Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=[C:9]3[NH:17][CH:18]=[CH:19][C:8]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:29]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=[C:9]3[NH:17][CH:18]=[CH:19][C:8]=23)[CH2:6][CH2:5]1)=[O:30])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: COC(=O)c1cnc2[nH]ccc2c1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cnc2[nH]ccc2c1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
Methyl 4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.23 g, 0.69 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.227 g, 0.759 mmol) were placed in DCM (5 mL) at room temperature. HOBT-H2O (0.147 g, 0.966 mmol), EDCI (0.172 g, 0.897 mmol) and triethylamine (0.48 mL, 3.45 mmol) were then added, and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with saturated Na2CO3 and extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give a crude residue. The residue was purified by column chromatography (500:7 DCM:MeOH) to give (R)-methyl 4-(4-(2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.11 g, 29.4% yield).
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[O-:15][C:16]#[N:17].[K+]>O1CCCC1>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[N:17]=[C:16]=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#C[O-]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1N=C=O
Reaction time: 15 h
Yield: 83 %

Procedure:
In an argon atmosphere, 8.33 g (35.8 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 30 mL of tetrahydrofuran and after adding 3.19 g (purity: 96%, 37.8 mmol) of potassium cyanate, the mixture was stirred for 15 hours under heating and refluxing. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 85° C./3.3×102 Pa) to obtain 1,3-di-tert-butyl-2-isocyanato-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NCO) as a colorless liquid (yielded amount: 7.07 g, yield: 83%). The thus-obtained Si(tBuNCHCHNtBu)(H)NCO was measured for the 1H and 13C NMR spectra, as a result, these spectra agreed with spectra of that obtained in Example-29.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.ClCCl.[CH3:12][N:13](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C#N)nc1
Yield: 56 %

Procedure:
A mixture of 2-bromo-5-methylpyridine (2.001 g, 11.63 mmol), zinc cyanide (830 mg, 7 mmol), zinc (dust, 35 mg, 0.53 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (192.5 mg, 0.24 mmol) in N,N-dimethylformamide (10 mL) was heated at reflux for 16 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. The organic solution was filtered through a plug of silica gel, washing dichloromethane. Removal of the solvent in vacuo, afforded 770 mg (56%) of 5-methyl-2-cyano-pyridine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](S(C2C=CC(C)=CC=2)(=O)=O)(SC)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][C:6]=1[N+:32]([O-:34])=[O:33])([CH3:4])([CH3:3])[CH3:2].Cl.C[OH:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:37])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][C:6]=1[N+:32]([O-:34])=[O:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CSC(Cc1ccc(C(C)(C)C)c([N+](=O)[O-])c1)(CC1CCCCC1)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(CC(=O)CC2CCCCC2)cc1[N+](=O)[O-]
Yield: 73 %

Procedure:
The whole of the 2-t-butyl-5-[3-cyclohexyl-2-(4-methylphenyl)sulfonyl-2-methylthiopropyl]-1-nitrobenzene prepared as described in step (i) above was dissolved in 50 ml of methanol. 5 ml of concentrated aqueous hydrochloric acid were added, and the resulting solution was heated for 2 hours under reflux. At the end of this time, the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in diethyl ether, and the solution was washed with water, with a saturated aqueous solution of sodium hydrogen carbonate, with water and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 150 g of silica gel. Elution with a 1:5 by volume mixture of ethyl acetate and hexane afforded 1.20 g (yield 73%) of the title compound as an oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]3C=CC=C[C:21]3=2)[CH:16]=[C:15]1[CH3:27])[CH3:13]>>[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:7]([C:3]2[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][N:4]=2)=[O:8])=[C:15]1[CH3:27])[CH3:13]
Reactant: O=C1OC(=O)c2nccnc21
Reactant: CCn1c(C)cc2ccc3ccccc3c21
Product: CCn1c(C)c(C(=O)c2nccnc2C(=O)O)c2ccccc21
Yield: 16.2 %

