Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[CH3:10][NH:11][C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([O:27]CCC)=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3>>[CH3:10][N:11]([C:7](=[O:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([OH:27])=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=C(O)Cc1cccs1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1cccs1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from thiophen-2-yl acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 383.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([O:12]CC)=O)(=[O:5])=[O:4].[NH2:20][CH2:21][CH:22]([OH:33])[CH2:23][N:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH3:19][N:2]([CH3:1])[S:3]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([NH:20][CH2:21][CH:22]([OH:33])[CH2:23][N:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:12])(=[O:4])=[O:5]
Reactant: NCC(O)CN1Cc2ccccc2C1
Reactant: CCOC(=O)COc1ccccc1S(=O)(=O)N(C)C
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccccc1OCC(=O)NCC(O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 13 %

Procedure:
To a solution of ethyl 2-(2-(N,N-dimethylsulfamoyl)phenoxy)acetate (100 mg, 0.35 mmol) in EtOH (1 mL) was added 1-amino-3-(isoindolin-2-yl)propan-2-ol (66.8 mg, 0.35 mmol). The reaction mixture was heated under microwave conditions at 120° C. for 0.5 h. The material was concentrated and purified by preparative HPLC purification. (20 mg, yield 13%) MS (ESI+) e/z: 434.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.85 (dd, J=7.78, 1.51 Hz, 1H), 7.70-7.61 (m, 1H), 7.27-7.16 (m, 6H), 4.75 (s, 2H), 4.05-3.91 (m, 5H), 3.55 (dd, J=13.68, 4.89 Hz, 1H), 3.40-3.35 (m, 1H), 2.92-2.77 (m, 8H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][S:28]([NH:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)(=[O:30])=[O:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][S:28]([NH:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:34][CH:33]=1)(=[O:30])=[O:29]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-methylsulphonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.Cl.[NH2:13][OH:14].[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[CH2:3]1
Reactant: CC1CC(=O)c2ccccc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CC(=NO)c2ccccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methylindan-1-one (221 mg, 1.51 mmol) and hydroxylamine hydrochloride (295 mg, 4.25 mmol) in MeOH (4.00 mL) was added a solution of NaOH (200 mg, 5.00 mmol) in H2O (2.00 mL) and the mixture was stirred at 80° C. for 2 h. The cooled reaction was concentrated in vacuo to remove most of the MeOH, and the residue was partitioned between DCM and H2O. The organic layer was concentrated in vacuo to afford the title compound as a waxy solid (232 mg, 95%). LC/MS: Rt=1.51 min, ES+ 162 (AA standard).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14](=[O:26])[C:13]([C:27](O)=[O:28])=[CH:12][C:11]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:1]1([CH2:7][NH:8][C:27]([C:13]2[C:14](=[O:26])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:10]([CH3:9])=[C:11]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:12]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: Cc1c(-c2ccccc2)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)cc(C(=O)NCC2CCCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
(Cyclohexylmethyl)amine in NMP (135 μl, 0.3M, 0.04 mmol) was added to a mixture of 6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydro-pyridine-3-carboxylic acid (12 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol), HOAT (7 mg, 0.04 mmol) and DIEA (13 mg, 0.1 mmol) in NMP (160 μl). The reaction mixture was stirred for 17 h at room temperature. The solvent was removed in vacuo, and the residue was dissolved in acetonitrile/water, 50/50, to a total volume of 1.6 ml, and purified using preparative HPLC to give the title compound (7 mg, 50%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:15][CH2:16][O:17]C)=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8])[CH:2]=[CH2:3].[C:19](N1C=CN=C1)([N:21]1C=CN=C1)=O.CN.Cl>O1CCCC1>[CH2:1]([C:4]1[C:5]2[O:15][C:16](=[O:17])[N:21]([CH3:19])[C:7](=[O:8])[C:6]=2[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:2]=[CH2:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=CCc1c(OC)ccc(C(=O)O)c1OCOC
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: C=CCc1c(OC)ccc2c(=O)n(C)c(=O)oc12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.5 %

