Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:40][CH2:41][CH:42]([N:49]([CH3:57])[C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:40][CH2:41][CH:42]([N:49]([CH3:57])[C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:10]1(=[O:18])=[O:19]
Reactant: O=S1(=O)Nc2ccccc2N1c1cccc(F)c1F
Reactant: CN(C(=O)OC(C)(C)C)C(CCO)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C(=O)OC(C)(C)C)C(CCN1c2ccccc2N(c2cccc(F)c2F)S1(=O)=O)c1ccccc1

Procedure:
In an analogous manner to general procedure II, 1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure I, 115 mg, 0.41 mmol) was treated with triphenylphosphine (0.13 g, 0.49 mmol), tert-butyl (3-hydroxy-1-phenylpropyl)methylcarbamate (0.12 g, 0.45 mmol), and diisopropylazodicarboxylate (0.095 mL, 0.49 mmol) to provide 0.12 g tert-butyl {3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-phenylpropyl}methylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH2:11])[CH:3]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20]([OH:29])(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23]>CN1CCCC1=O.C(OCC)(=O)C>[C:20]([OH:29])(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH:11][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Nn1cc(Cl)c2ccccc21
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C(O)c1ccccc1O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1cn(Nc2ccncc2)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of crude 3-chloro-1H-indol-1-amine (65.5 g) and 4-chloropyridine hydrochloride (45 g) in 1-methyl-2-pyrrolidinone (250 ml) was stirred at 60° C. for eight hours. The cooled reaction mixture was quenched into 5% aqueous sodium hydroxide, extracted into toluene, dried and concentrated to give an oil. A portion of this oil was dissolved in ethyl acetate. Salicylic acid (1.2 eq) was added to precipitate the salt. The solid was collected at room temperature and dried. This solid was recrystallized with a charcoal treatment from methanol and oven dried (75° C., house vacuum) overnight to yield 10.9 g of the title compound as a solid, m.p. 185°-186° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.CN(C=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[C:16]([Cl:15])=[N:17][CH:18]=[CH:19][N:20]=2)[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nccnc1Cl
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Yield: 45 %

Procedure:
3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol), 2,3-dichloropyrazine (1.3 mL, 12.5 mmol), and DMF (5.0 mL) were combined and heated to 100 C overnight with stirring. The reaction mixture was poured into H2O and extracted with EtOAc (3×). The combined EtOAc extractions were washed with sat'd NaHCO3 (2×), sat's NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (4:1 hexanes:EtOAc) to give 1.76 g (45%) of 3′-chloro-2-methyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) 8.08 (d, 1H), 7.86 (d, 1H), 4.22-3.76 (complex m, 3H), 3.48-3.17 (complex m, 4H), 1.48 (s, 9H), 1.19 (d, 3H) ppm. LC-MS (MH+)=257 (-t-butyl).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@H:3]([NH:11][C:12]([O:14][C@H:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=[O:13])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:21])([CH3:20])[C@H:3]([NH:11][C:12]([O:14][C@H:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=[O:13])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)O[C@H]1CCOC1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)O[C@H]1CCOC1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 59A (0.037 g, 0.123 mmol) in dichloromethane (1.2 mL) was added trifluoroacetic acid (1.2 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to give the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]4=[N:19][O:21][C:30]([C:27]5[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=5)=[C:15]4[CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4)cc23)cc1

