Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H]1[C@@]2(C)C(C[C@H](C)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[CH2:12][C:13]2=[O:21])=CC(=O)C1.[CH3:24][C@H:25]1[C@@:42]2([CH3:43])[C:29]([C@@H:30]([CH3:45])[CH2:31][C@@H:32]3[C@@H:41]2[CH2:40][CH2:39][C@@:37]2([CH3:38])[C@H:33]3[CH2:34][CH2:35][C:36]2=[O:44])=[CH:28][C:27](=[O:46])[CH2:26]1.C[C@H]1[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[CH2:58][C:59]2=[O:67])=CC(=O)C1>>[C:13]([O:46][C@H:27]1[CH2:26][C@@H:25]([CH3:24])[C@@:42]2([CH3:43])[C:29](=[C:30]([CH3:45])[CH2:31][C@@H:32]3[C@@H:41]2[CH2:40][CH2:39][C@@:37]2([CH3:38])[C@H:33]3[CH2:34][CH2:35][C@@H:36]2[O:44][C:59](=[O:67])[CH3:58])[CH2:28]1)(=[O:21])[CH3:12]
Reactant: C[C@@H]1CC(=O)C=C2[C@@H](C)C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Reactant: C[C@H]1CC2=CC(=O)C[C@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Product: CC(=O)O[C@@H]1CC2=C(C)C[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H](C)C1

Procedure:
Substituting 1α,7β-dimethyl-4-androstene-3,17-dione and 1β,6α-dimethyl-4-androstene-3,17-dione for the 1β-methyl-4-androstene-3,17-dione above results in the preparation of 1,62, 7αdimethyl-5-androstene-3β,17β-diol diacetate and 1β,6-dimethyl-5-androstene-3β,17β-diol diacetate, respectively.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:13]([F:24])[CH:12]=2)[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([F:24])[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:15]([F:17])[CH:16]=2)[CH2:6]1
Reactant: [N-]=[N+]=NCC1CN(c2cc(F)c(-c3cccnc3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: NCC1CN(c2cc(F)c(-c3cccnc3)c(F)c2)C(=O)O1
Reaction time: 16 h

Procedure:
(±)-5-(Azidomethyl)-3-[4-(3-pyridyl)-3,5-difluorophenyl]-2-oxazolidinone (PREPARATION 6, 354 mg, ~1.07 mmol) in methanol (40 ml) and palladium on carbon (10%, 50 mg) are mixed. The mixture is purged with nitrogen and then placed under an atmosphere of hydrogen (1 atm). The reaction is allowed to stir at 20°-25° for 16 hrs. After this time, the reaction is filtered and concentrated under reduced pressure to a solid amine. The crude amine is suitable for acetylation without further purification. An analytical sample is prepared by preparative TLC (SG) methanol/chloroform (10/90). The title compound is recovered as a solid, mp 143°-145°; FTIR (neat) cm-1 3368, 1757, 1646, 1412, 1244, 1025 and 714; MS (EI, m/z) 305, 276, 233, 219, 44 and 29; NMR (CDCl3) 8.71, 8.62, 7.79, 7.39, 7.33, 4.79-4.70, 4.06, 3.92, 3.18, 2.98 and 1.52 δ.
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C(O)(=O)C>[CH2:20]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:12][N:11]=[C:9]12)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCn1/c(=N/N=Cc2ccccc2)[nH]c(=O)c2[nH]cnc21
Solvent: CC(=O)O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(-c3ccccc3)nnc12
Yield: 21.5 %

Procedure:
A solution of benzaldehyde [(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2h-purin-2-ylidene]hydrazone (140 mg, 0.432 mmol) in acetic acid (5 ml) was stirred at 130° C. for 5 hours. The reaction mixture was concentrated in vacuo and purified by prep LCMS to yield the desired product (30 mg, 22% yield). LCMS calculated for C17H19N6O(M+H): 323.2; found: 323.2.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3([NH:29][C:30]([O:32][CH2:33][CH:34]4[C:46]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:40]5[C:35]4=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]>CO.C(O)(=O)C.[Pd]>[NH2:1][C:2]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3([NH:29][C:30](=[O:31])[O:32][CH2:33][CH:34]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=5[C:41]5[C:46]4=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: NC(=O)c1cccc2[nH]c(C3(NC(=O)OCC4c5ccccc5-c5ccccc54)CCN(C(=O)OCc4ccccc4)CC3)nc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1cccc2[nH]c(C3(NC(=O)OCC4c5ccccc5-c5ccccc54)CCNCC3)nc12
Yield: 65.8 %

