2,6-dichloro-phenoxy)-2-hydroxy-N-nonyl-benzamide (75 mg, 0.17 mmol) in dry THF (2 ml) at RT was added methyl malonyl chloride (19 μl, 0.18 mmol) with stirring. The resulting mixture was stirred at RT for 2 h then concentrated in vacuo. The residue was purified by preparative TLC (2% MeOH in CH2Cl2) to give the title compound of Step F (78 mg) as a solid. MS (APCI+) Calc.: 538.2, Found: 539.1 (M+1).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)O)[OH:4].[C:13](=[O:16])([O-])[O-].[K+].[K+].ClC[CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[OH:4][C:3]1[CH:5]=[C:6]([O:16][CH2:13][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]=[CH:9][C:2]=1[C:1]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: C[Si](C)(C)CCCCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCC[Si](C)(C)C)cc1O
Temperature: 90 °C

Procedure:
To a mixture of methyl gentisate (16.8 g, 0.1 mole) and potassium carbonate (15.2 g, 0.11 mole) in 80 ml of DMF in a nitrogen atmosphere at 80° C. is added chloropropyl trimethyl silane (16.6 g, 0.11 mole) drop by drop over a 20-minute period. The mixture is heated to 90° C. for 8 hours. It is cooled and then poured into 200 ml of water. Extraction is performed with diisopropyl ether. The organic phase is washed with water, dried with sodium sulfate, and then concentrated. After silica chromatography of the resulting yellow oil (eluent: Heptane/CH2Cl2 90:10) we obtain 3.3 g of a clean fraction of methyl 2-hydroxy-4-(3-trimethylsilanyl-propyloxy)-benzoate.