Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][C:13](=O)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:25][OH:26]>O1CCOCC1>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][C:13](=[N:25][OH:26])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: NO
Solvent: C1COCCO1
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(=NO)C1
Temperature: 60 °C
Yield: 55.2 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (100 mg, 0.22 mmol), prepared using procedures similar to those described in Example 6, in dioxane (1.0 mL) was added hydroxylamine (0.10 mL, 50% solution in water, 1.5 mmol), and the resulting solution was heated at 60° C. for 18 h. The mixture was cooled to room temperature and the crude product was purified by reverse phase HPLC to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one oxime (56 mg, 54% yield): 1H NMR (400 MHz, CDCl3), 8.43 (br s), 7.43-7.39 (m, 2H), 7.35-7.32 (dd, 1H), 7.19-7.15 (m, 1H), 6.87-6.81 (m, 1H), 6.65-6.59 (m, 1H), 4.89 (br s, 2H), 4.85 (br s, 2H); MS (EI) for C16H11F3IN3O2: 462 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[C:11]=3[C:10]([CH2:21][CH2:22][NH:23][CH2:24][C:25]34[CH2:32][CH2:31][N:28]([CH2:29][CH2:30]3)[CH2:27][CH2:26]4)=[CH:9]2)=[CH:5][CH:4]=1.O.[OH-].[Li+:37]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O-:19])=[O:18])[C:11]=3[C:10]([CH2:21][CH2:22][NH:23][CH2:24][C:25]34[CH2:26][CH2:27][N:28]([CH2:29][CH2:30]3)[CH2:31][CH2:32]4)=[CH:9]2)=[CH:5][CH:4]=1.[Li+:37]
Reactant: COC(=O)c1cccc2c1c(CCNCC13CCN(CC1)CC3)cn2Cc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(CCNCC34CCN(CC3)CC4)c3c(C(=O)[O-])cccc32)cc1

Procedure:
A mixture of methyl 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate (520 mg, 1.1 mmol) from Step D above and lithium hydroxide monohydrate (142 mg, 3.4 mmol) in tetrahydrofuran/water (30 mL, 1:1) was stirred at reflux until the reaction was complete by LC-MS. The solvent was removed under reduced pressure to give lithium 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate as a white solid (878 mg, crude): 1H NMR (500 MHz, CD3OD) δ 7.31 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.10-7.05 (m, 4H), 6.80 (d, J=8.5 Hz, 2H), 5.25 (s, 1H), 3.74 (s, 3H), 3.13 (t, J=7.0 Hz, 2H), 2.81 (t, J=7.0 Hz, 2H), 2.77 (t, J=7.5 Hz, 6H), 2.30 (s, 2H), 1.89 (s, 1H), 1.31 (t, J=7.5 Hz, 6H); MS (ESI+) m/z 448 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1>C(Cl)Cl.CN(C=O)C.O=[Mn]=O>[CH:13]([C:11]1[N:10]=[C:8]2[N:7]([CH:12]=1)[C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[S:9]2)=[O:14]
Reactant: COc1ccc2c(c1)sc1nc(CO)cn12
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)sc1nc(C=O)cn12

Procedure:
2-Formyl-7-methoxyimidazo[2,1-b]-benzthiazole was prepared according to the procedure outlined in Example 1, (Step 3). Starting from 7-methoxy imidazo[2,1-b]-benzthiazole-2-methanol (4.0 g 17 mmol) in methylene chloride/DMF(300 mL: 50 mL) and active MnO2 (12 g, excess), 822 mg (21% Yield) of the aldehyde derivative was isolated as brown solid. (M+H) 233.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[C:13]([CH3:14])=[CH:12][S:11][CH:10]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>CN(C=O)C>[CH2:35]([NH:39][C:16](=[O:18])[C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[C:13]([CH3:14])=[CH:12][S:11][CH:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:20])[CH3:19])[CH:36]([CH3:38])[CH3:37]
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1-c1cscc1C
Reactant: CC(C)CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)C(=O)NCC(C)C)ccc1-c1cscc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 2-(3-methoxy-4-(4-methylthiophen-3-yl)phenyl)-2-methylpropanoic acid (example 35b) (630 mg, 2.2 mmol) in DMF (7 mL) were added HOBt (297 mg, 2.2 mmol), EDC (434 mg, 2.2 mmol) and isobutyl amine (214 μL, 2.2 mmol). The mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was dissolved in EtOAc and successively washed with water, 10% citric acid, sat. NaHCO3 and water, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (30% EtOAc-hexanes) to give 190 mg (37%) of N-isobutyl-2-(3-methoxy-4-(4-methylthiophen-3-yl)phenyl)-2-methylpropanamide. 1H NMR (400 MHz, dMSO): δ 0.73-0.75 (d, 6H), 1.48 (s, 6H), 1.69-1.72 (m, 1H), 2.00 (s, 3H), 2.49-2.50 (m, 2H), 3.71 (s, 3H), 6.91-6.94 (m, 2H), 7.08-7.10 (d, 1H), 7.18 (s, 1H), 7.24-7.25 (d, 1H), 7.34-7.35 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(-c3ccncc3)cnn12