Procedure:
A mixture of Example 49A (0.175 g, 0.3 mmol) and 10% Pd/C (0.015 g) in MeOH (5 ml) and acetic acid (0.2 ml), was stirred overnight under a H2 atmosphere at room temperature. The mixture was filtered through a pad of silica then concentrated under vacuum. The residue was purified by HPLC on a C18 column with 0-100% CH3CN/H2O/0.1% TFA to provide 0.095 g (69%) of the desired product. MS (ESI) m/e 482 (M+H)+. 1H NMR (DMSO-D6) δ ppm 8.55 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.82-7.91 (m, 3H), 7.65-7.78 (s, 3H) 7.42 (d, J=7.67 Hz 2H), 7.29-7.34 (m, 2H), 4.31 (d, J=7.06 Hz, 2H), 3.5-3.28 (m, 7H), 2.42 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)[N:9]=[CH:10][C:5]2=[C:4]([C:11](=[O:12])[NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.2 %

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.5 g, 1.33 mmol) in DMF (5 mL), K2CO3 (0.275 g, 1.99 mmol) and tert-butyl 4-bromopiperidine-1-carboxylate (0.529 g, 2.01 mmol) was added. Resulting reaction mixture was stirred at 80° C. for 12 h. On completion of reaction, water was added to it and extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (0.5 g, 67.2%).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([CH2:24][OH:25])=[CH:23][C:18]=3[N:17]([CH3:26])[C:16]2=[O:27])CC[CH2:12]1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]=[O:25])=[CH:23][C:18]=2[N:17]([CH2:26][CH3:1])[C:16]1=[O:27])[CH3:12]
Reactant: Cn1c(=O)n(C2CCC2)c2ccc(CO)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCn1c(=O)n(CC)c2cc(C=O)ccc21
Temperature: 23 °C
Yield: 99.4 %

Procedure:
To a dichloromethane (50 mL) solution of oxalyl chloride (1.47 mL, 16.8 mmol) at −78° C. was added methyl sulfoxide (1.47 mL, 20.5 mmol). After 15 minutes 1-Cyclobutyl-5-hydroxymethyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (2.21 g, 10.0 mmol, in 20 mL dichloromethane) was added. After 20 minutes triethylamine (4.26 mL, 20.6 mmol) was added and the reaction was allowed to warm to 23° C. Upon dilution with saturated sodium bicarbonate and dichloromethane the product was extracted into dichloromethane. The organic layer was dried over sodium sulfate and concentrated to give 1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde (2.17 g).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#N)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:21].[OH-:22].[Na+]>C(O)C>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: N#CCCCCCCCCNS(=O)(=O)c1ccccc1
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCCCCCCCNS(=O)(=O)c1ccccc1

Procedure:
9-(Benzenesulphonamido)nonanenitrile (0.72 g) was dissolved in ethanol (50 ml) and water (10 ml) containing sodium hydroxide (1.5 g). The mixture was refluxed for 18 hours then the solvent was removed. The residue was dissolved in water and treated with hydrochloric acid to give a white precipitate. This was collected by filtration and recrystallised from methanol-water to give the title compound (0.52 g) m.p. 82°-84° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:37][CH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(CBr)c1
Reaction time: 24 h