Procedure:
The appropriate keto-acid is prepared as follows. A mixture of about 6 grams of 2,3-pyrazinedicarboxylic anhydride and about 10.5 grams of 1-ethyl-2-methyl-1H-benz[g]indole is heated on a steam bath for about 24 hours. The mixture is extracted with toluene. About 2 grams of (1-ethyl-2-methylindol-3-yl)-(2-carboxypyrazin-3-yl)ketone is obtained having a melting point of 212°-213° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24]Cl.O>CN(C)C=O>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]([F:13])([F:14])[F:15]
Reactant: CC(=O)c1ccc(O)c(OC(F)(F)F)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C(C)=O)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-hydroxy-3-trifluoromethoxyphenyl)ethanone (1.55 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.46 g) and chloromethyl methyl ether (0.64 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.54 g) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH:12]C(OCC2C=CC=CC=2)=O)=[O:10])[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>CO.C1COCC1.[C].[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: COc1nc(C(=O)NNC(=O)OCc2ccccc2)ccc1-n1cnc(C)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.2 %

Procedure:
Under a nitrogen atmosphere, to a mixture of benzyl 2-{[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]carbonyl}hydrazinecarboxylate (14.6 g) in methanol (150 mL) and THF (100 mL) was added 5% palladium-carbon (1.5 g) at room temperature, and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere. Under a nitrogen atmosphere, the catalyst was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. To a mixture of the residue in ethanol (200 mL) and THF (400 ml) was added 5% palladium-carbon (1.5 g) at room temperature, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. Under a nitrogen atmosphere, the catalyst was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The residue was collected by filtration, washed with ethyl acetate and dried to give the title compound (3.9 g). The solvent in the mother liquor was evaporated under reduced pressure, and the residue was collected by filtration, washed with ethyl acetate and dried to give the title compound (2.6 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][NH:38][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: COCCN
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 61.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with commercially available 2-methoxyethylamine (0.138 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.200 g, 62%) as a white solid. MS (ISP) 528.2 [(M+H)+]; mp 126° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[C:18]=[CH:17][CH2:16][NH2:19])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: C=CCN
Solvent: CCO
Product: COc1cc(C=C=CCN)c([N+](=O)[O-])cc1OC
Yield: 99.9 %

Procedure:
A suspension of 6-nitroveratraldehyde (84 g, 0.4 mole) and ethanol (1200 ml) was refluxed with a solution of allylamine (21 g, 0.44 mole) and ethanol (100 ml) for 1.5 hrs. The resulting dark solution was concentrated to dryness in vacuo leaving 100 g of a dark oil which solidified.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:60])([C:56]([F:59])([F:58])[F:57])[CH2:46][CH2:47][CH2:48][S:49][CH2:50][C@@H:51]1[CH2:55][CH2:54][CH2:53][NH:52]1>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:52]3[CH2:53][CH2:54][CH2:55][C@H:51]3[CH2:50][S:49][CH2:48][CH2:47][CH2:46][C:45]([F:44])([F:60])[C:56]([F:57])([F:58])[F:59])[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC[C@@H]2Cc3cc(OCc4ccccc4)ccc3[C@H]3CC[C@]4(C)C(=O)CC[C@H]4[C@H]23)cc1
Reactant: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Yield: 72.5 %

Procedure:
Under the conditions of Example 23h, 4.58 g of 3-benzyloxy-7α-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17-one is reacted with 3.17 g of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine, worked up, and the crude product is chromatographed on silica gel with hexane/ethyl acetate. 3.9 g of 3-benzyloxy-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentyl-thiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained as oil. [α]D22=+32.5° (c=0.117 in chloroform).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])=[O:7])(C)(C)C.[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:30]=[CH:29][C:25](C(O)=O)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>CN(C=O)C>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][O:16][CH2:21][CH2:20]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.4 %