Yield: 72 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125 mg, 0.5 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (135 mg, 72%). MS (ISP) 375.3 [(M+H)+]; mp 274° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][CH2:50][CH2:51][NH2:52])=[CH:45][CH:44]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9](=[O:11])[NH:52][CH2:51][CH2:50][NH:49][C:46]2[CH:47]=[CH:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=2)[NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(NCCN)cc1
Reactant: Cc1cccc(C(=O)NC(C(=O)O)c2ccc(F)cc2)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(NCCNC(=O)C(NC(=O)c2cccc(C)c2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
4-Fluoro-phenyl glycine 1 (20 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0° C., then m-toluoyl chloride (16 μL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (4-Fluoro-phenyl)-(3-methyl-benzoylamino)-acetic acid 2 (34 mg, 0.12 mmol, quant.) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.67–7.08 (m, 8H), 5.66 (s, 1H), 2.38 (s, 3H). MS calcd. for C16H15FNO3 (M+H+) 288.10. found 288.4. Step B: (4-Fluoro-phenyl)-(3-methyl-benzoylamino)-acetic acid 2 (34 mg, 0.12 mmol) was dissolved in DCM (2 mL), HOBt (20 mg, 0.14 mmol) and DIC (23 μL, 0.14 mmol) were added and the solution was stirred for 10 min at room temperature. N-(4-Methoxyphenyl)-ethane-1,2-diamine (24 mg, 0.14 mmol) was added and the solution was stirred for 3 h at room temperature. The solvent was removed in vacuo, and the remainder was purified by reverse HPLC to afford N-{(4-Fluoro-phenyl)-[2-(4-methoxy-phenylamino)-ethylcarbamoyl]-methyl}-3-methyl-benzamide 3 (19 mg, 0.04 mmol, 36%) as a white solid:
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:56]1[N:60]2[CH:61]=[CH:62][CH:63]=[N:64][C:59]2=[C:58]([C:65](O)=[O:66])[CH:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH2:5][CH2:6][N:7]1[C:65]([C:58]1[CH:57]=[N:56][N:60]2[CH:61]=[CH:62][CH:63]=[N:64][C:59]=12)=[O:66]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1C(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a solution of (3S)-3-methyl-1-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)piperazine (may be prepared as described in Description 13) (300 mg, 0.925 mmol), HOBt (142 mg, 0.925 mmol), HBTU (351 mg, 0.925 mmol) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (151 mg, 0.925 mmol) in DMF (50 ml) was added DIPEA (0.485 ml, 2.78 mmol) and the resulting mixture stirred at room temperature overnight, then concentrated under vacuum. The residue was redissolved in EtOAc, washed with aqueous NaHCO3 and brine, then concentrated under vacuum. Flash chromatography (silica; EtOAc) and concentration of the desired fractions gave the title compound (157 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4]([N:21]=[N+]=[N-])[N:3]=1.C(O)=O.N>[Pd].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:14][O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18]2)=[C:4]([NH2:21])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(N=[N+]=[N-])nc(N)nc32)CO1
Agent: [Pd]
Agent: N
Solvent: O=CO
Solvent: CO
Product: CC1(C)OCC(CCn2cnc3c(N)nc(N)nc32)CO1
Yield: 65 %

Procedure:
A mixture of 2-amino-6-azido-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (318 mg, 1.0 mmol), formic acid (0.15 ml, 4.0 mmol), concentrated ammonia (0.22 ml, 4.0 mmol), 10% palladium-on-charcoal (30 mg) and methanol (10 ml) was heated under reflux for 1 hour. The solution was allowed to cool, filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (20:1 and 15:1) to give 2,6-diamino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (190 mg, 65%), m.p. 202°-204° C.); νmax (KBr) 1670, 1640, 1595, and 1410 cm-1 ; δH (CDCl3 -CD3OD) 1.42 (6 H, s, C(CH3)2), 1.6-2.0 (3 H, m, CHCH2CH2), 3.5-4.2 (6 H, m, 2×CH2O and CH2N), and 7.68 (1 H, s, 8-H) (Found: C, 52.88; H, 6.78; N, 28.36%; M+ 292.1652, C13H20N6O2 requires C, 53.41; H, 6.90; N, 28.75%; M+ 292.1648).