Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br[CH:26]([CH2:28][CH3:29])[CH3:27]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:26]([CH2:28][CH3:29])[CH3:27])[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(C)Br
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Product: CCCCN1CCN(CCNC(=O)c2nn(C(C)CC)c3ccccc23)CC1

Procedure:
The title compound was synthesized by using N-[2-(4-n-butyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 10 and 2-bromobutane according to the same process as in Example 12.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:7](=[O:20])[CH:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[NH:9][C:10](=O)[C:4]=2[CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:43])=O>C1(C)C=CC=CC=1>[Cl:43][C:10]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:31]=[CH:30][C:5]=2[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:7](=[O:20])[CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)NC(=O)c3cc(Cl)ccc32)cc1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Temperature: 90 °C
Yield: 100.4 %

Procedure:
7-Chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (0.65 g, 1.43 mmol) was suspended in anhydrous toluene (10 mL) under a nitrogen atmosphere. N,N-Dimethylaniline (0.36 mL, 2.9 mmol) was added followed by phosphorus oxychloride (0.20 mL, 2.1 mmol) and the mixture was heated at 90° C. for 4 hours. After cooling to ambient temperature, the mixture was diluted with 40 mL of ethyl acetate:hexanes (1:2), washed with ice water (10 mL), ice cold 1 M hydrogen chloride (2×10 mL), and brine, then dried with sodium sulfate, decanted and concentrated in vacuo. The residue was redissolved in a small amount of ethyl acetate, then poured onto a silica plug. The product was eluted with 100 mL of ethyl acetate:hexanes (1:2) to yield (E)-5,7-dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (680 mg, 100%) which was used without further purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:50][N:51]1[C:60]2[C:55](=[CH:56][N:57]=[C:58]([CH3:61])[CH:59]=2)[CH:54]=[C:53]([C:62]2[CH:63]=[C:64]([NH:69]/[C:70](/[NH2:73])=[N:71]/O)[CH:65]=[CH:66][C:67]=2[CH3:68])[C:52]1=[O:74]>CN(C=O)C>[CH3:50][N:51]1[C:60]2[C:55](=[CH:56][N:57]=[C:58]([CH3:61])[CH:59]=2)[CH:54]=[C:53]([C:62]2[CH:63]=[C:64]([NH:69][C:70]3[N:71]=[C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:9][N:73]=3)[CH:65]=[CH:66][C:67]=2[CH3:68])[C:52]1=[O:74]
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4ccccc4)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of benzoic acid (0.67 g, 5.5 mmol), HATU (2.09 g, 11 mmol) and DIPEA (1.05 mL, 6 mmol) in dry DMF (10 mL) at rt in the presence of anhydrous Na2SO4 (7 g, 50 mmol) was added 17 (1.69 g, 5 mmol) slowly. The consumption of 17 was determined to be completed by LC/MS. Additional anhydrous DMF (40 mL) was added and the mixture was heated at 100° C. for 1 h. Solid was filtered off and most of DMF was removed under vacuum. The residue was partitioned between a mixture of water (150 mL), aqueous Na2CO3 (2 M, 10 mL), EtOAc (200 mL) and MeOH (20 mL). The organic phase was washed further with water (2×50 mL). After drying and removal of EtOAc, the solid residue was suspended and stirred in ACN (40 mL) for 16 h. Filtration and washing with copies amounts of ACN yielded A7 as a solid. 1H NMR (400 MHz, d4-MeOH) δ 9.03 (s, 1H), 8.12 (s, 1H), 8.1 (d, J=1.5 Hz, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7.65 (d, J=6.2 Hz, 1H), 7.59 (d, J=6.3 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.5 (d, J=2.4 Hz, 1H), 7.43 (dd, J=8.3, 2.5 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 2.83 (s, 3H), 2.18 (s, 3H). MS m/z 424.1 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[S:21][C:22](Br)=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(N(CC)CC)C.O>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.[Cu]I.CCOCC>[Si:1]([O:18][CH2:19][C:20]1[S:21][C:22]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1ccc(Br)s1)(c1ccccc1)c1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottom flask was flame-dried under high vacuum. The vacuum was broken by the addition of dry argon, and the flask was allowed to cool to room temperature. The flask was charged with 2.16 g (5.0 μmmol) of (5-bromothiophen-2-yl)methyl tert-butyldiphenylsilyl ether (Compound 12), 2.12 mL (15 mmol) of (trimethylsilyl)acetylene, and 17.5 mL of triethylamine. The solution was purged with argon for 15 min and bis(triphenylphosphine)palladium (II) chloride (88 mg, 0.125 mmol) and copper (I) iodide (24 mg, 0.125 mmol) were added and the solution stirred at ambient temperature for 3 days. The solution was poured into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted 3 times with ether. The combined ether layers were washed once with brine, and dried over magnesium sulfate, and the solvents were removed under reduced pressure. The residue was purified by silica gel chromatography (hexane) to give the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[N:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([O:20][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:16]=[N:17][C:18]=1[F:19]
Reactant: Oc1cnc(F)c(F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cnc(F)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 5,6-difluoropyridin-3-ol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:24])[CH2:11][CH2:12][CH2:13][C:14]1([CH3:23])[O:22][CH:15]1[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CC[O:28]CC.C(=O)(O)[O-].[Na+]>CC(C)=O.[Cl-].[Na+].O>[CH2:1]([O:8][CH2:9][CH:10]([CH3:24])[CH2:11][CH2:12][CH2:13][C:14]([CH:15]1[O:22][C:18]([CH2:19][Br:20])([OH:21])[CH2:17][CH2:16]1)([OH:28])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: CC(CCCC1(C)OC1CCC(=O)CBr)COCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: CC(CCCC(C)(O)C1CCC(O)(CBr)O1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
11-Benzyloxy-1-bromo-6,10-dimethyl-5,6-epoxy-undecan-2-one (16.2 g, 41 mM) in acetone (170.5 ml) is treated with 0.2 N hydrochloric acid (18.75 ml) at 0° C. for 0.75 hours. The reaction mixture is then stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue obtained is treated with ether, brine and saturated sodium bicarbonate. The phases are separated and the aqueous phase is extracted with ether. The combined extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give crude 7-benzyloxy-2-(2-bromomethyl-2-hydroxy-tetrahydrofuran-5-yl)-6-methyl-heptan-2-ol (17 g).
Reaction SMILES: [Na].CO[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=3)(=[O:21])=[O:20])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)=[NH:5].[H-].[Na+].O>CN(C=O)C>[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=3)(=[O:21])=[O:20])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)#[N:5]
Reactant: COC(=N)c1cc(-c2nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccnc(C#N)c2)nc1OC
Temperature: 0 °C