Procedure:
1.20 g of 3-allyl-4-methoxy-2-(methoxymethoxy)benzoic acid was dissolved in 15 ml of anhydrous tetrahydrofuran, and 0.84 g of 1,1′-carbonyldiimidazole was then added thereto. The obtained mixture was stirred at room temperature under nitrogen atmosphere for 25 minutes. Thereafter, 11.8 ml of methylamine (a 2.0 M tetrahydrofuran solution) was added to the reaction solution, and the obtained mixture was then stirred at room temperature for approximately 5 hours. Thereafter, the reaction mixture was cooled on ice, and 2.5 ml of concentrated hydrochloric acid was added thereto. The obtained mixture was stirred at room temperature for 15 minutes. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water 3 times and then washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution. The resultant product was then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. 20 ml of anhydrous tetrahydrofuran was added to the obtained residue, and then, 1.53 g of 1,1′-carbonyldiimidazole was added thereto. The reaction mixture was heated to reflux under nitrogen atmosphere for approximately 2 hours. The reaction solution was cooled to a room temperature, and the solvent was then removed under a reduced pressure. Ethyl acetate and water were added to the residue, so as to separate an organic layer. The obtained organic layer was washed with water twice and then with a saturated sodium chloride solution. The resultant product was then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was reprecipitated from ethyl acetate-n-hexane, so as to obtain 0.97 g of the subject compound.
Reaction SMILES: ClCI.[CH2:4]=[C:5]1[CH2:9][C@@H:8]([C:10]([O:12][CH3:13])=[O:11])[C@H:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1.[Zn](CC)[CH2:21]C>ClCCCl>[C:14]1([C@@H:7]2[CH2:6][C:5]3([CH2:21][CH2:4]3)[CH2:9][C@H:8]2[C:10]([O:12][CH3:13])=[O:11])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC[Zn]CC
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Agent: ClCI
Solvent: ClCCCl
Product: COC(=O)[C@@H]1CC2(CC2)C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chloroiodomethane (6.3 g, 35.5 mmol) was added to a 0° C. mixture containing 2.4 g (11.1 mmol) of methyl trans-4-methylene-2-phenylcyclopentanecarboxylate (J. Am. Chem. Soc. 1983, 105, 2315) in 25 mL of DCE followed by the addition of 17.8 mL (17.8 mmol) of Et2Zn (1M in hexanes). The reaction was stirred at 0° C. for 1 h before it was quenched with 1N HCl. The mixture was extracted with DCM (three times) and the combined extracts were dried over MgSO4 and concentrated. Column chromatography (9:1 Hexanes/EtOAc) afforded the desired compound as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([NH:17][C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1Nc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene-1,2-diamine (10.2 g, 55 mmol), then triethylamine (TEA) (17 ml, 122 mmol) slowly. The whole was stirred at room temperature (RT) overnight. Filtration gave a white solid 1 (6.5 g). The filtrate was worked up with water (300 ml), then extracted with DCM (300 ml) three times. The organic phase was collected and dried over MgSO4, concentrated and recrystallized in DCM/hexanes to give another portion of white solid 1 (10.6 g). Total amount of product 1 is 17.1 g, in 93% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:22](CC)CC)C.ClC(OC(CC)C)=O.N>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([NH2:22])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CCC(C)OC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
trans-1-Benzyloxycarbonyl-4-hydroxy-L-proline (3.55 g) was dissolved in dry tetrahydrofuran (60 ml), and triethylamine (2.80 ml) was added thereto, followed by addition of sec-butyl chloroformate (2.75 g) at 0° to 5° C. under nitrogen stream. The resultant mixture was stirred at the same temperature for 30 minutes and cooled to -50° C. 28 Aqueous ammonia (3.62 ml) was added thereto, and the resulting mixture was stirred at the same temperature for 30 minutes, followed by removal of the solvent. The residue was diluted with ethyl acetate and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2S,4R)-1-benzyloxycarbonyl-2-aminocarbonyl-4-hydroxypyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:6]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)=[O:28])[CH:22]=1.O>CN(C=O)C>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([C:27]([C:23]3[N:24]=[CH:25][N:26]=[C:21]([N:17]4[CH2:18][CH2:19][CH:14]([C:7]5[C:8](=[O:13])[NH:9][C:10]6[C:5]([CH:6]=5)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=6)[CH2:15][CH2:16]4)[CH:22]=3)=[O:28])=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]c(=O)c(C3CCN(c4cc(C(=O)c5cc(C)c6c(c5)oc(=O)n6C)ncn4)CC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 mg (0.087 mmol) 6-methoxy-3-piperidin-4-yl-1H-quinoline-2-one, 30 mg (0.10 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 50 μl (0.36 mmol) TEA were combined in 3 mL DMF and stirred overnight at RT. Then the reaction mixture was added to water, the precipitate formed was suction filtered and washed with MeOH. Next, the precipitate was boiled in DMF/MeOH and the precipitate was suction filtered.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[OH:22])=[O:6]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1F
Temperature: 80 °C
Yield: 48.9 %

