Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)Cl.[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Nc1nccnc1C(=O)O
Reactant: Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nccnc1C(=O)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 3-aminopyrazine carboxylic acid (7.0 g, 50.32 mmol), methylene chloride (60 mL), dimethylformamide (40 mL), 4-dimethylaminopyridine (15.37 g, 126 mmol), 2-chloroaniline (5.82 mL, 55.35 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.58 g, 60.38 mmol) was stirred overnight at ambient temperature. The solvent was removed and the residue was mixed with ethyl acetate and 1 N lithium chloride. The precipitate which formed was filtered and rinsed with 1 N lithium chloride, ethyl acetate, and ether and then air dried to afford 6.22 g (50%) of 3-aminopyrazine-2-carboxylic acid 2-chlorophenylamide as fluffy yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH2:14]([NH2:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([NH:21][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=1[O:2][CH3:1])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: CCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCNC(=O)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 2,3-dimethoxybenzoic acid (4.55 g, 25.0 mmol) in methylene chloride (250 mL) were added heptylamine (2.78 g, 27.5 mmol) and DMAP (3.36 g, 27.5 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g, 27.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was washed with 5% HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL) and dried over MgSO4. Concentration in vacuo afforded 6.81 g (98%) of a colourless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][C:17]#[CH:18]>>[N:19]1([CH2:15][CH2:16][C:17]#[C:18][C:2]2[N:7]=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C#CCCN1CCCCC1
Reactant: Brc1cccc(CN2CCOCC2)n1
Product: C(#Cc1cccc(CN2CCOCC2)n1)CCN1CCCCC1
Yield: 19 %

Procedure:
The title compound (19%) was prepared in a manner similar to that described in Example 18, Step D, using 4-(6-bromo-pyridin-2-ylmethyl)-morpholine (0.278 g, 1.08 mmol) and 1-but-3-ynyl-piperidine (0.297 g, 2.16 mmol). MS (ESI): exact mass calcd. for C19H27N3O, 313.45; m/z found, 314.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.52 (t, J=7.8, 1H), 7.32 (dd, J=8.0, 1.1, 1H), 7.20 (dd, J=7.1, 1.1, 1H), 3.65 (t, J=4.6, 4H), 3.58 (s, 2H), 2.65-2.55 (m, 4H), 2.46-2.37 (m, 8H), 1.57-1.49 (m, 4H), 1.41-1.34 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]#[CH:15])[C:8](=[O:16])[CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>>[Br:29][C:7]1[C:8](=[O:16])[N:9]([CH2:13][C:14]#[CH:15])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=1[F:1]
Reactant: C#CCn1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Reactant: O=C1CCC(=O)N1Br
Product: C#CCn1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 56.9 %

Procedure:
Bromination of 4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-prop-2-ynylpyridin-2(1H)-one (500 mg, 1.67 mmol) with NBS (300 mg, 1.67 mmol) was carried out in the manner described above to give 350 mg (57%) of the desired compound. 1H-NMR (DMSOd6/300 MHz) δ 7.67 (app q, J=9.0 hz, 1H), 7.36 (app dt, J=10.5, 2.4 hz, 1H); 7.23-7.16 (m, 1H); 6.60 (s, 1H), 5.29 (s, 2H), 4.90 (d, J=2.4, Hz, 1H), 3.35 (s, 3H), 3.32 (s, 1H), 2.53 (s, 3H); ES-HRMS m/z 368.0107 (M+H calcd for C16H13BrF2NO2=368.0098).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[N+:15]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O)([O-:17])=[O:16]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][CH:28]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc([N+](=O)[O-])c3)nc2n(CC)c1=O
Yield: 44.9 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.68 g (13.9 mmol) of 3-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.01 g (yield 30%) of Compound 152 as a yellow powder.
Reaction SMILES: [OH:1][C@H:2]([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:28]([NH:35][CH2:36][C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:31]([O:30][C:28]([NH:35][CH2:36][C:37]([O:1][C@H:2]([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:38])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1C[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
To a solution of (R)-benzyl 1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (500 mg, 1.36 mmol), Boc-glycine (263 mg, 1.50 mmol), DMAP (17 mg, 0.136 mmol) in dry CH2Cl2 (5 mL) was added EDCI (417 mg, 2.18 mmol). The mixture reaction was stirred for 3 h at rt. TLC analysis showed that the starting material was consumed completely. The organic layer was then washed with water (3 mL×2), aqueous NaH2PO4 (3 mL×2, 2N) and water (3 mL×2). The organic phase was dried over anhydrous Na2SO4, filtrated and concentrated in vacuo to afford the title compound as a thick oil (750 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:20])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:20][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[N:30][C:22]=3[CH3:21])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ncccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1ncccc1C(=O)Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Yield: 40 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-cyclopropylmethoxy-9H-β-carbolin-8-ylamine and 2-methylnicotinic acid in a 40-60% yield. 1H-NMR (300 MHz, MeOH-d4): 60.29 (m, 2H), 0.55 (m, 2H), 1.29 (m, 1H), 2.78 (s, 3H), 3.95 (m, 2H), 7.46 (dd, 1H), 8.08 (m, 1H), 8.30 (m, 3H), 8.59 (m, 1H), 8.81 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 2.18 min. MS (M+H+): 405.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])[CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:23][CH:22]=1)#[N:20]>C(#N)C>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: BrCCCCCc1ccccc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCCCc2ccccc2)CCc2ccc(C#N)cc2)cc1
Yield: 99.5 %