Procedure:
The title compound, yellow solid (35 mg, 26%), MS (ISP) m/z=386.3 [(M+H)+], mp 153° C., was prepared in accordance with the general method of example 1 from 1-(4-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate C) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22](=[O:30])[NH:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[CH2:10][CH2:11][C:12]([O:14][CH2:15]C1C=CC=CC=1)=[O:13])=O)(C)(C)C.[ClH:31].CO>CO>[ClH:31].[ClH:31].[NH2:8][C@H:9]([C:22](=[O:30])[NH:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: Cn1ccnc1NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)CC[C@H](N)C(=O)Nc1nccn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl (4S)-4-t-butoxycarbonylamino-4-[(1-methylimidazol-2-yl)carbamoyl]butyrate (113 mg) was dissolved in methanol (2.7 ml), and 20% hydrochloric acid-methanol (1.8 ml) was added. The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was triturated in ether, separated by filtration, washed with ether, and dried to give the title compound (83 mg).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9](O)=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CCN(CC)CC.C(O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>N1C=CC=CC=1.[O-]S([O-])(=O)=O.[Cu+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:14]([CH2:13][CH2:12][C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=43)[C@@H:15]1[CH2:16][CH2:17][C:18]2=[O:19]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccccc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 1 h
Yield: 65.3 %

Procedure:
At 0° C., 1.0 g (3.7 mmol) of estrone (73) was dissolved in 50 mL of dry pyridine and 1.24 mL (7.4 mmol) of trifluoroacetic anhydride (Tf2O) was added slowly to the solution. After 1 h, the crude solution was poured into a cold aqueous solution of CuSO4 (1M) and the organic phase washed with the same solution until the blue color disappear. Next, the solution was extracted with EtOAc and the organic phase washed with water, and dried over MgSO4. After evaporation of the solvent, the crude estrone-triflate was dissolved in 50 mL of dry DMF. To the resulting mixture, we added 1.54 mL (11 mmol) of Et3N, 0.41 mL (11 mmol) of HCOOH, 0.143 mg (0.55 mmol) of PPh3, and 30.8 mg (0.14 mmol) of Pd(OAc)2. After 3 h at room temperature, the solution was quenched with aqueous HCl (5%) and extracted with CH2Cl2. The organic phase was washed with water, dried over MgSO4, and solvents evaporated to dryness. The crude compound was purified by flash chromatography with hexanes/EtOAc (9:1) as eluent to give 615 mg (65% two steps) of 1,3,5(10)-estratrien-17-one (74). White solid; IR ν (film): 1738 (C═O); 1H NMR (CDCl3) δ 0.94 (s, 3H, 18-CH3), 2.94 (m, 2H, 6-CH2), 7.16 (m, 3H, 1-CH, 2-CH, 3-CH), 7.32 (d, J=5.9 Hz, 1H, 4-CH); 13C NMR (CDCl3) δ 13.76 (C-18), 21.51 (C-15), 25.61 (C-11), 26.42 (C-7), 29.29 (C-6), 31.56 (C-12), 35.77 (C-16), 38.04 (C-8), 44.40 (C-9), 47.88 (C-13), 50.49 (C-14), 125.22 (C-3), 125.73 (C-2 and C-1), 128.98 (C-4), 136.37 (C-5), 139.62 (C-10), 220.63 (C-17).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.[O:19]1CCOCC1>O>[CH2:17]([O:16][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH:1]=[O:19])[CH:15]=1)[CH3:18]
Reactant: C1COCCO1
Reactant: CCOc1cc(C)nc2c1ccc1cccnc12
Solvent: O
Product: CCOc1cc(C=O)nc2c1ccc1cccnc12
Yield: 16 %