Procedure:
A mixture of 0.49 g of 3-fluoroisonicotinic acid, 0.62 g of 2-amino-4-(trifluoromethyl)phenol, 1.00 g of WSC and 6 ml of pyridine was stirred while heating at 80° C. for two hours. The reaction mixture was cooled to room temperature, and then concentrated. Water was poured into the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a tert-butyl methyl ether-hexane mixture solvent to give 0.51 g of 3-fluoro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O>C1(C)C=CC=CC=1>[CH3:17][C:16]1[N:1]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[C:12]([CH3:14])=[CH:11][CH:15]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc2[nH]ccc2c1
Yield: 72.3 %

Procedure:
A mixture of 5-aminoindole (1.32 g, 10.0 mmol), acetonylacetone (4.0 mL, 34 mmol, 3.4 eq) and toluene (25 mL) was heated at reflux under nitrogen using a Dean-Stark trap for 24 hours. The reaction was cooled and then poured through a silica gel (approximately 200 g) filter followed by 10% ether in hexanes to afford the title compound (1.52 g, 72%) as an off-white, crystalline solid: Rf =0.75 in diethyl ether; 13C NMR (CDCl3) δ 135.0, 131.4, 129.5, 128.1, 125.6, 122.4, 120.3, 111.3, 105.0, 103.0, 13.2. Anal. calcd for C14H14N2 ; C, 79.97; H, 6.71; N, 13.32. Found: C, 79.72; H, 6.75; N, 13.13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:32])[CH:9]=2)=[N:6][CH:7]=1.[OH-].[Na+].C1COCC1.Cl>CO>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[CH2:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:10]([CH3:32])[CH:9]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(Cl)cn3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ncc(Cl)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A reaction mixture of methyl 4-((1-(4-(5-chloropyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (9.63 g), 1M aqueous sodium hydroxide solution (83 mL), THF (40 mL) and methanol (40 mL) was stirred at 70° C. for 6 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([OH:14])[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@@H]1c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O[C@H]1OCCN(Cc2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of 3.72 g (13.9 mmol) of 4-benzyl-3-(R)-phenyl-2-morpholinone, prepared from (R)-phenyl-glycine as described in Example 14, in 28 mL of CH2Cl2 was cooled in a −78° C. bath under a N2 atmosphere and 14 mL of a 1.5 M solution of DIBAL-H (21 mmol) in toluene were added. After stirring the resulting solution for 0.5 h, it was allowed to warm to −50° C. and mantained at this temperature for 0.5 h. The reaction mixture was quenched by adding 10 mL of aqueous potassium sodium tartarate. The mixture was diluted with CH2Cl2 and the layers were separated. The aqueous layer was extracted 3 times with CH2Cl2. The CH2Cl2 layers were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate furnished 3.32 g (88%) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine suitable for use in the next step.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:60])([CH3:59])CCC(C(OC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:45])[CH2:24][CH:25]2[O:44][CH:26]2[CH:27]([CH3:43])C(C(OC2C=CC([N+]([O-])=O)=CC=2)=O)CC)[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].[CH2:61]([NH:63][CH2:64][CH3:65])[CH3:62]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:6]([OH:60])([CH3:59])[CH2:16][CH2:17][CH:5]([O:4][C:1](=[O:3])[N:63]([CH2:64][CH3:65])[CH2:61][CH3:62])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:45])[CH2:24][CH:25]2[O:44][CH:26]2[CH:27]([CH3:43])[CH:14]([O:13][C:11](=[O:12])[N:63]([CH2:64][CH3:65])[CH2:61][CH3:62])[CH2:15][CH3:18])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCNCC
Reactant: CCC(C(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(C(=O)Oc2ccc([N+](=O)[O-])cc2)CCC(C)(O)C(OC(C)=O)C=CC1C
Agent: CCC(C(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(C(=O)Oc2ccc([N+](=O)[O-])cc2)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(OC(=O)N(CC)CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(OC(=O)N(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(OC(=O)N(CC)CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(OC(=O)N(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Reaction time: 21 h