Procedure:
464.2 mg (2.04 mmol) of (5-bromopentyl)benzene and 353.05 mg (2.55 mmol) of potassium carbonate are added to a solution of 700.8 mg (1.7 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 65 ml of acetonitrile, and the mixture is stirred under reflux for 12 hours. After cooling, the potassium carbonate is filtered off and the filtrate is evaporated. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 945 mg (1.7 mmol, 99.5% yield) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:33])([CH3:32])[CH2:12][C:13]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:14]=[N:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:33])([CH3:32])[CH2:12][C:13]([OH:31])([C:27]([F:28])([F:30])[F:29])[CH2:14][NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cccc2n1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cccc2n1
Reaction time: 24 h
Yield: 74.6 %

Procedure:
5-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-2-methylquinoline (266 mg, 0.58 mmol) and sodium bicarbonate (250 mg) in methanol (15 ml) are stirred for 15 minutes at room temperature. Sodium borohydride (152 mg, 4 mmol) is added thereto in 4 portions over 24 hours. After the reaction is completed (TLC monitoring), the batch is mixed with saturated NaHCO3 solution (10 ml) and concentrated by evaporation. The residue is taken up in ethyl acetate (30 ml) and water (20 ml), and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4) and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 200 mg of the product.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]2[C:25]3[CH2:24][CH2:23][N:22](C(=O)C(F)(F)F)[CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:16]=2[Cl:32])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([S:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]2[C:25]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:16]=2[Cl:32])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)SCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)SCc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
Dissolve 6-[(6-tert-butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.46 g, 9.24 mmol) in methanol (20 mL). Add a solution of potassium carbonate (5.1 g, 37 mmol) in water (10 mL) and stir at room temperature for 12 h. Remove methanol in vacuo, dilute the residue with water, and extract the aqueous phase with DCM. Purify the crude mixture by SCX chromatography (20 g) eluting with methanol and a solution of NH4OH (40 mL) in methanol (140 mL). Concentrate in vacuo to obtain pure 6-[(6-tert-butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.6 g, 100%). MS (APCI+) m/z: 390 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][C:12]=3[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])[C:7](=[O:31])[C:6]=2[C:5]([OH:32])=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O>C1(C)C=CC=CC=1>[OH:32][C:5]1[C:6]2[C:7](=[O:31])[C:8]3[C:13](=[C:12]([NH:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH:38]4[C:34]4[NH:33][CH:37]=[CH:36][CH:35]=4)[CH:11]=[CH:10][C:9]=3[NH:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH:38]3[C:34]3[NH:33][CH:37]=[CH:36][CH:35]=3)[C:14](=[O:16])[C:15]=2[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Solvent: Cc1ccccc1
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN3CCOC3c3ccc[nH]3)ccc(NCCN3CCOC3c3ccc[nH]3)c21

Procedure:
A suspension of 3.11 g. of 1,4-dihydroxy-5,8-bis[[2-(2-hydroxyethylamino)ethyl]amino]anthraquinone [prepared as described in Example 1(A)] in 55 ml. of toluene containing 2.0 g. of pyrrole-2-carboxaldehyde is stirred and refluxed as for Example 1(B). The hot solution is filtered. The filtrate is concentrated and allowed to stand at room temperature. The title compound separates as blue-black crystals.
Reaction SMILES: [Na].F[C:3]1[N:8]=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:15][OH:16]>>[CH3:15][O:16][C:3]1[N:8]=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: N#CC1(c2cccc(F)n2)CCC1
Agent: [Na]
Product: COc1cccc(C2(C#N)CCC2)n1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To anhydrous methanol (6 mL) at 0° C. under nitrogen was added sodium metal (ca 1 g) and the mixture stirred for 30 min. 1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile (1.6 g, 9.1 mmol) was then added, and the resulting mixture heated to 75° C. for 45 min. The solution was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the desired product (1.7 g) as an oil.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:13].[Na+].O1CCOCC1>O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][C:5]=2[CH:4]=[C:3]([CH:1]=[O:13])[N:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c(nn1)OCC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc2c(nn1)OCC2
Reaction time: 3 h
Yield: 20.7 %