Procedure:
A solution of SeO2 (1.01 g, 9.1 mmol) in a mixture of dioxane (50 mL) and water (2 mL) was heated to reflux in a two-neck 250 mL round-bottomed flask. A solution of 2-methyl-4-ethoxy-[1,10]phenanthroline (0.87 g, 3.6 mmol) in hot dioxane (50 mL) was added through an addition funnel over a period of 30 minutes and the reaction mixture was refluxed for 1 hour. The reaction mixture was filtered while hot and the residue rinsed with more hot dioxane (20 mL) and filtered. The filtrates were combined and concentrated in vacuo and the residue was treated with methylene chloride (100 mL) and a 10% K2CO3 aqueous solution (100 mL). The aqueous layer was extracted with methylene chloride (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (SiO2, MeOH/DCM, 1:30 to 1:15) to afford the pure product as a light brown solid (0.15 g, 16%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1>CC(N(C)C)=O>[O:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)c1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6.73 g. sodium hydride (57% suspension in mineral oil-0.165 mole) in 200 ml. dry dimethylacetamide, there is added dropwise 14.1 g. (0.15 mole) of phenol in 50 ml. dimethylacetamide maintaining the temperature below 25°C. After the addition is complete, the resulting mixture is stirred for 1 1/2 hours at room temperature. A solution of 38.3 g. (0.15 mole) α-bromo-p-pivaloyl toluene in 50 ml. dimethylacetamide is then added dropwise at room temperature and the resulting mixture is stirred for 18 hours at room temperature. The mixture is then treated with 10 ml. of methanol and the solvent removed in vacuo. The resulting residue is partitioned between ether and water, and the ether layer is washed twice with 200 ml. of 2N sodium hydroxide, once with water and once with brine. The organic layers are combined and dried over anhydrous magnesium sulfate, decolorized and evaporated. The resulting solid is triturated with petroleum ether to give p-(phenoxymethyl)pivalophenone, m.p. 79.5° to 80°C.
Reaction SMILES: [CH2:1]([N:4]([C:18]1[C:19]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:20]=2[N:21]=[CH:22][N:23]=1)[C@H:5]1[CH2:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)[CH2:2][CH3:3].Cl>O1CCOCC1>[NH:7]1[CH2:8][CH2:9][CH2:10][C@H:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:18]2[C:19]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:6]1
Reactant: CCCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCNC1
Yield: 100.5 %

Procedure:
A solution of (S)-tert-butyl 3-(propyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (300 mg, 0.58 mmol) in 1,4-dioxane (5 mL) was treated with 4 N HCl in 1,4-dioxane (10 mL) at rt for 1 h. The solvent was removed in vacuo and the residue was suspended in water (10 mL). The aqueous layer was adjusted to a pH 9 with solid NaHCO3 and the solution was extracted with EtOAc (3×25 mL). The combined organic layer was dried over Na2SO4, concentrated in vacuo to yield titled intermediate (241 mg, 83%), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.23 (1s, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.69 and 7.65 (2d, 0.1=4.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 6.81 (d, J=4.0 Hz, 1H), 3.69-3.64 (m, 3H), 3.51-3.47 (m, 2H), 3.25-3.18 (m, 2H), 52.85-2.83 (m, 1H), 2.35 (s, 3H), 1.94-1.89 (m, 2H), 1.79-1.76 (m, 1H), 1.55-1.53 (m, 1H), 1.16 and 0.93 (t, J=7.2 Hz, 3H). LC-MS: m/z [M+1]=414.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].CN1CCOCC1.Cl[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:48]=[CH:47][C:35]([O:36][C:37]2[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>ClCCl.CN(C=O)C>[Cl:31][C:32]1[CH:48]=[CH:47][C:35]([O:36][C:37]2[CH:38]=[CH:39][C:40]([S:43]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])(=[O:45])=[O:44])=[CH:41][CH:42]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a suspension of D-tert-leucine (0.250 g., 1.91 mmol, Aldrich) in dichloromethane (3 mL) and DMF (1.5 mL) was added N-methylmorpholine (0.50 mL., 4.55 mmol), followed by chlorotrimethylsilane (0.30 mL., 2.36 mmol) and the mixture stirred at room temperature for 6 hours. Diisopropylethylamine (0.300 mL., 1.72 mmol) was added, followed by 4-(4-chlorophenoxy)benzenesulfonyl chloride (0.636 g., 2.10 mmol, from example 1(c)) portionwise via a solid addition funnel. The resulting solution was then stirred at room temperature for 3.5 hours, and then partitioned between ethyl acetate and 1N aq. sodium bisulfate. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 40% ethyl acetate in hexane followed by 10% methanol in dichloromethane, to give N-[4-(4-chlorophenoxy)benzenesulfonyl]-D-tert-leucine as a white solid in 62% yield: mp 138-140° C.; 1H--NMR (CDCl3) δ 0.949 (s, 9H), 3.51-3.54 (d, 1H, J10.3 Hz), 5.55-5.59 (m, 1H), 6.94-7.83 (m, 8H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc2sc(S(N)(=O)=O)cc2c1
Reaction time: 18 h
Yield: 76.6 %