Procedure:
To a solution of 2.93 g of 4-[4-(5-isopropyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboximidic acid methyl ester sodium salt in DMF (60 ml) was added under ice cooling NaH (0.8 g of a 60% NaH suspension in oil). The mixture was stirred for 1,5 h at 0° C. The mixture was poured into water, the pH adjusted to pH=6 and the product extracted into EtOAc. The organic layer was washed with water, dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/EtOAc: 5/1). Combination of the purified fractions and evacuation in vacuo afforded 5-isopropyl-pyridine-2-sulfonic acid [2-(2-cyano-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a light yellow crystalline solid. ISN mass spectrum, m/e 531.1 (M−1 calculated for C26H24N6O5S: 531).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])[C:14]2=[O:30])[CH:3]=1.CC([OH:35])(C)C.C1C(=O)N(Br)C(=O)C1>C1COCC1.[Zn]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:35])[N:8]2[CH3:11])=[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])[C:14]2=[O:30])[CH:3]=1
Reactant: CC(C)(C)O
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2ccn3C)c2ccccc21
Agent: O=C1CCC(=O)N1Br
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2CC(=O)N3C)c2ccccc21
Temperature: 25 °C
Yield: 25 %

Procedure:
To a solution of 3-[3-(6-bromo-1-methyl-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (71 mg, 0.15 mmol) in THF (11 mL) was added t-BuOH (1 mL). A solution of NBS (58 mg, 0.32 mmol) in THF (0.5 mL) was added and the resulting mixture was stirred at ambient temperature for 15 m, concentrated and used directly. This crude intermediate was dissolved in acetic acid (1.5 mL). Zn powder (70 mg, 1.1 mmol) was added and the resulting mixture was agitated for 15 m. The reaction mixture was filtered and the mother liquors were concentrated and purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient to provide 12 mg (25%) of the title compound. LCMS (ESMS): m/z 486.88 (M+H).
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[C:22]2=[O:40])=[CH:17][CH:16]=1)C.CO>ClCCCl>[CH3:39][N:36]1[CH2:37][CH2:38][N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH:23]2[CH2:24][CH2:25][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:14]([N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[O:13])=[CH:16][CH:17]=3)[C:22]2=[O:40])[CH2:34][CH2:35]1
Reactant: CCOC(=O)c1ccc(N2CCC(Cc3ccccc3N3CCN(C)CC3)C2=O)cc1
Reactant: C1COCCN1
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCCl
Product: CN1CCN(c2ccccc2CC2CCN(c3ccc(C(=O)N4CCOCC4)cc3)C2=O)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Trimethyl aluminum (2 M in toluene, 700 uL, 1.4 mmol) was added dropwise to a solution of morpholine (124 uL, 1.4 mmol) in 1,2-dichloroethane (4 mL) at 0° C. Upon completion of addition, the cold bath was removed and the solution was stirred 30 minutes at 23° C. A solution of 4-{3-[2-(4-methyl-piperazin-1-yl)-benzyl]-2-oxo-pyrrolidin-1yl}-benzoic acid ethyl ester (Example 2, 150 mg, 0.36 mmol) in 1,2-dichloroethane (2 mL) was then added and the solution was heated at 70° C. for ca. 18 hours. The solution was cooled to room temperature, methanol was carefully added to quench excess methyl aluminum species, and the mixture was then treated with sodium sulfate decahydrate (1.5 g). The mixture was stirred rapidly for 3 hours, the salts were filtered off, the solvent was removed in vacuo and the residue was purified by silica gel chromatography (20:1 chloroform-methanol w/1% ammonium hydroxide) to afford 160 mg (96% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 176.28, 170.23, 152.12, 141.26, 135.00, 130.88, 130.52, 128.25, 127.71, 124.54, 120.84, 119.35, 67.14, 67.09, 55.90, 54.36, 52.97, 46.81, 46.36, 44.91, 32.48, 24.58; MS (AP/Cl) 463.2 (M+H)+. The enantiomers were separated by HPLC (60/40 heptane/ethanol; Chiralcel OJ, 10 cm×50 cm; 27.5 mL/min). Approximate retention times: t1=45 minutes; t2=60 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: C1CNC1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: O=c1[nH]c2cc(CN3CCC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and azetidine to give a yellow solid. MS m/z: 375.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[C:19]3[CH2:25][CH:24]4[N:26](C(=O)C(F)(F)F)[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH:21]12[NH:26][CH:24]([CH2:23][CH2:22]1)[CH2:25][C:19](=[C:10]1[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:3][OH:2])[C:18]=3[O:17][C:16]3[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:20]2
Reactant: COC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: OCc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylic acid methyl ester in methylene chloride (0.001 to 1 M solution) at −78° C. may be treated with diisobutyl aluminum hydride (1M in cyclohexane; 2 to 10 equiv), and the mixture may be allowed to slowly warm up to 0° C. After stirring at that temperature for a period of 1 to 5 hr, an aqueous solution of Rochelle's salt may be added. The mixture may be extracted with an appropriate organic solvent such as ethyl acetate, and the organic layer may be dried over a suitable drying agent such as potassium carbonate. After filtration and evaporation, the residue may be purified via reverse phase column chromatography to yield Compound 2e.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[C:28]([OH:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[C:28]([OH:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)c(O)c4)C3)nc3scnc23)cc1OC
Reaction time: 16 h
Yield: 14 %

Procedure:
To a stirred solution of methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-hydroxybenzoate in 5 mL of THF and 5 mL of methanol was added a solution of 1N NaOH (5 mL) at room temperature. After the addition, the reaction was stirred at this temperature for 16 hours. The solvent was evaporated and the residue was diluted with water and adjusted to pH=2 by HCl (aq.). The suspension was filtered and dried. The crude was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 45% acetonitrile/55% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-hydroxybenzoic acid (15 mg, 14% over two steps). 1H NMR (300 MHz, DMSO): δ 9.72 (s, 1H), 8.85 (s, 1H), 8.76 (d, 1H, J=6.0 Hz), 7.86 (s, 1H), 7.84 (s, 1H), 7.43-7.37 (m, 3H), 6.92 (d, 1H, J=8.4 Hz), 4.56 (brs, 1H), 3.77-3.73 (m, 11H), 2.27-2.23 (m, 1H), 2.09-2.07 (m, 1H). LC-MS: 537 [M+H]+, tR=1.37 min. HPLC: 99.62% at 214 nm, 99.22% at 254 nm, tR=3.53 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=O)[C:17]3[C:12](=[CH:13][C:14]([OH:21])=[C:15]([OH:20])[CH:16]=3)[O:11][CH:10]=2)=[CH:5][CH:4]=1>C(O)C.[Pd].S(=O)(=O)(O)O>[OH:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[OH:21])[O:11][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:18]2
Reactant: COc1ccc(-c2coc3cc(O)c(O)cc3c2=O)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1ccc(C2COc3cc(O)c(O)cc3C2)cc1

