Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]I.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:32][CH2:31][C:16]3([C:21]4=[CH:22][CH:23]=[CH:24][N:20]4[C:19]4[CH:25]=[CH:26][C:27]([CH2:29][OH:30])=[CH:28][C:18]=4[O:17]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:33][CH3:34])[CH3:4].[H-].[Na+]>CN(C=O)C>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([O:17][C:18]4[CH:28]=[C:27]([CH2:29][O:30][CH3:1])[CH:26]=[CH:25][C:19]=4[N:20]4[CH:24]=[CH:23][CH:22]=[C:21]34)[CH2:31][CH2:32]2)=[O:12])=[CH:7][C:6]=1[O:33][CH3:34])[CH3:4]
Reactant: CI
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2cccc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(COC)ccc2-n2cccc23)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
MeI (7.2 μL, 0.12 mmol) was added to a solution of (4-ethyl-3-methoxy-phenyl)-[7′-(hydroxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (50 mg, 0.12 mmol) and NaH (4.6 mg, 0.12 mmol) in DMF (1 mL) and was stirred at room temperature for 1 hour. The reaction was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O). Pure fractions were combined and evaporated to yield (4-ethyl-3-methoxyphenyl)(7-(methoxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 446.5, found 447.5 (M+1)+; Retention time: 2.11 minutes (3 min run).
Reaction SMILES: [H-].[Na+].O1C[CH2:6][CH2:5][CH2:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.ICCC>CN(C)C=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH2:4][CH2:5][CH3:6])=[CH:11][CH:10]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCOCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a mixture of sodium hydride (66%, 360 mg, 15 mmol) and tetrahydrofuran (10 mL) was added 2-(4-bromophenyl)ethanol (1.5 g, 7.5 mmol) on an ice bath, the solution was stirred at room temperature for 1 hour. 1-Iodopropane (1.5 mL, 15 mmol) and N,N-dimethylformamide (10 mL) were added to the reaction solution on an ice bath, and the solution was stirred overnight at 45° C. The reaction solution was partitioned with water (100 mL) and heptane (200 mL). The organic layer was separated, and washed with brine. this solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane:ethyl acetate=30:1), and the title compound (0.80 g, 3.3 mmol, 44%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=c1cc(CO)occ1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To the solution of kojic acid (28 g) in DMF (200 ml) was added potassium carbonate (32 g), and the mixture was stirred at room temperature for 30 minutes. After benzyl chloride (25 g) was added, the mixture was further stirred for 60 minutes. The solvent was evaporated. The residue was then extracted with ethyl acetate, washed with water and dried. After the solvent was evaporated, the residue was crystallized from ethyl acetate to give 5-benzyloxy-2-hydroxymethyl-4-oxo-4H-pyran (34.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-fluoro-biphenyl-4-ol and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a white solid (150 mg, 73%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[C:12](=O)[NH:11][C:10]3=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][C:10]3=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC(=O)C2(c3ccc(Cl)c(Cl)c3)CC12
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1NCC2CC12c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione and toluene were combined in a 500 mL round-bottomed flask and stirred under Ar (g) for 10 min while cooling in an ice bath. Red-Al® was added via addition funnel drop-wise over several minutes. Upon complete addition, the ice bath was removed and the reaction stirred at ambient temperature overnight. The reaction mixture was cooled in an ice bath and 150 mL of 5N NaOH was carefully added. The phases were separated and the aqueous phase was extracted with toluene (2×100 mL), DCM (3×100 mL), and the organic layers combined. The organic layer was washed with brine (200 mL) and dried over sodium sulfate for 8 h. The mixture was filtered, concentrated in vacuo, and dried to afford 5 g of a dark brown semi-solid. The semi-solid was purified on a silica gel column eluting with 20% EtOAc in hexanes increasing the polarity to 30% EtOAc and finally 50% EtOAc. The desired fractions containing the product were combined, concentrated, and dried to afford a light yellow solid. Yield: 2.0 g 30%; LCMS (+) ESI: m/z=242 [M]+; m/z=264 [M+Na]+; 1H NMR (300 MHz, CDCl3) δ□ 7.52 (d, 1H, ArH), 7.39 (d, 1H, ArH), 7.28 (dd, 1H, ArH), 6.02 (bs, 1H, NH), 3.64 (dd, 1H, NHCH2), 3.40 (d, 1H, NHCH2), 2.28 (m, 1H, NHCH2CH), 1.50 (dd, 1H, ArCCH2), 1.26 (m, 1H, ArCCH2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:14]2)=[CH:10][CH:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:14]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccco3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccco3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-furylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (624 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 3 hours, and 1N hydrochloric acid (3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and 