Procedure:
2-Methyl-4-nitro-1-pentafluoroethyl-benzene (2.55 g) was dissolved in CCl4 (30 ml) and AIBN (164 mg) and NBS (1.96 g) were added. The reaction was heated to reflux and stirred for 24 h. The mix was diluted with CH2Cl2, washed with sat'd NaHCO3, dried over MgSO4 and concentrated to give the compound as an oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(F)c(N)cc1Br
Temperature: 0 °C
Yield: 31.9 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0 g) in ethanol (300 mL) was added SnCl2.2H2O (51.8 g, 0.230 mol) at room temperature. The mixture was heated at reflux for 3 h. The solvent was evaporated under reduced pressure to give a residue, which was poured into ice water. The aqueous phase was basified with sat. NaHCO3 to pH 7. The solid was filtered off and the filtrate was extracted with dichloromethane (200 mL×3). The combined organics were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=10/1) to afford 5-bromo-2-fluoro-4-methylaniline (5.0 g, 30% yield for two steps). 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=8.8 Hz, 1H), 6.86 (d, J=11.6 Hz, 1H), 3.64 (br, 2H), 2.26 (s, 3H). MS (ESI) m/z (M+H+) 204.0.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53]([OH:55])=O)[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:27]=[C:28]([F:30])[CH:29]=1.[CH3:56][N:57]1CC[O:60][CH2:59][CH2:58]1.CNCCO>CN1C(=O)CCC1>[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53]([N:57]([CH2:58][CH2:59][OH:60])[CH3:56])=[O:55])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNCCO
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Product: CN(CCO)C(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
TBTU (102 mg, 0.32 mmol) was added to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (105 mg, 0.21 mmol), 4-methylmorpholine (0.070 mL, 0.63 mmol) and 2-(methylamino)ethanol (0.022 mL, 0.28 mmol) dissolved in NMP (1.5 mL). The resulting solution was stirred at room temperature for 16 h then purified by preparative HPLC. The fractions were evaporated to dryness and triturated in diethyl ether to afford a solid. This material was collected by filtration, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (77 mg, 71%) as a white solid.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(Cl)Cl.[C:15]1([CH3:34])[CH:20]=[CH:19][C:18]([S:21]([O:24][C:25]2[C@@H:26]([OH:33])[C@@H:27]3[O:32][CH2:31][C@H:29]([CH:30]=2)[O:28]3)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(OCC)C>[C:15]1([CH3:34])[CH:16]=[CH:17][C:18]([S:21]([O:24][C:25]2[C:26](=[O:33])[C@@H:27]3[O:32][CH2:31][C@H:29]([CH:30]=2)[O:28]3)(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC2=C[C@H]3CO[C@H](O3)[C@@H]2O)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2=C[C@H]3CO[C@H](O3)C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
360 mg of pyridinium chlorochromate was added to 20 ml of a dry methylene chloride solution containing 50 mg of 1,6-anhydro-3-O-p-toluenesulfonyl-4-deoxy-β-D-erythro-hex-3-enopyranose, and the mixture was stirred at room temperature for 48 hours. Disappearance of the starting material was confirmed by thin layer chromatography, and then 60 ml of diethyl ether was added thereto. The mixture was further stirred at room temperature for 15 minutes. Then, the reaction mixture was filtered by silica gel and washed with 200 ml of diethyl ether. The washing solution was concentrated under reduced pressure together with the filtrate. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane=1:2) to obtain 34 mg of the desired product (Intermediate No. 3) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:24](=[O:27])[CH:25]=[CH:26][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:10]=3.O>C(O)(=O)C.Br>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:24](=[O:27])[CH:25]=[CH:26][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=3
Reactant: CC(C)(C)OC(=O)COc1cc2c(=O)ccn3c4cc(Br)ccc4c(c1)c23
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)COc1cc2c(=O)ccn3c4cc(Br)ccc4c(c1)c23
Yield: 92.1 %

Procedure:
9-bromo-2-t-butoxycarbonylmethyloxy-4H-pyrido[3,2,1-jk]carbazole-4-one (120 mg) produced in Example 118 was dissolved in acetic acid (5 ml) and 48% HBr (5 ml), and the solution was stirred at room temperature for 12 hours. The reaction mixture was poured into water and the crystals precipitated were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (96 mg, 92%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30]([OH:32])=O)=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:72][C@@H:73]([C:75]1[O:76][CH:77]=[C:78]([CH2:80][OH:81])[N:79]=1)[CH3:74]>CN(C=O)C>[OH:81][CH2:80][C:78]1[N:79]=[C:75]([C@H:73]([NH:72][C:30]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[C:14]5[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=5)[N:17]([CH3:20])[N:16]=4)[N:22]=3)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[CH:28]=2)=[O:32])[CH3:74])[O:76][CH:77]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)c1nc(CO)co1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CO)co1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
In a round-bottomed flask, [2-((R)-1-amino-ethyl)-oxazol-4-yl]-methanol trifluoroacetate (crude from Step 5) was dissolved in DMF (1.5 ml) and N,N-diisopropylethylamine (0.70 ml, 4.0 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (140 mg, 0.32 mmol was added followed by HATU (133 mg, 0.35 mmol). The reaction was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-100% EtOAc) to afford 118 mg (66%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-amide as a light brown foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([Cl:11])[C:3]=1Br.O.CCOC(C)=O.C(Cl)Cl.[CH3:23][N:24](C=O)C>>[C:8]([C:5]1[C:4]([Cl:11])=[C:3]([C:23]#[N:24])[C:2]([NH2:1])=[CH:7][CH:6]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(Br)c1Cl
Reactant: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(N)c(C#N)c1Cl
Reaction time: 0.25 h

