Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45](O)=[O:46].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:46]
Reactant: Cc1cccc(C)c1OCC(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.019 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (s, 9 H), 1.41 (t, J=11.77 Hz, 1 H), 1.58 (m, 1 H), 2.10 (s, 6 H), 2.77 (m, 4 H), 3.57 (s, 3 H), 3.65 (m, 1 H), 3.81 (d, J=9.56 Hz, 1 H), 4.07 (m, 4 H), 5.02 (d, J=5.52 Hz, 1 H), 6.92 (m, 4 H), 7.25 (m, 8 H), 7.56 (d, J=9.56 Hz, 1 H), 7.85 (m, 3 H), 7.96 (d, J=8.46 Hz, 2 H), 8.64 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C=O.O>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CCC(N(Cc2ccc(F)cc2)C(=O)OC(C)(C)C)CC1
Reaction time: 0.67 h

Procedure:
To a solution of O-tert-butyl (1-acetylpiperidin-4-yl)carbamate (0.97 g) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride (0.18 g) at ambient temperature. After stirring for 40 minutes, 4-fluorobenzyl bromide (0.6 ml) was added to the reaction mixture. After additional stirring for 4 hours, the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and water (10 ml). An organic phase was separated and washed with water and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 100 ml, toluene:ethyl acetate=1:1 to 1:2). After crystallization from diisopropyl ether and n-hexane, O-tert-butyl N-(4-fluorobenzyl)-N-(1-acetylpiperidin-4-yl)carbamate (922 mg) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[NH:35][NH2:36]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:36][NH:35][C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:12])[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1H-indole-7-carboxylic acid (510.9 mg, 2.85 mmol, commercially available from e.g. Maybridge, Apollo or Fluorochem) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (443 mg, 2.85 mmol) in Dichloromethane (15 ml) stirred under argon at room temp was added solid 1-H-1,2,3-benzotriazol-1-ol (43.7 mg, 0.285 mmol) in dichloromethane (15 ml). The reaction mixture was stirred at RT for 1 hr. Solid t-butyl carbazate (571 mg, 4.28 mmol) was added and the reaction mixture stirred at room temp for 18 hr. The reaction mixture was partitioned between dichloromethane (˜50 ml) and saturated sodium bicarbonate solution (˜25 ml). The aqueous phase was extracted with dichloromethane (2×25 ml) and the combined organic extracts washed with saturated sodium bicarbonate solution (˜25 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product as a yellow gum. The residue was purified via Biotage (1:1 Hex/EtOAc; 25+M Biotage column) to afforded the required product as a white foam in 360.0 mg.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:9]=[C:8]2[C:24]1[N:33](S(C2C=CC(C)=CC=2)(=O)=O)[C:27]2=[N:28][CH:29]=[C:30]([F:32])[CH:31]=[C:26]2[CH:25]=1>O.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:9]=[C:8]2[C:24]1[NH:33][C:27]2=[N:28][CH:29]=[C:30]([F:32])[CH:31]=[C:26]2[CH:25]=1
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCOCC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(-c3cc4cc(F)cnc4[nH]3)cn(CCN3CCOCC3)c2cc1OC
Yield: 60.8 %

Procedure:
A solution of 2.08 g of potassium hydroxide in 7 ml of water is added to a solution of 0.83 g of 2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 100 ml of methanol brought to reflux. The mixture is agitated at reflux for 3 hours 30 minutes. After returning to around 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 50 ml of water and extracted with three times 80 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: ethyl acetate/methanol (90/10 by volume)]. 0.37 g of 2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [NH:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[CH2:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19]Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:19][CH:18]([CH2:16][CH3:17])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1cccc2ccc(O)cc12
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc2cccc(NC(C)=O)c2c1
Yield: 81.2 %