Procedure:
Under nitrogen, a solution of 5-(2-bromoethyl)-2-sulfamoylbenzo[b]thiophene (1.2 g, 0.0037 mol), NaN3 (0.6 g, 0.0092 mol) and DMF (25 ml) was heated at 100° C. After 18 hours, the solution was cooled, poured into H2 0, and filtered to yield 0.8 g of product. The filtrate was extracted with ethyl acetate (2×). The organic layers were dried, filtered and concentrated to dryness to yield an additional 0.4 g of product (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:3]=1[O:4][CH:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>Cl.O1CCOCC1>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[Cl:1][C:2]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:3]=1[O:4][CH:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCC(Oc2cc(Cl)ccc2Cl)c2ccccc2)CC1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1COCCO1
Product: Clc1ccc(Cl)c(OC(CCCN2CCNCC2)c2ccccc2)c1
Temperature: 25 °C
Yield: 49 %

Procedure:
The product from step (a) (0.20 g, 0.42 mmol) was dissolved in 4M hydrogen chloride in dioxan (10 ml) and stirred for 3hat room temperature. The solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and aqueous saturated sodium bicarbonate solution (50 ml). The layers were separated and the aqueous portion was extracted with ethyl acetate (2×50 ml). The combined organic portions were washed with water (3×30 ml), dried (magnesium sulphate) and evaporated. The residue was dissolved in methanol and treated with one equivalent of fumaric acid, stirred for ten minutes and then the solvent was removed in vacuo. The solid residue was triturated with ethyl acetate and the white solid obtained filtered off and dried to give the title compound (0.10 g, 49%).,
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[O:10][C:11]([CH3:18])=[CH:12][C:13]=1[S:14](Cl)(=[O:16])=[O:15].[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:35][CH3:36])=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=2)[CH:25]=1>ClCCl>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:35][CH3:36])=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]([NH:34][S:14]([C:13]3[CH:12]=[C:11]([CH3:18])[O:10][C:9]=3[CH3:8])(=[O:16])=[O:15])[CH3:33])=[CH:28][CH:27]=2)[CH:25]=1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Reactant: COc1ccc(F)cc1-c1ccc(C(C)N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
Triethylamine (41.1 μl, 0.295 mmol) then 2,5-dimethyl-3-furansulfonyl chloride (19.1 mg, 0.0982 mmol) were added to a solution of 1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20 mg, 0.082 mmol) in dichloromethane (1 ml) and the resulting solution shaken at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (500 μl) and the organic phase separated, dried over anhydrous magnesium sulfate and the solvent evaporated. The crude product was purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (3.9 mg, 0.0097 mmol, 11.8%). 1H NMR (400 MHz, CDCl3): δ 7.40, 7.23 (a/b, 4H), 7.05-6.88 (m, 3H), 5.99 (s, 1H), 4.67 (m, 1H), 4.55 (m, 1H), 3.78 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H), 1.52 (d, 3H) ppm; MS (ESI) m/z: 426 [M+Na]+.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:61][CH3:62])[C:44]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[OH:60])=[N:45][C:46]=1[CH:47]1[CH2:49][CH2:48]1>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:61][CH3:62])[C:44]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[O:60][CH2:2][CH3:3])=[N:45][C:46]=1[CH:47]1[CH2:49][CH2:48]1
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-6-cyclopropyl-3-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: MS (ESI+) for C27H30ClN3O2 m/z 465 (M+H)+.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH2:15]([C:18]1[C:35]2[CH2:34][C:33]3[C:24](=[C:25]([CH2:39][CH2:40][CH3:41])[C:26]4[C:31]([C:32]=3[CH2:36][CH2:37][CH3:38])=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:23][C:22]=2[C:21]([CH2:42][CH2:43][CH3:44])=[C:20]([C:45]([O:47][CH3:48])=[O:46])[C:19]=1[C:49]([O:51][CH3:52])=[O:50])[CH2:16][CH3:17]>O1CCOCC1>[CH2:15]([C:18]1[C:35]2[C:22](=[CH:23][C:24]3[C:33]([CH:34]=2)=[C:32]([CH2:36][CH2:37][CH3:38])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=3[CH2:39][CH2:40][CH3:41])[C:21]([CH2:42][CH2:43][CH3:44])=[C:20]([C:45]([O:47][CH3:48])=[O:46])[C:19]=1[C:49]([O:51][CH3:52])=[O:50])[CH2:16][CH3:17]
Reactant: CCCc1c2c(c(CCC)c(C(=O)OC)c1C(=O)OC)Cc1c(c(CCC)c3ccccc3c1CCC)C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCCc1c(C(=O)OC)c(C(=O)OC)c(CCC)c2cc3c(CCC)c4ccccc4c(CCC)c3cc12
Yield: 74.1 %

