Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[OH-].[Na+]>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[C:14]([CH3:13])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Yield: 92 %

Procedure:
A solution of commercially available 2,4,5-trifluoro-nitrobenzene (25a) (5.0 mL, 43.5 mmol), diethyl methylmalonate (6.2 mL, 36.1 mmol), and sodium hydroxide (1.57 g, 39.1 mmol) in DMF (55 mL) was allowed to react in the same manner as in (a) in Production Example 1. The crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (10:1) solution to give 11.0 g (76%) of compound (26a) of interest as clear brown oil.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+]=[N-].O.NN>[Ni].CO>[NH2:1][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N=[N+]=[N-])C[C@@H]12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N)C[C@@H]12

Procedure:
1.0 g 16β-azido-3-methoxy-estra-1,3,5(10)-triene-17β-ol are reduced with 20 ml methanol, 2 ml 80% hydrazine hydrate and one spatula tip of Raney nickel by procedures as described for the purification of 16β-Amino-3-methoxy-estra-1,3,5(10)-triene-17α-ol. Recrystallization is performed from methanol/ether. Yield: 0.7 g (76%). F=152-157° C.; [α]D+59° (pyridine). IR: 3300 (broad), 3417 (OH, NH), 3601 (OH).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:60])=[C:54]([CH:56]=[CH:57][C:58]=2[F:59])[NH2:55])[CH:38]=[CH:37][N:36]=1.[F:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[S:69](Cl)(=[O:71])=[O:70]>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:60])=[C:54]([NH:55][S:69]([C:63]3[CH:64]=[C:65]([F:68])[CH:66]=[CH:67][C:62]=3[F:61])(=[O:71])=[O:70])[CH:56]=[CH:57][C:58]=2[F:59])[CH:38]=[CH:37][N:36]=1
Reactant: Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline (900 mg, 2.196 mmol) and 2,5-difluorobenzenesulfonyl chloride (0.355 mL, 2.64 mmol) the title compound of Step H was obtained as a light yellow solid (774 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J=5.5 Hz, 1H), 7.48-7.57 (m, 4H), 7.29 (t, J=8.8 Hz, 1H), 6.57 (d, J=5.5 Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55 (m, 4H). MS (ESI): 585 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=1[CH3:24].[C:25]([NH:28][C:29]1[NH:30][C:31](=[O:46])[C:32]([CH2:42][CH2:43][CH:44]=O)=[C:33]([N:35]([C:39](=[O:41])[CH3:40])[C:36](=[O:38])[CH3:37])[N:34]=1)(=[O:27])[CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.CO>[C:25]([NH:28][C:29]1[NH:30][C:31](=[O:46])[C:32]([CH2:42][CH2:43][CH2:44][NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=2[CH3:24])=[C:33]([N:35]([C:36](=[O:38])[CH3:37])[C:39](=[O:41])[CH3:40])[N:34]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(C)c1)C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Both diethyl N-(4-amino-3-methylbenzoyl)-(L)-glutamate (2.18 g, 6.49 mmoles) and 3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde (2.00 g, 6.49 mmoles) were stirred in absolute ethanol (50 mL) under nitrogen while glacial acetic acid (3 mL) was added dropwise during 1 minute. After solution was achieved (1 hour), activated 3 Å molecular sieves (10 mL) were added and stirring was continued 5 hours. The reaction mixture was chilled (ice bath) and sodium cyanoborohydride (408 mg, 6.49 mmoles) added in one portion. After stirring cold 0.5 hour, the bath was removed and the reaction mixture allowed to warm to ambient temperature. The solids were filtered and rinsed with ethanol (100 mL) after 16 hours. The filtrate was spin evaporated to a residue that was partitioned between ethyl acetate and water (100 mL each). The organic phase was separated, washed (1×100 mL 1:1 water/brine), dried (MgSO4), filtered, and spin evaporated to a small volume (15 mL). The solution was chromatographed on silica gel (175 g) using an ethyl acetate rinse (450 mL) followed by elution of the product with 5% added methanol. Like fractions were combined by spin evaporation and dried to give a clear semi-solid; yield, 1.45 g (36%); 1H-NMR (DMSO-d 6) δ 1.15 and 1.16 (2t overlapped, 6H), 1.66 (m, 2H), 2.00 (m, 2H), 2.08 (s, 3H), 2.11 (s, 3H), 2.19 (s, 6H), 2.29 (m, 2H), 2.39 (t, 2H), 3.11 (m, 2H), 3.9-4.1 (2q overlapped, 4H), 4.33 (m, 1H), 5.46 (m, 1H), 6.47 (d, Jo=8 Hz, 1H), 7.53 (s, 1H), 7.57 (d, Jo=8 Hz, 1H), 8.20 (d, 1H), 11.8 (v br s, 1H); uv (MeOH) 301 nm max (31000), 258 min (6050); mass spec (FAB) m/e 628 (8%), 426 (100), 384 (95).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH2:22][OH:23])=[CH:16]2)=[O:11]>C(O)C.O=[Mn]=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH:22]=[O:23])=[CH:16]2)=[O:11]
Reactant: O=C(Nc1ccc2[nH]c(CO)cc2c1)c1cc2ccccc2o1
Agent: O=[Mn]=O
Solvent: CCO
Product: O=Cc1cc2cc(NC(=O)c3cc4ccccc4o3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
To a solution of 20(100 mg, 0.33 mmol) in ethanol (15 mL) was added MnO2 (0.5 g) and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was filtered through celite and the solid was washed with ethanol. Solvent was removed in vacuo and a grey solid 21 was obtained (54 mg, 54% yield). An analytical sample was recrystallized in ethyl acetate. mp: 253° C. (dec). 1H NMR (DMSO-d6, ppm): 10.60 (brs, 1 H, NH), 9.85, (s, 1 H, NH), 8.26 (s, 1 H, CHO), 7.84-7.35 (m, 9 H, Ar--H). Anal. (C18H12N2O3 0.3H2O), C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[C:11]=1I.[CH3:13]B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[C:11]=1[CH3:13]
Reactant: Fc1ccc2nc(Cl)c(I)n2c1
Reactant: CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1c(Cl)nc2ccc(F)cn12
Temperature: 100 °C