Procedure:
81 g of 1-acetamino-7-hydroxy-naphthalene and 85 g of 2-ethylhexyl bromide were reacted with each other in 250 ml of dimethylformamide in the presence of 66.5 g of anhydrous potassium carbonate over a steam bath for 5 hours to obtain 102.4 g of 1-acetamino-7-(2-ethylhexyloxy)naphthalene. This compound was dissolved in a mixed solution of 100 ml of acetic anhydride and 200 ml of glacial acetic acid. 44.2 g of concentrated nitric acid having a specific gravity of 1.42 was dropwise added thereto over about one hour at a temperature of not higher than 10° C., and the components were reacted for about 3 hours at about 10° C. Crystals which precipitated were collected by filtration to obtain 43.5 g of 1-acetamino-4-nitro-7-(2-ethylhexyloxy)naphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1/[CH:24]=[CH:25]/[CH2:26]Br.Cl>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:26]/[CH:25]=[CH:24]/[C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrC/C=C/c1ccc2ccccc2c1
Reactant: CC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)C(C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1
Yield: 78 %

Procedure:
2.56 g of p-chlorophenylacetone was dissolved in a mixed solution of 5 ml of dimethylformamide and 5 ml of benzene, and a dimethylformamide 8 ml/benzene 8 ml solution containing 0.62 g of 60% oily sodium hydride and 3.50 g of (E)-3-(2-naphthyl)-2-propenyl bromide, was added under cooling with ice with stirring, followed by stirring at room temperature for 2 hours. The reaction solution was acidified by an addition of 1N hydrochloric acid and extracted by an addition of water and ethyl ether. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 3.70 g of the above-identified compound.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C@@H:12]([N:15]=[N+]=[N-])[C@H:11]([N:18]=[N+]=[N-])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([N:9]1[CH2:14][CH2:13][C@@H:12]([NH2:15])[C@H:11]([NH2:18])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=N[C@@H]1CCN(C(=O)c2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: N[C@@H]1CCN(C(=O)c2ccccc2)C[C@H]1N
Reaction time: 24 h

Procedure:
A solution of the diazide (D26) (450 mg, 1.7 mmol) in ethanol (30 ml) was treated with Lindlar catalyst (5%Pd/CaCO3, 250 mg) and stirred under hydrogen (1 atm) for 24 hour. The mixture was filtered and solvent removed in vacuo to afford the title compound as oil, 350 mg (94%).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[F:28])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:29][CH3:30])[CH:12]=3)[N:17]=[CH:16][N:15]=2)=[C:22]([F:28])[CH:23]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Yield: 81.4 %

Procedure:
A solution of 7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (9.4 g, 19.1 mmol) in TFA (90 ml) was heated at reflux for 50 minutes. The mixture was allowed to cool and was poured on to ice. The resulting precipitate was collected by filtration and dissolved in methanol (70 ml). The solution was adjusted to pH9-10 with concentrated aqueous ammonia solution. The mixture was concentrated to half initial volume by evaporation. The resulting precipitate was collected by filtration, washed with water and then ether, and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (5.66 g, 82%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(COCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a mixture of crude 8-benzyloxymethyl-1,4-dioxa-spiro[4.5]decane (297 g) in THF (600 mL) is added 3N HCl (900 mL) at room temperature, and the mixture is stirred overnight. After addition of sat. NaHCO3 aq., the mixture is extracted with EtOAc. The water layer is extracted with EtOAc, and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude mixture is purified by silica gel column chromatography to afford 4-benzyloxymethylcyclohexanone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1cccc(F)c1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cccc(F)c1F