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].S=[C:7]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][NH:8]1.C(OCC)C>CO>[OH:3][N:2]=[C:7]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=S)CC1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNC(=NO)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A solution of hydroxylamine hydrochloride (2 eq.) in methanol was added to an equimolar methanolic solution of potassium hydroxide. Potassium chloride was filtered off and the filtrate was added to a solution of the above tert-butyl 5-thioxo-1,4-diazepane-1-carboxylate (1 eq.) in methanol. The mixture was stirred at 55° C. overnight, then cooled to room temperature and the solvent was removed under reduced pressure. The residue was taken in chloroform, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give, after trituration with ethyl ether, the title amidoxime. 1H NMR (300 MHz, CDCl3) δ 6.4-6.1 (bs, 1H), 5.8 (broad triplet, 1H), 3.6-3.5 (m, 4H), 3.35-3.22 (m, 2H), 2.5-2.4 (m, 2H), 1.45 (s, 9H); MS (ES) C10H19N3O3 requires 229. Found: 230 (M+H+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:13][Si:14]([CH3:17])([CH3:16])Cl>C[Si](C)(C)N[Si](C)(C)C>[F:12][C:2]([F:11])([F:1])[C:3]1[C:4]([O:10][Si:14]([CH3:17])([CH3:16])[CH3:13])=[N:5][C:6]([O:9][Si:14]([CH3:17])([CH3:16])[CH3:13])=[N:7][CH:8]=1
Reactant: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)Oc1ncc(C(F)(F)F)c(O[Si](C)(C)C)n1

Procedure:
In 50 ml of hexamethyldisilazane, 6.16 g of 5-trifluoromethyluracil was suspended and then 0.22 ml of trimethylchlorosilane was added to the suspension, followed by heating the resulting mixture to reflux for 5 hours. After the reaction, the excess hexamethyldisilazane was removed by evaporation and the resultant was distilled in vacuum. All of the fractions of distillate obtained at about 60° C. under 1 mmHg were collected. Yield: 10.3 g
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC.CN(C=O)C.[H-].[Na+]>CO>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 4 %

Procedure:
To a mixture of Solketal (66.1 g, 0.5 mol), 1-bromotetradecane (159.4 g, 0.575 mol), and DMF (800 ml) was added 60% NaH (26.0 g, 0.65 mol) in oil dispersion in 3 portions for 1 hr. The mixture was stirred at room temperature for 1 day and methanol (20 ml) was added to destroy the excess NaH. This was then poured into 1500 ml of ice-water and the aqueous layer was extracted with hexanes (2000 ml). The combined organic layers were evaporated to dryness and the oily residue was refluxed in 10% HCl/methanol (conc. HCl, 250 ml and methanol, 675 ml) for 30 min followed by stirring at room temperature overnight. The white flaky solid was filtered and washed with methanol (122 g). The additional product was obtained from the filtrate (5.7 g); Total 127.7 g (88.5%). The crude product was recrystallized from diethyl ether; Yield 99.7 g (69.1%), mp 57°-58° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:32])[C@@H:15]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]([CH3:33])[N:9]=2)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C>[Pd].CO>[CH3:33][N:10]1[C:11]([NH:13][C:14](=[O:32])[C@@H:15]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[CH:2][CH:7]=2)=[N:9]1
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a 100 ml flask was added 1.4 g of 17.8.A, 500 mg of Pd on carbon, 150 ml of MeOH and 520 μl of diisopropylethylamine. The air was removed from the flask and replaced with hydrogen gas. This process was repeated four more times and then the reaction was stirred at room temperature for 2 hours, at which time the reaction was filtered over a bed of celite. The solvent was then removed and the crude was purified with a silica gel column (eluting with 2-5% MeOH in DCM) to give 800 mg of (S)-tert-butyl 2-(1-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylamino)acetate 17.8.B as a solid. (Rf silica=0.27 in 5% MeOH in DCM).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:21]([CH:18]3[CH2:20][CH2:19]3)=[O:22])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)C1CC1