Procedure:
A mixture of the title compound from Example 3 Step A (0.500 g, 1.69 mmol), palladium acetate (0.038 g, 0.169 mmol), methyl boronic acid (0.202 g, 3.37 mmol), cesium carbonate (1.65 g, 5.06 mmol) and triphenyl phosphine (0.088 g, 0.337 mmol) in tetrahydrofuran (8.43 mL) was heated in a sealed tube at 100° C. for 18 hours. The mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-20% ethyl acetate in hexanes) provided the title compound: LCMS m/z 184.9 [M+H]+ 186.86 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J=2.4 Hz, 1H), 7.51 (dd, J=9.7, 4.9 Hz, 1H), 7.14-7.102 (m, 1H), 2.44 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:15][CH2:14][C@:13]2([OH:16])[C@:4]34[CH2:19][CH2:18][N:17]([CH2:20][CH:21]5[CH2:23][CH2:22]5)[C@@H:12]2[CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:24][CH2:25][O:26][CH3:27])=[C:6]([O:28][C@@H:3]13)[C:5]4=2.C(N(CC)CC)C.[C:36]1([S:46](Cl)(=[O:48])=[O:47])[C:37]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH:21]1([CH2:20][N:17]2[CH2:18][CH2:19][C@:4]34[C:5]5[C:6]6[O:28][C@H:3]3[C@H:2]([N:1]3[S:46](=[O:48])(=[O:47])[C:36]7[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=7[S:42]3(=[O:44])=[O:43])[CH2:15][CH2:14][C@@:13]4([OH:16])[C@H:12]2[CH2:11][C:10]=5[CH:9]=[CH:8][C:7]=6[O:24][CH2:25][O:26][CH3:27])[CH2:22][CH2:23]1
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Reactant: COCOc1ccc2c3c1O[C@H]1[C@H](N)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc2c3c1O[C@H]1[C@H](N4S(=O)(=O)c5ccccc5S4(=O)=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Yield: 108.7 %

Procedure:
In 5 mL of dichloromethane, 117 mg (0.30 mmol) of 6β-amino-17-cyclopropylmethyl-4,5α-epoxy-3-methoxymethoxy-morphinan-14-ol was dissolved, and 0.04 mL (0.29 mmol) of triethylamine and 79 mg (0.31 mmol) of benzene-1,2-disulfonyl dichloride were added, followed by heating the mixture to reflux for 1 hour. After allowing the reaction solution to cool to room temperature, aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain 192 mg of 2-(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl)-benzo[1,3,2]dithiazol-1,1,3,3-tetroxide as a crude product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)=[O:10].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.O>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:12]=1)=[O:10]
Reactant: Clc1ccc2ccccc2n1
Reactant: COC(=O)c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccn(-c2ccc3ccccc3n2)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 65.8 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.625 g (5 mmol) of 3-methoxycarbonyl-1H-pyrrole and 0.82 g (5 mmol) of 2-chloroquinoline dissolved in 10 mL of dimethyl sulphoxide. After stirring at 100° C. for 23 hours, the reaction mixture is poured into 30 mL of water and is then allowed to crystallise at 20° C. for 1 hour. After filtering off and air-drying the solid residue, 0.83 g of 3-methoxycarbonyl-1-(quinol-2-yl)-1H-pyrrole is obtained in the form of a beige-coloured solid melting at 136° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:48]3[CH2:47][CH2:46][CH:45]([N:42]4[CH2:41][CH2:40][N:39]([CH3:38])[CH2:44][CH2:43]4)[CH2:50][CH2:49]3)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(Br)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 120 °C
Yield: 44.4 %