Procedure:
2,3-Dichloro-5,6-dicyanobenzoquinone (0.050 g, 0.22 mmol) was added to a solution of dimethyl 5,12-dihydro-1,4,6,11-tetrapropylnaphthacene-2,3-dicarboxylate (0.103 g, 0.2 mmol) in 1,4-dioxane (5 ml). Subsequently, the mixture was refluxed for 3 hours. After filtration, the solvent in the mixture was removed in vacuum. Chloroform was added and the mixture was again filtered. Recrystallization from chloroform/methanol gave 0.076 g of the title compound as red needle-like crystals. The NMR yield was 97% and the isolated yield was 71%. The X-ray crystal structure analysis of the title compound is show in FIG. 4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH2:23])[CH:17]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[C:31](Cl)(Cl)=[O:32]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:31](=[O:32])[NH:23][C:18]=4[CH:17]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(-c2nc(-c3ccc(O)c(N)c3)cs2)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(-c3ccc4oc(=O)[nH]c4c3)cs2)cc1OC
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
In 20 ml of tetrahydrofuran was dissolved 300 mg of 2-(3,4-dimethoxyphenyl)-4-(3-amino-4-hydroxyphenyl)thiazole. Thereto was added 0.46 ml of triethylamine at room temperature. The mixture was stirred at the same temperature for 30 minutes. 100 mg of phosgene was blown thereinto, and the resulting mixture was stirred for 2 hours. The solvent was distilled off. The residue was washed with diethyl ether, followed by filtration to collect crystals. The crystals were recrystallized from methanol to obtain 50 mg of 2-(3,4-dimethoxyphenyl)-4-(benzoxazol-2-on-5-yl)thiazole as a white powder.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.C(Cl)Cl>CO.O1CCCC1>[O:6]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (3.78 g, 100 mmol) was added in four portions to a stirred solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (4.94 g, 20 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) in methanol/tetrahydrofuran (1:1, 100 mL) at 0° C. and the resulting solution was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. Methylene chloride was added and the solution was washed with water and dried over sodium sulfate. The solvents were removed and the residue was solidified upon standing (5.0 g, 100%); 1H NMR (300 MHz, CDCl3) δ 1.84 (t, J=5.7 Hz, 4H), 3.33 (t, J=5.7 Hz, 4H), 3.99 (s, 4H), 4.59 (d, J=5.8 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 7.24 (d, J=8.7 Hz, 2H); MS (ES) m/z: 249.9 (MH+); HRMS Calcd. for C14H20NO3 (MH+): 250.1443. Found: 250.1434.