Procedure:
Fifteen grams of texasin (6,7-dihydroxy-3-(methoxyphenyl)chromone) were dissolved and partially suspended in 500 ml of ethanol and hydrogenated at normal pressure and room temperature using 10% palladium/charcoal as a catalyst under addition of 20 drops of concentrated sulfuric acid. The catalytic hydrogenation is continued until neither texasin nor any of the 6,7-dihydroxy-3-(4-methoxyphenyl)chromanon-4 was detected by thin layer chromatography. The further purification was identical to that described in Example 12. The product has the formula C16H16O4, molecular weight 272, and melting point 160° C. It was characterized by UV, NMR, IR and Mass spectroscopy and determined to be 6,7-dihydroxy-3-(4-methoxyphenyl)chroman. As in Example 12, the product is actually a mixture of optical isomers but since the isomers exhibit the same properties further characterization was not deemed necessary for the purposes of this disclosure. Therefore, it is to be understood that the scope of the disclosure and claims embraces the optical isomers of the compounds discussed herein.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[CH2:7][NH:6][CH2:5][C@H:4]1[OH:8].C(N(CC)C(C)C)(C)C.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[C:20]=[O:21]>ClCCl.C(OCC)(=O)C>[OH:8][C@@H:4]1[CH2:5][N:6]([C:20]([NH:19][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)=[O:21])[CH2:7][C:3]1([CH3:9])[CH3:2]
Reactant: CC1(C)CNC[C@H]1O
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
To 200 mg (1.3 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride and 0.25 mL (1.3 mmol) of N,N-diisopropylethylamine in 4 mL of dichloromethane was added dropwise 0.19 mL (1.3 mmol) of 1-isocyanato-4-(trifluoromethyl)benzene. The reaction mixture was stirred at room temperature for 18 h. It was then diluted with ethyl acetate, and the resulting solution was washed with 1 N hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 390 mg (quantitative yield) of (4S)-4-hydroxy-3,3-dimethyl-N-[4-(trifluoromethyl)phenyl]-1-pyrrolidinecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.73 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 5.08 (s, 1H), 3.74-3.55 (m, 2H), 3.27-3.09 (m, 3H), 0.97 (s, 3H), 0.95 (s, 3H). Cl-LCMS m/z 303 (M+H).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: O=C1NCc2ccccc21
Reactant: COc1cccc(CCl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(CN2Cc3ccccc3C2=O)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol), 1-chloromethyl-3-methoxy-benzene (0.094 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(3-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.053 g, 42%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.80 (s, 3H), 4.26 (s, 2H), 4.80 (s, 2H), 6.88 (d, 3H), 7.22-7.52 (m, 4H), 7.90 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=1)=[O:4].CN>C(O)C>[CH3:27][N:2]([CH3:1])[C:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:7]=1)=[O:4]
Reactant: CN(C)C(=O)Sc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: CN
Solvent: CCO
Product: CN(C)C(=O)Sc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
Phthalimide 530 (1.1 g, 2.8 mmol) was dissolved in a solution containing 6.6% methylamine in ethanol (100 mL) and allowed to stir at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 10:1:0.1, v/v) to afford the free amine 540 (0.31 g, 42%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.51 (m, 2H), 1.65 (m, 2H), 2.66 (m, 4H), 3.02 (m, 6H), 7.23 (d, 2H), 7.35 (d, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCCC#CCC1=CC(O)CC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCCC#CCC1=CC(O)CC1=O
Yield: 81.4 %

Procedure:
A stirred mixture of 5.8 g of 7-(4-hydroxycyclopent-2-en-1-on-2-yl)-5-heptynoic acid, 3.95 g of potassium carbonate, 7.4 g of iodomethane and 52 ml of acetone was refluxed for 2.5 hours. Most of the acetone was evaporated and the residue was partitioned with water and ether. The ether layer was separated, washed with brine, dried and concentrated, giving 5.02 g of the desired compound as an oil; PMR δ 3.72 (3H, s, methyl ester).