Procedure:
A mixture of 4'-amino-3'-bromo-2'-chloroacetophenone (17 g, 58 mmol) and cuprous cyanide (5.2 g, 58 mmol) is warmed in DMF (85 mL) to 80°-100° C. for 6 hours, then poured into H2O (1.5 L), stirred for 15 minutes and filtered. The brown solid was washed with H2O (200 mL) and then boiled in EtOAc (500 mL) and filtered. This extraction is repeated. The EtOAc filtrate is washed twice with 20% NH4Cl (500 ml), twice with H2O (500 mL), dried with Na2SO4, and evaporated to give a brown solid. After flash column chromatography (SiO2, EtOAc-CH2Cl2, 1:20), the product is isolated as a yellow solid; yld. 5.5 g (48%); m.p. 189°-193° C.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[C:19]=3[F:29])(O)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2C3C(=C(F)C=CC=3)C(O)(C3C(O)=CC4OCCOC=4C=3)C2=O)C=CC=CC=1>>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[C:19]=3[F:29])[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)cc2c(c1F)OCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C1(O)c1cc2c(cc1O)OCCO2
Product: O=C1C(c2c(O)cc3c(c2F)OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 82C and making non-critical variations using 1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (85%) as an off-white solid: MS (ES+) m/z 467.9 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([O:21][CH2:22][CH2:23]Cl)[CH3:20].O>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:20][CH2:19][O:21][CH2:22][CH3:23])[C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1c(-c2ccccc2)[nH]c2ccccc12
Reactant: CCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(-c2ccccc2)c(Br)c2ccccc21
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
Under ice-cooling, sodium hydride (60% in oil, 0.48 g, 12.0 mmol) was added to a solution of 3-bromo-2-phenyl-1H-indole (2.72 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) by small portions, and the mixture was stirred under a nitrogen atmosphere at the same temperature for 30 min. To the reaction mixture was added 2-chloroethyl ethyl ether (1.65 mL, 15.0 mmol), and the mixture was stirred at 70° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane) to give the title compound (2.60 g, yield 76%) as a red oil.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.B(F)(F)F.CCOCC.O>C1(C)C=CC=CC=1>[C:7]1([C:1]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:2][CH2:3][CH:4]=[CH2:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: C=CCCC(=O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCC=C(c1ccccc1)N1CCCC1
Yield: 78.9 %

Procedure:
In 50 ml of toluene, 1.60 g of 4-pentenophenone, 2.13 g of pyrrolidine and 0.14 g of boron trifluoride etherate were dissolved. The mixture was refluxed for 46 hours using a Cope water separator and molecular sieve 4A as the dehydrating agent. After having distilled out the solvent under a reduced pressure, the residue was subjected to a distillation under a reduced pressure to obtain 1.68 g of the desired enamine (yield: 79%).
Reaction SMILES: C(=O)([O-])[O-:2].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])=[CH:23][CH:22]=1>O.CN(C=O)C>[OH:2][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])=[CH:23][CH:22]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: O=C(Cc1ccc(CBr)cc1)OCC(Cl)(Cl)Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(CO)cc1)OCc1ccc(CC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of caesium carbonate (1.63 g, 5.00 mmol) in water (50 ml) was added 4-bromomethylphenylacetic acid (12) (1.15 g, 5.00 mmol), and the mixture was refluxed for one hour. After cooling, the reaction mixture was concentrated to dryness under reduced pressure. The residue obtained was suspended in DMF (10 ml). Thereto was added 2,2,2-trichloroethyl 4-bromomethylphenylacetate (13) (1.80 g, 5.00 mmol), and the resulting mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an oil which was purified by silica gel column chromatography (eluent; dichloromethane:ethyl acetate=15:1) to give 2,2,2-trichloroethyl 4-(4-hydroxymethylphenylacetoxymethyl)phenylacetate (14) as a white solid (994 mg, yield 45%).