Procedure:
A solution of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1,3-dihydro-isoindol-2-yl)-methanone (200 mg; 0.36 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (80 mg; 1.2 equiv.) in toluene (5 ml) was treated with (2-biphenyl)-di-tert-butylphosphine (6 mg; 5 mol %), tris(dibenzylidene)palladium(0) (10 mg; 2.5 mol %) and sodium tert-butoxide (50 mg; 1.4 equiv.) then heated at 120° C. for 30 minutes in a CEM explorer microwave synthesiser. The reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (Biotage SP4-25S, 25 mL/min) eluting with DMAW 240-120-90 followed by evaporation of product containing fractions gave 105 mg of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-{5-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-1,3-dihydro-isoindol-2-yl}-methanone as the acetic acid salt.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([CH:7]=[CH:8][C:9]3[O:10][C:11](=[O:18])[C:12]([CH3:17])([CH3:16])[C:13]=32)=[CH:5][C:4]=1[C:19]#[N:20].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.[Na].O>CN(C)C=O>[CH3:16][C:12]1([CH3:17])[C:11](=[O:18])[O:10][C:9]2[CH:8]=[CH:7][C:6]3[C:14]([C:13]1=2)=[CH:15][C:3]([CH2:2][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[C:4]([C:19]#[N:20])[CH:5]=3
Reactant: c1nc[nH]n1
Reactant: CC1(C)C(=O)Oc2ccc3cc(C#N)c(CBr)cc3c21
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Oc2ccc3cc(C#N)c(Cn4cncn4)cc3c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 8-bromomethyl-1,2-dihydro-1,1-dimethyl-2-oxonaphtho[2,1-b]furan-7-carbonitrile in N,N-dimethylformamide (3 ml) was treated with sodium 1,2,4-triazole (0.18 g) and the mixture was stirred at room temperature for 4 h, then treated with water (20 ml). The mixture was extracted twice with ethyl acetate and the combined extracts were dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography using methanol:ethyl acetate, 1:99 v/v, as eluant to give 1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho(2,1-b)-furan-7-carbonitrile, m.p. 198°-198° after recrystallisation from a mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[C:2]1([C:1](=[O:8])[CH2:9][C:10](=[O:12])[CH2:11][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CCCCCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCC(=O)CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1 g (6.1 mmol) of benzoylacetone in 6 mL of THF at −78° C. was added 8.2 mL (12.3 mmol) of a 1.5 M LDA solution in THF. Warmed to 0° C. over 2 h, then 2.6 mL (12.3 mmol) of 1-iodohexane was added. The mixture was stirred at rt for 3 h before quenching with saturated aqueous NH4Cl solution and dilution with Et2O. The organics were dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (15/1 hexanes/Et2O) to yield Intermediate 19: TLC Rf=0.52 (1/10 Et2O/Hexanes); 1H NMR (400 MHz, CDCl3, enol form) δ7.88 (m, 2H), 7.54-7.43 (m, 3H), 6.17 (s, 1H), 2.42 (t, 2H, J=7.6), 1.66 (m, 2H), 1.4-1.25 (m, 8H), 0.85 (m, 3H); low resolution MS(ES+) m/e 269.0 (M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:40]1[CH:45]=[CH:44][C:43]([CH:46]=[CH:47][C:48](=[NH:50])[NH2:49])=[CH:42][CH:41]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:40]1[CH:45]=[CH:44][C:43]([CH:46]=[CH:47][C:48](=[NH:49])[NH2:50])=[CH:42][CH:41]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)C=Cc1ccc(OC(=O)CCCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a solution of 4.5 g of 6-benzyloxycarbonylaminocaproic acid in 45 ml of dried pyridine, while being cooled in ice, was added 4.2 g of DCC. After 30 minutes of stirring, 4.4 g of 4-(β-amidinoethenyl)phenol methanesulfonate was added to the solution and stirred overnight at room temperature. The reaction mixture was freed from the precipitated DCU by filtration and the DCU was washed with pyridine. Ethyl ether was added to the combined filtrate to precipitate an oily substance. The oily substance was separated from the supernatant, washed a few times with ethyl ether, and dissolved in ethanol. Ethyl ether was added to the ethanol solution to precipitate a white solid substance which on recrystallization from an ethanol-ethyl ether mixture yielded 4.8 g of colorless granular crystals of 4-(β-amidinoethenyl)phenyl 6-benzyloxycarbonylaminocaproate methanesulfonate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:36])[CH2:11][C:12]1[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=[CH:15][N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(C)=O.Cl>[CH2:1]([O:8][CH2:9][C@H:10]([OH:36])[CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H](COCc1ccccc1)Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: O[C@@H](COCc1ccccc1)Cc1ncc[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of (2R)-1-(benzyloxy)-3-(1-trityl-1H-imidazol-2-yl)-2-propanol (1.40 g) in acetone (8 ml), 1 N hydrochloric acid (8 ml) was added, followed by stirring at 50° C. for 1 hour. Additionally, 1 N hydrochloric acid (8 ml) was added, followed by stirring at 50° C. for 2 hours. After concentration and addition of water, the reaction mixture was twice washed with diethyl ether. After neutralization with aqueous sodium bicarbonate, the water layer was extracted with ethyl acetate and washed with saline, after which it was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol=10:1) to yield the titled compound (424 mg) as a colorless oily substance.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44](Cl)=[O:45])=[CH:43][C:38]=2[O:37][CH2:36]1>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:44]([C:42]3[CH:41]=[CH:40][C:39]4[O:35][CH2:36][O:37][C:38]=4[CH:43]=3)=[O:45])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc4c(c3)OCO4)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 1,3-benzodioxole-5-carbonyl chloride as a pale yellow oil (94%). M+ (ESI): 588.3. HPLC, Rt: 5.69 min (Purity: 99.4%).
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:9]=1[C:10]1[C:11]([CH2:24][O:25][CH3:26])=[C:12]([C:21]([OH:23])=[O:22])[N:13]=[CH:14][C:15]=1[NH:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[C:9]([O:22][C:21]([C:12]1[N:13]=[CH:14][C:15]2[NH:16][C:17]3[C:9]([C:10]=2[C:11]=1[CH2:24][O:25][CH3:26])=[C:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:20]=[CH:19][CH:18]=3)=[O:23])([CH3:17])([CH3:10])[CH3:8]
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Solvent: O
Product: COCc1c(C(=O)OC(C)(C)C)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Yield: 74.6 %