Procedure:
In the manner described in example 3 2-bromophenylacetic acid is condensed with 2,3-difluoroaniline to yield 2-[(2,3-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCOC(C)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][S:32]([CH3:31])(=[O:34])=[O:33])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc(O)c2)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc(OS(C)(=O)=O)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of the crude product from Step A (52.6 mmol) in 150 mL of dichloromethane at 0° C. was added triethylamine (14.66 mL, 105 mmol), followed by methanesulfonyl chloride (6.52 mL, 84.3 mmol). After 30 minutes, the reaction was poured into EtOAc and washed with water, saturated NH4Cl solution, saturated NaHCO3 solution, and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a white solid which was used without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[CH:23]=3)[CH2:18]2)=[O:16])([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[CH:32](=O)C.[O-]S([O-])(=O)=O.[Mg+2].C([BH3-])#N.[Na+]>CO>[CH2:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[CH:23]=3)[CH2:18]2)=[O:16])([CH3:14])[CH2:12][CH2:13]1)[CH3:32]
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1)C2
Reactant: CC=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CCN1CCC(C)(C(=O)N2CCc3cc(C(=O)OC)ccc3C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A solution of methyl 2-{[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-6-carboxylate.[HCl] (0.260 g, 0.737 mmol) in MeOH (8.0 mL) was treated with acetaldehyde (0.414 g, 7.37 mmol) and MgSO4 (excess). The reaction mixture was stirred at rt for 1 h, and sodium cyanoborohydride (93 mg, 1.47 mmol) was added in portions. The resulting mixture was stirred for 3 h at rt and then filtered to remove the MgSO4. The filtrate was washed with water and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography (SiO2, 0-20% MeOH in DCM) to give methyl 2-[(1-ethyl-4-methylpiperidin-4-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (55 mg, 22%). LC-MS: (FA) ES+ 345; 1H NMR (400 MHz, CDCl3) δ 7.86-7.80 (m, 2H), 7.18 (d, J=7.9 Hz, 1H), 4.78 (s, 2H), 3.89 (s, 3H), 3.88-3.83 (m, 2H), 2.91 (t, J=5.5 Hz, 2H), 2.77-2.67 (m, 2H), 2.42 (q, J=7.2 Hz, 2H), 2.36-2.20 (m, 4H), 1.75-1.65 (m, 2H), 1.30 (s, 3H), 1.09 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([C@@H]1CC[C@@H](C)C[C@H]1[O:11][C:12]([C@@H:14]1[CH2:27][C:26]2[CH:25]=[C:24]3[C:19]([O:20][C@H:21]([C:30]4[CH:35]=[CH:34][C:33]([O:36]CC5C=CC(Cl)=C(Cl)C=5)=[CH:32][CH:31]=4)[C:22](=[O:29])[N:23]3[CH3:28])=[CH:18][C:17]=2[CH2:16][N:15]1[C@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:13])(C)C.B(Cl)(Cl)Cl>C(Cl)Cl.CCCCCC>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([C@H:21]2[O:20][C:19]3[C:24](=[CH:25][C:26]4[CH2:27][C@@H:14]([C:12]([OH:13])=[O:11])[N:15]([C@H:46]([C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)[CH2:47][CH3:48])[CH2:16][C:17]=4[CH:18]=3)[N:23]([CH3:28])[C:22]2=[O:29])=[CH:31][CH:32]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: ClB(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Reaction time: 3 h
Yield: 129.1 %