Product: C[C@]1(c2cc(NC(=O)C3CC3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and cyclopropanecarboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=310.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=O.[C:21](C1NC=CN=1)([C:23]1[NH:24][CH:25]=[CH:26]N=1)=O.C(NCC)C>CN(C)C=O>[CH2:23]([N:24]([CH2:25][CH3:26])[C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=[O:1])[CH3:21]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A mixture of 10.0 g (0.037 mol) of d-lysergic acid in 500 ml of dry dimethyl formamide (DMF), under argon, was treated with 9.0 g of carbonyl diimidazole and stirred at room temperature for 1 hour. The reaction was then treated with 38 ml of diethylamine and stirred at room temperature overnight. The reaction was concentrated under reduced pressure. The residue was taken up in 500 ml of methylene chloride and washed with 500 ml of water. Insoluble material was removed by filtration and the layers were separated. The organic portion was washed with 250 ml of saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on 800 g of silica gel using 3% methanol in methylene chloride to yield 9.0 g (75%) of d-lysergic acid diethylamide (LSD) as a light brown amorphous solid after evaporation of the solvents.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:11][OH:12])[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NO)c1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To a solution of 4-bromobenzonitrile (5.0 g, 27.5 mmol) in ethanol (42 ml) at room temperature, hydroxylamine hydrochloride (1.91 g, 27.5 mmol) and DIPEA (4.8 ml, 27.5 mmol) were added. The reaction mixture was stirred at 90° C. for 5 hours. After cooled to room temperature, the resulting mixture was concentrated to yield a colorless viscous liquid. The liquid was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and then concentrated to give a crude compound, which was washed with n-hexane to yield product 15 as a white solid (5.0 g).
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[S:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1.[Cl-].[NH4+]>O1CCCC1>[CH:16]1([O:15][C:9]2[CH:8]=[C:7]([C:23]3([OH:26])[CH2:24][CH2:25][S:21][CH2:22]3)[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Reactant: O=C1CCSC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCSC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirring suspension of magnesium turnings (3.45 g) in dry tetrahydrofuran (60 mL) is treated with 1,2-dibromoethane (0.8 mL), and the mixture is stirred under a nitrogen atmosphere for 30 minutes. It is then treated dropwise with a solution of 4-bromo-2-cyclopentyloxyanisole (25 g); which is prepared as described in Reference Example 4 in tetrahydrofuran (20 mL), and the resulting solution is heated at reflux for 30 minutes. The solution is then cooled to room temperature and treated with a solution of tetrahydrothiophen-3-one (6.9 mL) in tetrahydrofuran (20 mL), and allowed to stand for 16 hours. It is then treated with saturated aqueous ammonium chloride solution (50 mL), and the mixture is partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous phase is further extracted with dichloromethane (100 mL). The combined organic phases are dried over magnesium sulphate and evaporated. The resulting residue is subjected to flash chromatography on silica gel, using a mixture of ethyl acetate and toluene as eluent to give 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxytetrahydrothiophene, in the form of a viscous oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@H:23]([O:25]CC4C=CC=CC=4)[CH3:24])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:8]=2)[CH2:3]1.C(OC(=O)N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1)(C)(C)C>>[NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@@H:23]([OH:25])[CH3:24])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:8]=2)[CH2:3]1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Agent: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Product: C[C@H](O)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4), by substituting acetic acid (S)-1-{(1S,2R,3S,4R)-4-[2-((R)-3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-ethyl ester (Example 182, step 3) for {(R)-1-[9-[(1R,2S,3R,4S)-4-((R)-2-benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Example 181, step 3).