Procedure:
A mixture of 3-ethenyl-5,6-dihydrofuro[2,3-c]pyridazine (110 mg, 0.74 mmol), 4% osmium tetroxide in water (0.66 ml), sodium periodate (367 mg), 1,4-dioxane (6.6 ml) and water (1.3 ml) was stirred for 3 hours. The mixture was evaporated and the residue treated with chloroform and added to the top of a column. Elution with ethyl acetate afforded the product (23 mg).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COc1ccc(N)cc1
Solvent: CC#N
Product: COc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Temperature: 140 °C
Yield: 39.3 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.300 g, 1.001 mmol), (4-methoxyphenyl)amine (0.136 g, 1.101 mmol) and TEA (0.140 ml, 1.001 mmol) in MeCN (3 ml) was heated in a microwave reactor at 120° C. for 20 mins, 130° C. for 30 mins, 140° C. for 30 mins and then using an oil bath at 120° C. for 24 h. The mixture was evaporated and the residue was purified by silica gel column chromatography using a 17% EtOAc in petroleum ether 40-60° C. as eluent, to give the title compound (0.152 g, 39%). 1H NMR (500 MHz, CDCl3): δ 7.24-7.14 (m, 1H), 7.12-7.08 (m, 1H), 7.07 (bs, 1H), 6.62 (d, 2H), 6.50 (d, 2H), 3.67 (s, 3H), 1.77 (s, 9H); 13C NMR (125 MHz CDCl3): δ 160.2, 157.2, 131.2, 129.6, 129.4, 128.9, 128.1, 125.1, 123.9, 113.8, 109.9, 61.9, 55.7, 27.9; Mass Spectrum: M+H+ 387.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]([CH3:43])[CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[CH3:43][N:33]([CH3:32])[CH2:34][CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][N:40]([CH:18]=[C:17]2[C:16]3[C:15]([CH3:30])([C:14]4[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]5([CH3:31])[CH:8]([C:13]=4[C:21](=[O:22])[C:20]=3[OH:19])[CH2:9][CH2:10][CH:11]5[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]2=[O:24])[CH2:41][CH2:42]1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CN(C)CCCN1CCNCC1
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCN(CCCN(C)C)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 1-(3-dimethylaminopropyl)piperazine (80 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 603 (M+H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@H:59]1[CH:64]2[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]2)[CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@H:59]5[CH:64]6[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]6)[CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-(−)-3-aminoquinuclidine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.42 (m, 3H) 1.57-1.92 (m, 12H) 2.71-89 (m, 4H) 2.96 (m, 1H) 3.13 (m, 1H) 3.31 (s, 3H) 3.95 (s, 3H) 3.97-4.10 (m, 2H) 4.45 (m, 1H) 7.47 (d, J=8.0 Hz, 1H) 7.50 (s, 1H) 7.93 (s, 1H) 8.19 (d, 1H) 8.21 (s, 1H) 8.26 (d, J=8.0 Hz, 1H). [M+H] calculated for C29H37F2N7O3, 570. found 570.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:16]1(C)C=CC=C[CH:17]=1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)cc1Br
Temperature: 90 °C
Yield: 100 %

Procedure:
A mixture of 2-bromo-4-chlorobenzoic acid (235 mg, 1 mmol) and thionyl chloride (238 mg, 146 ul, 2 mmol) in toluene (5 ml) was heated at 90° C. for 1 hour. The reaction mixture was cooled and the solvent evaporated. The residue was dissolved in THF (1 ml) and treated with ethanol (1 ml). The solution was evaporated to dryness leaving the title compound as a yellow oil 263 mg 100%
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=1[CH3:21])=[O:8].[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=2[CH3:21])=[O:8])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35]
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Reactant: COc1c(C)c(C)c(C(=O)CCCCCBr)c(C)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)c2c(C)c(C)c(OC)c(OC)c2C)ccc(C(=O)OC)c1O
Yield: 83 %

Procedure:
A mixture of 0.194 g (2.6 mmol) of 6-bromo-1-(3,4-dimethoxy-2,5,6-trimethylphenyl)-1-hexanone, 0.55 g (2.6 mmol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 1.10 g (7.8 mmol) of potassium carbonate in 20 mL of acetone and 2 mL of DMF was stirred at reflux for 17 hours. After workup as in Example 16, the crude product was purified by chromatography on 100 g of silica gel. Elution with 10% ethyl acetate-hexane gave 1.05 g (83% yield) of 4-[[6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid methyl ester. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 486 (C28H28O7).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCCC2)CC1
Yield: 15 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (15%).