Procedure:
300 mg of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid is heated with 2 ml of aminal ester for 3 hours to 120° C., whereby a solution is produced. After diluting with water, it is extracted with ethyl acetate. The organic phase is dreid, filtered, concentrated and chromatographed over silica gel with acetone:hexane=1:1 as eluant. 130 mg of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid t-butyl ester with a decomposition point of 150° C. is obtained.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br>>[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1COC1CCCCC1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](COC3CCCCC3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.2 %

Procedure:
(2R,4S)-Methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (190 mg, 0.56 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 4.43 mL, 25.27 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(cyclohexyloxymethyl)piperidin-4-yl)isoxazol-3(2H)-one (5 mg, 3%). 1H NMR (600 MHz, dmso) δ 1.03-1.25 (m, 6H), 1.32-1.48 (m, 2H), 1.55-1.68 (m, 2H), 1.70-1.90 (m, 4H), 2.56-2.66 (m, 1H), 2.68-2.79 (m, 2H), 2.99-3.06 (m, 1H), 3.06-3.83 (m, 3H), 5.70 (s, 1H). HRMS Calculated for [C15H24N2O3+H]+: 281.1865. Found: 281.1860
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.Cl.[CH3:19][C:20]1([CH3:45])[CH:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:23]2[C:32]([CH3:44])=[C:33]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:34]([CH3:37])=[C:35]([CH3:36])[C:22]=2[O:21]1>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:19][C:20]1([CH3:45])[CH:24]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:23]2[C:32]([CH3:44])=[C:33]([N:38]3[CH2:43][CH2:42][N:41]([C:9]4[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=4)[CH2:40][CH2:39]3)[C:34]([CH3:37])=[C:35]([CH3:36])[C:22]=2[O:21]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(C2c3c(C)c(N4CCNCC4)c(C)c(C)c3OC2(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C2c3c(C)c(N4CCN(c5ccc([N+](=O)[O-])cc5)CC4)c(C)c(C)c3OC2(C)C)cc1
Yield: 85.7 %

Procedure:
Triethylamine (0.31 mL, 2.25 mmol) and 4-fluoronitrobenzene (159 μL, 1.5 mmol) were added to a suspension of 1-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)piperazine hydrochloride obtained in Example 1 (301 mg, 0.75 mmol) in acetonitrile (6 ml) at room temperature and the mixture was refluxed for 10 hours. The resulting mixture was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography (hexane/ethyl acetate=4/1) and crystallized from hexane to obtain 312 mg (yield 86%) of the title compound. mp. 203–205° C. (hexane-ethyl acetate).