Procedure:
A solution of 1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17; 104 mg, 0.5 mmol) in DMF (1.6 ml) was added to 4-morpholinobenzoic acid (149 mg, 0.5 mmol) followed by 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (Method 18, 138 mg, 0.5 mmol) and the reaction mixture stirred at ambient temperature for 48 hours. The solvent was removed in vacuo and the resultant residue partitioned between ethyl acetate and water. The organic phase was separated, then washed with water, brine and dried over sodium sulfate then filtered. The organic extracts were concentrated by half and a 4M solution of hydrogen chloride in 1,4-dioxane (1 ml) added. The reaction mixture was stirred at ambient temperature for a further 64 hours and the resultant precipitate was collected by filtration. This solid was purified by preparative mass triggered HPLC, eluting with an increasing gradient of acetonitrile in water (which contains 5% (v/v) of a 1% (v/v) solution of formic acid in methanol) to afford the title compound (17 mg, 12%); NMR Spectrum: (DMSO-d6) 3.25 (m, 4H), 3.76 (m, 4H), 4.83 (s, 2H), 6.60 (m, 1H), 6.79 (dd, 1H), 6.96 (m, 1H), 7.01 (d, 2H), 7.16 (dd, 1H), 7.90 (d, 2H), 9.31 (brs, 1H); Mass Spectrum: M+H+ 298.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Cl[CH2:7][C:8](=O)[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([F:23])[CH:12]=1)[CH3:10]>O>[F:23][C:13]1[CH:12]=[C:11]([CH:9]([C:8]2[N:5]=[C:3]([NH:2][CH3:1])[S:4][CH:7]=2)[CH3:10])[CH:16]=[CH:15][C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C(=O)CCl)c1ccc(-c2ccccc2)c(F)c1
Reactant: CNC(N)=S
Solvent: O
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Yield: 70.6 %

Procedure:
To N-methylthiourea (5.55 g, 61.6 mmol) in water was heated with 1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (16.50 g, 59.6 mmol) at 90° C. for 3 hr. Treatment in same manner of Example 1 to give 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (13.15 g, 71% yield): mp 129°-129.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][C:18](OCC)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: FB(F)F
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a stirred solution of (R)-ethyl 3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate (574 g) in tetrahydrofuran (5.7 L) at about -78° C. was added boron trifluoride etherate (295.4 g) and then diisobutylaluminum hydride (1.5M in toluene, 3.91 L, 3.1 eq) added (over two hours) maintaining the temperature below -62° C. The resulting solution was stirred (between -78° and -62° C.) for three hours and then quenched into aqueous citric acid solution (2 kg citric acid in 5 L water plus 4 L ice) over about 40 minutes. The phases were separated and the aqueous phase extracted with ethyl acetate (2×2.1 L). The combined organic solution was dried (over magnesium sulphate) and evaporated, then the residual oil purified by chromatography through silica gel, eluting with mixed ethyl acetate/hexane (9:1 to 4:1) to give the title compound as an oil (260 g), as produced in Example 12A (as an alternative, the residual oil can be purified by chromatography through silica gel eluting with ethyl acetate:hexane (1:1)).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]#[N:9].[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>C(O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([OH:16])[CH2:18]1)=[NH:9]
Reactant: OC1CCCNC1
Reactant: N#CNc1ccccc1-c1ccccc1
Solvent: CCO
Product: N=C(Nc1ccccc1-c1ccccc1)N1CCCC(O)C1

Procedure:
A mixture of 2-biphenylylcyanamide (4 g), 3-hydroxypiperidine (2.5 g) and ethanol (30 ml) was heated at 90°-95° C. for 8 hours to give a brown solid which was purified by chromatography on an aluminia column eluted successively with hexane, 1:4, 2:3, 3:2 and 4:1 mixtures of dichloromethane and hexane and then a 99:1 mixture of dichloromethane and methanol to yield a solid which was recrystallised from ethyl acetate to give N-(2-biphenylyl)-3-hydroxypiperidine-1-carboxamidine (m.p. 144°-145° C.).
Reaction SMILES: [CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=[O:12])[C:6]([O:8][CH3:9])=O)([CH3:4])[CH3:3].[NH2:14][OH:15].Cl>N1C=CC=CC=1>[CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=[O:12])[C:6](=[N:14][OH:15])[O:8][CH3:9])([CH3:4])[CH3:3]
Reactant: COC(=O)C(C)(CC=O)C(C)(C)C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COC(=NO)C(C)(CC=O)C(C)(C)C
Temperature: 0 °C
Yield: 103.9 %