Procedure:
(8E,12E,14E)-7-Acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,21-di(4-nitro-phenylcarboxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (12.6 mg) was dissolved in tetrahydrofuran (0.5 mL), and diethylamine (20 μL) was added thereto, followed by stirring for 21.0 hours. The reaction solution was diluted with ethyl acetate (20 mL), and washed with purified water (4 mL) twice and brine (4 mL). The resulting organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated. The resulting crude product was purified by thin layer chromatography (MERCK Silicagel 60 F254, 0.5 mm, developing solution; ethyl acetate) to obtain the title compound (10.7 mg, 14.5 μmol, 100.0%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:21][N:22]([CH:24](N(C)C)N(C)C)[CH3:23]>C1(C)C=CC=CC=1>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:17])[CH:16]=[CH:21][N:22]([CH3:24])[CH3:23])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2cccc(C(C)=O)c2C1
Reactant: CN(C)C(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(C(=O)C=CN(C)C)c2C1
Reaction time: 2 h
Yield: 107.9 %

Procedure:
A solution of 2-di-n-propylamino-8-acetyl-1,2,3,4-tetrahydronaphthalene (0.3 g, 1.1 mmol), prepared as in Example 5, and tris(dimethylamino)methane (0.32 g, 2.2 mmol) in toluene was heated to reflux for 5 hours and at 60° for 18 hours. An additional aliquot of tris(dimethylamino)methane (0.16 g, 1.1. mmol) was added and the reaction stirred at 60° for an additional 2 hours. The reaction was concentrated to give 2-di-n-propylamino-8-(1-oxo-3-(dimethylamino)-prop-2-enyl)-1,2,3,4-tetrahydronaphthalene (0.39 g) as a viscous, orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[Cl:31]
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: Clc1ccccc1CBr
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1C(=O)N(Cc2ccccc2Cl)c2cccc(Cl)c21
Yield: 94.5 %

Procedure:
Partially dissolve 4-chloro isatin (118 mg, 0.65 mmol) in acetonitrile (4 mL). Add 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (0.207 ml, 0.72 mmol) and after 5 min add 2-chlorobenzyl bromide (0.084 mL, 0.65 mmol). After 4 h dilute with ethyl acetate (50 mL) and wash with 1N HCl (2×20 mL), water, and brine. Dry (Na2SO4), filter and concentrate in vacuo to give 188 mg (94%) of the title compound as crude material as a red solid. MS (ES): m/z=306 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C[CH2:13][N:14](CC)[CH2:15]C.CNC.O>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:14]([CH3:15])[CH3:13])=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 3-(chloromethyl)benzoyl chloride (426 μL, 3 mmol) and Et3N (626 μL, 4.5 mmol) in THF (5 mL) was treated with dimethylamine (1.5 mL, 2-M in THF, 3 mmol), stirred at room temperature for 1 h, poured into water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo to give the title compound (580 mg, 98%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.46-7.34 (4H, m), 4.59 (2H, s), 3.11 (3H, s) and 2.98 (3H, s); Anal. Calcd for C12H12N6O2.0.2H2O: C, 49.38; H, 4.28, N, 28.79. Found: C, 49.25; H, 4.09; N, 28.47.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 97 %

Procedure:
4-(6-Chloropyrimidin-4-yloxy)phenylamine (663 mg, 3.00 mmol) and phenyl isocyanate (393 mg, 3.30 mmol) were stirred in dimethylformamide (5 ml) at room temperature for 18 hours. The reaction solution was poured into water and the precipitated crystals were filtered out, washed with water and ethanol and blow-dried to obtain the title compound (988 mg, 2.91 mmol, 97%) as colorless crystals.