3-[1-[4-(2-furylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (386 mg, yield: 66%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[CH3:52][C:53](OC(C)=O)=[O:54]>C(Cl)Cl>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[O:44][C:53]([CH3:52])=[O:54])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To erythromycin A (2.674 mmol) dissolved in 100 mL of CH2Cl2 at ambient temperature and then cooled to 0° C. was added 1.1 equivalents of Ac2O (0.28 mL). The reaction mixture was allowed to warm to ambient temperature, stirred for 3 hours and extracted with CH2Cl2. The combined organic extracts were washed once with 8% sodium bicarbonate solution, tarice with water and once with brine, dried over Na2SO4 and concentrated in vacuo to afford the crude product as a white powder. Recrystallization from acetonitrile afforded the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]([Br:23])=[C:20]([Br:22])[CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]([Br:23])=[C:20]([Br:22])[CH:21]=2)=[O:16])[CH2:9]1)=[O:33]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1cc(Br)c(Br)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc(Br)c(Br)[nH]1

Procedure:
60.3 Using general method H, 4,5-dibromo-1H-pyrrole-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give 4,5-dibromo-1H-pyrrole-2-carboxylic acid {(R)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidin-3-ylmethyl}-amide. White solid. MS 582.1 ([M+H]+)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18]>>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CCc2ccccc2)CC1

Procedure:
1-(2-Phenylethyl)-4-piperidone oxime is prepared from 1-(2-phenylethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24]>CN1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CI
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 65.3 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 153 mg, 0.5 mmol) and iodomethane (0.16 mL, 2.55 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube overnight. The reaction mixture was purified by preparative HPLC to give a brown semi-solid which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, and evaporated to give (4R,7S)-2-(2,4-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (104 mg, 65%) as an off-white solid. ES(+)-MS (M+H) 319.
Reaction SMILES: OC(C(F)(F)F)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][C@H:41]([CH3:45])[CH2:42][O:43][CH3:44])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[NH:40][C@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH2:30][CH2:29]1
Reactant: COC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (161.4 mg, 0.253 mmol) in THF (2.53 mL) was treated with Pd(OH)2 (20 wt %, 53.3 mg, 0.076 mmol). Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The vent needle was removed and the reaction mixture was allowed to stir under hydrogen atmosphere at room temperature for 2 h. The reaction mixture was opened to air and filtered through a pad of Celite™, eluting with MeOH and EtOAc. The filtrate was collected and concentrated under reduced pressure to give (R)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(1-methoxypropan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine, as a TFA salt, as a yellow oil, which was carried forward without additional purification. ESI-MS m/z [M+H]+ 434.5.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([NH:18][C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[N:28]=[C:27]([C:37]4[O:38][C:39]([CH:42]=[O:43])=[CH:40][CH:41]=4)[N:26]=3)[CH:22]=[CH:23][CH:24]=2)=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([NH:18][C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[C:29]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[N:28]=[C:27]([C:37]4[O:38][C:39]([CH2:42][OH:43])=[CH:40][CH:41]=4)[N:26]=3)[CH:22]=[CH:23][CH:24]=2)=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2cccc(-c3cc(N4CCOCC4)nc(-c4ccc(C=O)o4)n3)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2cccc(-c3cc(N4CCOCC4)nc(-c4ccc(CO)o4)n3)c2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (0.076 g) was added portionwise to a mixture of 4-[3-(1-tert-butoxycarbonylpiperidin-3-ylcarbonylamino)phenyl]-2-(5-formylfuran-2-yl)-6-morpholinopyrimidine (0.112 g) and ethanol (5 ml) and the reaction mixture was stirred at ambient temperature for 3 hours. The mixture was evaporated to give 4-[3-(1-tert-butoxycarbonylpiperidin-3-ylcarbonylamino)phenyl]-2-(5-hydroxymethylfuran-2-yl)-6-morpholinopyrimidine which was used without further purification. A mixture of the material so obtained, trifluoroacetic acid (1.5 ml) and methylene chloride (2.5 ml) was stirred at ambient temperature for 1 hour and then heated to 40° C. for 10 minutes. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The aqueous layer was separated, basified by the addition of aqueous ammonium hydroxide (d=0.88) and extracted with methylene chloride. The organic extracts were combined, dried over magnesium sulphate and evaporated. The residue was purified by HPLC using a Waters ‘Xterra’ preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d=0.88)] and acetonitrile as eluent. There was thus obtained the title compound as a solid (4.4 mg); NMR Spectrum: (CD3OD) 1.47-1.58 (m, 1H), 1.64-1.75 (m, 2H), 1.91-1.97 (m, 1H), 2.5-2.65 (m, 2H), 2.82 (m, 1H), 2.9-2.94 (m, 1H), 3.07 (m, 1H), 3.17-3.28 (m, 8H), 4.53 (s, 2H), 6.38 (d, 1H), 6.85 (s, 1H), 7.15 (d, 1H), 7.34 (t, 1H), 7.6 (d, 1H), 7.69 (d, 1H), 8.16 (s, 1H); Mass Spectrum: M+H+ 464.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([N:20]2[CH2:23][CH:22]([O:24][C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][N:26]=3)[CH2:21]2)=[O:19])[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([N:20]2[CH2:21][CH:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[CH:27][N:26]=3)[CH2:23]2)=[O:19])[N:12]=1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Temperature: 100 °C