Procedure:
A solution of the aldehyde, methyl 2-(1,1-dimethylethyl)-2-methyl-4-oxobutanoate (2.05 g, 11 mmol) and H2NOH.HCl (1.15 g, 16.5 mmol) in dry pyridine (10 mL) was stirred at 60° C. for 4 h in a nitrogen atmosphere. After cooling the reaction mixture was poured into ice cold HCl (3N, 50 mL), and extracted with ether (3×40 mL). The combined ether extract was washed sequentially with 40 mL portions of saturated NaHCO3, water, and brine, and dried over MgSO4. The solvent was removed in vacuo to give 2.30 g of pale brown colored viscous liquid. Flash chromatography over silica gel (hexanes-EtOAc, 4:1) followed by bulb-to-bulb distillation (pot temp. 100°-105° C. (0.4 mmHg)) afforded the anti- and syn- oxime mixture (2.03 g, 92%) in the ratio of 58/42 as a colorless viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]([OH:39])=O)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:40][N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN.CO>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]([NH:41][CH3:40])=[O:39])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)O)nc(-c4cncc(Cl)c4)c32)CC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc2nc(N3CCOC[C@H]3c3ccccc3)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Reaction time: 2 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Example 3.22, prepared from Example 2.1, Step 4 using a procedure similar to that described for Example 1.1, Step 5; 50 mg, 0.09 mmol) in DMF (2.0 mL) were added HATU (15 mg, 0.11 mmol), DIPEA (0.03 mL, 0.18 mmol), and 2.0 M methylamine in MeOH (0.09 mL, 0.18 mmol) at room temperature. After being stirred for 2 hours, the reaction mixture was diluted with H2O (10 mL), the aqueous layer was extracted with EtOAc and then the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column (0 to 10% MeOH/CH2Cl2) afforded 4-(5-chloropyridin-3-yl)-N-methyl-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxamide. 1H NMR (300 MHz, CD3OD) δ 8.71 (d, J=2.1 Hz, 1H), 8.66 (s, 1H), 8.17-8.19 (m, 2H) 7.40-7.42 (m, 2H), 7.24-7.26 (m, 3H), 4.66-4.69 (m, 1H), 3.98-4.06 (m, 4H), 3.66-3.75 (m, 2H), 3.41-3.50 (m, 2H), 3.48 (s, 3H), 1.28-1.43 (m, 2H), 1.10-1.19 (m, 1H), 0.82-0.99 (m, 2H), 0.74 (d, J=6.3 Hz, 3H) 0.61-0.65 (m, 3H), 0.41-0.45 (m, 2H). MS APCl calc'd. for C31H35ClN6O2 [M+H]+ 559. found 559.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21]([Cu])#[N:22]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([C:21]#[N:22])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3cc(OC)cc(C#N)c3o2)cc1
Temperature: 150 °C
Yield: 50.7 %

Procedure:
To 7-bromo-5-methoxy-2-(4-methoxy-phenyl)-benzooxazole (200 mg) in DMF (5 mL) was added CuCN (80 mg). The mixture was placed in an oil bath and heated to 150° C. for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate and washed with 1N HCl, brine (3×), dried (Na2SO4), and concentrated. Flash chromatography on silica gel eluting with 20% ethyl acetate-hexane afforded 85 mg (50%) of the title compound as a solid. MS: 281 (MH+), HPLC tR: 2.71 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:24]=2[C:25]([NH:27][CH2:28][C:29]#[CH:30])=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:18]([CH3:19])[C:17](=[O:20])[O:16][CH2:15][CH2:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1>C(#N)C.[Au](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:22][C:23]2[C:24]([C:25]3[O:26][C:29](=[CH2:30])[CH2:28][N:27]=3)=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:18]([CH3:19])[C:17](=[O:20])[O:16][CH2:15][CH2:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: C=C1CN=C(c2cccc(F)c2Nc2nc(Nc3ccc4c(c3)CCOC(=O)N4C)ncc2Cl)O1
Reaction time: 16 h
Yield: 74.1 %

Procedure:
A suspension of 2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide (108 mg) and gold (III) chloride (20 mg) in acetonitrile (20 mL) was stirred for 16 hours and filtered. The filtrate was concentrated and purified by silica gel chromatography to provide 2-{5-chloro-4-[2-fluoro-6-(5-methylene-4,5-dihydro-oxazol-2-yl)-phenylamino]-pyrimidin-2-ylamino}-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (80 mg): 1H NMR (300 MHz, CDCl3) δ 10.10 (bs, 1H), 8.20 (s, 1H), 7.84 (dd, 1H), 7.46-7.34 (m, 4H), 7.14 (bs, 1H), 7.06 (d, 1H), 4.96 (dd, 1H), 4.82 (t, 1H), 4.56-4.50 (m, 2H), 3.45 (s, 3H), 2.92 (t, 1H).