Procedure:
To a solution of (3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (0.2 mmol) in DCM (3 mL) was added 1N BCl3 solution in hexane (0.5 mL) at 0° C. and the mixture was stirred for 3 h. The mixture was evaporated to dryness and the residue was quenched with water. The mixture was basified using sodium bicarbonate solution to pH 7. The residue was extracted with EtOAc and 10% THF. The organic layer was washed and dried to get (3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid as a yellow solid (122 mg). This solid was used as is for the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:33])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17]C(/C=C/C=C/C=C/C=C/C(O)=O)=O)[C@H:10]1[O:31][CH3:32])[CH3:8].C1CCC(NC2CCCCC2)CC1.[OH-].[Na+].CCOCC.CC(C)=CC[C@H]1O[C@@]1([C@@H]1[C@]2(OC2)CC[C@@H](OC(/C=C/C=C/C=C/C=C/C(O)=O)=O)[C@H]1OC)C>O>[CH3:32][O:31][C@@H:10]1[CH:11]([OH:17])[CH2:12][CH2:13][C@@:14]2([O:16][CH2:15]2)[CH:9]1[C@:6]1([CH3:8])[C@@H:5]([CH2:4][CH:3]=[C:2]([CH3:33])[CH3:1])[O:7]1
Reactant: CO[C@@H]1[C@H](OC(=O)/C=C/C=C/C=C/C=C/C(=O)O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CO[C@@H]1C(O)CC[C@]2(CO2)C1[C@@]1(C)O[C@@H]1CC=C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of fumagillin DCHA salt (10 g, 0.022 mol), 800 mL of 0.1 N NaOH solution in H2O, and 800 mL of Et2O was stirred at RT for 3 h. LC/Mass showed that the fumagillin had been consumed. The mixture was treated with 400 mL of Ether and the layers were separated. The water layer was extracted with ether (3×500 mL) and the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a Biotage (EtOAc/hexanes) to provide ANT-2970 (4.1 g, 6.16 g theoretical, 66%). 1H NMR (300 MHz, CDCl3,) δ 1.21 (s, 3H), 1.65 (s, 3H), 1.75 (s, 3H), 1.90-2.05 (m, 3H), 2.18-2.26 (m, 2H), 2.34-2.39 (m, 2H), 2.55 (d, 1H), 2.59 (t, 1H), 2.92 (m, 1H), 3.48 (s, 3H), 3.62 (dt, 1H), 4.38 (m, 1H), 5.21 (m, 1H); LC-MS 283 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31](OC2C=CC([N+]([O-])=O)=CC=2)=[O:32])=[CH:5][CH:4]=1)#[N:2].[CH3:43][S:44]([C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=1)(=[O:46])=[O:45]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:54][CH2:53][C:50]2[CH:49]=[CH:48][C:47]([S:44]([CH3:43])(=[O:46])=[O:45])=[CH:52][CH:51]=2)=[O:32])=[CH:7][CH:8]=1)#[N:2]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(CNC(=O)N2C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C2c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 200 mg, 0.347 mmol) and (4-(methylsulfonyl)phenyl)methanamine (193 mg, 1.04 mmol in acetonitrile (5 mL) is stirred at room temperature for 1 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 92 mg; ESI mass spectrum [M+H]+=623; Retention time HPLC: 0.66 min (X012_S01).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[Br:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:12][CH2:13][CH2:14][O:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: BrCCBr
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(OCCBr)c1
Temperature: 120 °C
Yield: 115.3 %

Procedure:
122.5 g (800 mmol) 5-methyl-2-nitrophenol, 751.0 g (4000 mmol) 1,2-dibromoethane, 110.7 g (800 mmol) K2CO3 were suspended in 400 ml anhydrous DMF. The suspension was heated at 120° C. for 1 hour, then cooled and most of the liquid was evaporated. The residue was dissolved in 1 l CHCl3 and 1 l water. The organic layer was washed with 2×1 l of 1.8% NaOH till the aqueous layer became pale yellow. The organic layer was dried over Na2SO4 for 18 h, filtered and the solvent was evaporated to give ˜240 g oil. The oil was triturated with 240 ml boiling methanol and allowed to settle for 2 h. The resultant precipitate was filtered, washed with 2×100 ml cold methanol and dried at RT for 18 h to afford 89.4 g (43%) off-white crystal. H1NMR (CDCl3) δ (ppm): 2.40(s, 3H), 3.65(t,2H), 4.30(t,2H), 6.85(d,2H), 7.75(d,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]2([C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][CH2:38]2)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]2([C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:8]([C:6](=[O:7])[C:5]4[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]([CH3:19])[CH2:10]3)[CH2:38]2)[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CN2CCC3(CC2)CNc2ccccc23)cc1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CC4(CCN(Cc5ccccc5)CC4)c4ccccc43)CC2C)cc1OC
Yield: 52.4 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 1′-benzylspiro[indoline-3,4′-piperidine] (849 mg, 3.05 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (376 mg, yield: 44%) as a colorless oil. (cis:trans=1:1.5)
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1
Product: Cc1ccc(Oc2ccc(NC(=O)[C@@H](N)COCc3ccccc3)cc2)cc1
Yield: 92 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(p-tolyloxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(p-tolyloxy)phenyl)propanamide (350 mg, 92%).