Yield: 53.2 %

Procedure:
A solution of 4-fluorophenyl boronic acid (0.254 mg, 1.81 mmol) in THF/H2O (10:1; 10 mL) was added to a microwave vial containing 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (Example 7, Step 1) (0.480 g, 1.21 mmol) and potassium carbonate (0.50 g, 3.63 mmol). Nitrogen gas was bubbled through the mixture for 5 mins then 1,1-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2(0.099 g, 10 mole %) was added and the vial sealed and heated at 100° C. in microwave synthesiser for 30 min. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with saturated aqueous sodium carbonate solution (20 mL) then saturated sodium chloride solution (20 mL). The mixture was dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo to afford a brown gum, which was purified by flash chromatography, eluting with a gradient of 50% to 100% ethyl acetate in hexane to a afford a white solid (0.235 g, 53%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[C:43]([CH3:59])=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][OH:58])[CH2:52][CH2:51]2)=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[C:43]([CH3:59])=[C:44]([C:48]([N:50]6[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][OH:58])[CH2:52][CH2:51]6)=[O:49])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1c(Br)cccc1C(=O)N1CCN(CCO)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCN(CCO)CC4)c3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (3-bromo-2-methyl-phenyl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (188 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-phenyl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-159) as a pale yellow powder (23 mg, 23%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[O:29]=[C:27]1[N:14]2[CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]3[C:15]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:28]1
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Nc1cccc2c1NC1CCN(C(=O)OCC)CC21
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)CN3C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
To a solution of ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (2.2 g, 6.6 mmol) in DMF (20 mL) at 0° C. was added NaH (660 mg, 16.5 mmol), DMAP (878 mg, 7.2 mmol), acetyl chloride (0.6 mL, 7.2 mmol) and stirred at rt for 16 hours. The solution was diluted with water (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (1.1 g, 57%) as a clear oil. MS [M+H]+374. 1H NMR (CDCl3, 300 MHz): δ 6.75 (t, 1H, J=7.7 Hz), 6.59 (m, 1H), 6.45 (m, 1H), 4.05 (m, 1H), 3.60-4.00 (m, 7H), 3.40 (m, 1H), 3.00 (m, 3H), 1.92 (m, 2H), 0.91 (m, 1H), 0.85 (m, 6H) ppm.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][CH:49]=1.[F:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH2:61].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH:61][C:48]1[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][CH:49]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: NCc1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ccc(NCc2cccc(F)c2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
In a flame-dried Schlenk tube, Pd(OAc)2 (304 mg, 1.3 mmol), Binap (1.69 g, 2.7 mmol), and 4-bromobenzonitrile (5.00 g, 27.1 mmol) were added under Ar to a stirring solution of 3-fluorobenzylamine (3.80 g, 30.4 mmol) and Cs2CO3 (13.20 g, 40.6 mmol) in dioxane (55 mL). The mixture was stirred at 80° C. (16 h) and then the volatiles were evaporated. CH2Cl2 (100 mL) and H2O (100 mL) were added and the layers separated. The aqueous layer was washed with CH2Cl2 (2×100 mL). The organic layers were combined, dried and concentrated under vacuum. The crude residue was purified by column chromatography (SiO2; EtOAc/hexanes 0/10 to 3/7) to obtain 4.90 g (78%) of a yellow solid: Rf=0.36 (1/9 EtOAc/hexanes); mp 63-64° C.; IR (nujol mull) 2934, 2861, 2214, 1739, 1605, 1527, 1457, 1375, 1285, 1248, 1164, 915, 824, 784, 730 cm−1; 1H NMR (CDCl3) δ 4.39 (s, CH2N), 4.59-4.74 (br m, NH), 6.57 (d, J=8.8 Hz, 2H3), 6.94-7.05 (m, 2 ArH), 7.11 (d, J=7.5 Hz, H6′), 7.28-7.36 (m, 1 ArH), 7.42 (d, J=8.8 Hz, 2H2); 13C NMR (CDCl3) δ 46.8 (d, J=1.7 Hz, NCH2), 99.9 (CN), 112.4 (ArC), 113.9 (d, J=22.2 Hz, C4′ or C2′), 114.4 (d, J=21.1 Hz, C2′ or C4′), 120.3 (ArC), 122.5 (d, J=2.9 Hz, C6′), 130.3 (d, J=8.6 Hz, C5′), 133.7 (ArC), 140.6 (d, J=6.8 Hz, C1′), 150.9 (ArC), 163.1 (d, J=245.3 Hz, C3′); HRMS (M+H+) (ESI+) 227.0985 [M+H+] (calcd for C14H11FN2H+ 227.0984).