Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([C:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[S:13][C:14]=2[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1>C(O)C.[Pt](=O)=O>[F:1][C:2]1[C:3]([CH:8]([C:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[S:13][C:14]=2[CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(c1ncccc1F)c1c(CCN(C)C)sc2ccccc12
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(c1ncccc1F)c1c(CCN(C)C)sc2ccccc12
Reaction time: 4 h

Procedure:
To a solution of (2-{3-[1-(3-fluoro-pyridin-2-yl)-vinyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 18-2) (26 mg, 0.080 mmol) in ethanol (1 mL), platinum dioxide (9 mg, 0.04 mol) was added. The reaction was shaken at 30 psi for 4 hours under H2 atmosphere and monitored by LC/MS. The reaction was filtered and washed with EtOH and subsequently purified by mass triggered preparative HPLC to afford (2-{3-[1-(3-fluoro-pyridin-2-yl)-ethyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 18-3). MH+=329. tR=4.7 min (Method 2).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[N:2]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1>>[Cl:19][C:18]1[C:13]([O:11][C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[N:14][CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: Oc1cc2ccccc2cn1
Product: O=[N+]([O-])c1cnc(Oc2cc3ccccc3cn2)c(Cl)c1

Procedure:
Isoquinolin-3-ol was reacted with 2,3-dichloro-5-nitro pyridine to obtain 3-(3-chloro-5-nitropyridin-2-yloxy)isoquinoline which was further converted to 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine as per the procedure described in preparation 1, step iii and iv.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([N:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C(OC(C)(C)C)=O)[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]=1[Cl:10])=[O:4]>ClCCl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1c(Cl)c(Cl)c(Cl)n1N(Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(Cl)c(Cl)c(Cl)n1NCc1ccccc1
Yield: 100.9 %

Procedure:
1-(Benzyl-tert-butoxycarbonyl-amino)-3,4,5-trichloro-1H-pyrrole-2-carboxylic acid methyl ester (509 mg, 1.17 mmol) was stirred in a mixture of dichloromethane (5 mL) and TFA (5 mL) at rt for 30 m in; then concentrated, the residue was dissolved in EtOAc, washed with diluted sodium bicarbonate, and saturated NaCl solution, dried over sodium sulfate, filtered, concentrated to give the crude product (394 mg) as white solid. ESI (m/z): 334 (M+H)+.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Cl:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: Nc1ncc(Cl)cc1I
Reactant: C#CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC#Cc1cc(Cl)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Propyne (35 g, 0.87 mol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (100 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-chloro-3-iodo-pyridin-2-ylamine (81.4 g, 0.32 mol), bis(triphenylphosphine)dichloropalladium(0) (4.49 g, 6.4 mmol), copper (I) iodide (1.46 g, 7.67 mmol) and triethylamine (97.3 g, 134 mL, 0.98 mol) in THF (900 mL). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a brown solid (53.8 g, quantitative yield). LCMS (Method B): RT=3.55 min, M+H+=167/169. 1H NMR (300 MHz, CDCl3): 7.92 (d, J=2.5 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 5.00 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])[C:6]([CH3:22])=[CH:5][C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)#[CH:2].[N:33]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[N+:34]=[N-:35].[Na].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O>CN(C=O)C.O.[Cu]I>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:33]2[CH:2]=[C:1]([C:3]3[N:8]=[C:7]([C:9]([N:11]4[CH2:16][CH2:15][CH:14]([N:17]5[CH2:21][CH2:20][CH2:19][CH2:18]5)[CH2:13][CH2:12]4)=[O:10])[C:6]([CH3:22])=[CH:5][C:4]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)[N:35]=[N:34]2)=[CH:42][CH:41]=1
Reactant: C#Cc1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3nc(C(=O)N4CCC(N5CCCC5)CC4)c(C)cc3-c3cccc(C(F)(F)F)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of 0.30 g (0.68 mmol) of [6-ethynyl-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 24) and 0.116 g (0.71 mmol) of 1-azidomethyl-4-methoxy-benzene in 3.0 ml of DMF was treated with 0.013 g (0.066 mmol) of (+)-sodium-L-ascorbate and 0.129 g (0.68 mmol) of copper(I) iodide in 1.0 ml of H2O and the reaction was stirred at RT for 2 hours. Then, the solvents were removed by evaporation in high vacuum, the residue was diluted with H2O/NH4OH (25%) and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.363 g (88%) of the title compound as light brown oil. MS: 605.4 (MH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([O:7][C:8]2[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([C:16]3([NH:19][C:20]([C:22]4[CH:23]=[N:24][C:25](S(C)(=O)=O)=[N:26][CH:27]=4)=[O:21])[CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[C:5]([C:36]([F:39])([F:38])[F:37])[CH:4]=1.[C-:40]#[N:41].[K+].N>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([O:7][C:8]2[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([C:16]3([NH:19][C:20]([C:22]4[CH:23]=[N:24][C:25]([C:40]#[N:41])=[N:26][CH:27]=4)=[O:21])[CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[C:5]([C:36]([F:39])([F:38])[F:37])[CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(S(C)(=O)=O)nc4)CC3)cc2)c(C(F)(F)F)c1
Agent: N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(C#N)nc4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 51 %

Procedure:
A solution of 50 mg (0.089 mmol) of 2-methanesulphonyl-pyrimidine-5-carboxylic acid{1-[4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylcarbamoyl]-cyclopropyl}-amide (product from Example 149) in 2 mL DMF was combined with 9 mg (0.13 mmol) of potassium cyanide and then heated to 100° C. for 10 minutes in a microwave apparatus. The mixture was then combined with 2 mL concentrated ammonia solution and extracted with dichloromethane. The crude product obtained after evaporation was purified by chromatography (reversed phase HPLC).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>C1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH2:12][Br:38])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(Br)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1cccc(Br)c1CBr
Yield: 100 %

Procedure:
A suspension of methyl 3-bromo-2-methylbenzoate (26.6 mmol), benzoyl peroxide (2.7 mmol) and NBS (32 mmol) in benzene (80 mL) was allowed to stir at reflux for 5 hr. The reaction mixture was filtered and the solid was washed with diethyl ether. The organic solutions were combined and washed with 10% Na2S2O3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give methyl 3-bromo-2-(bromomethyl)benzoate (26.6 mmol, 100%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].I[CH:28]([CH3:30])[CH3:29]>CC(C)=O>[CH3:14][C:7]1([CH3:13])[C:6]2[C:11](=[C:2]([O:1][CH:28]([CH3:30])[CH3:29])[CH:3]=[C:4]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: CC(C)I
Reactant: CC1(C)CCC(=O)c2c(O)cc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(C#C[Si](C)(C)C)cc2c1C(=O)CCC2(C)C
Temperature: 25 °C

Procedure:
A solution of 8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 66, 0.32 g, 1.12 mmol) in acetone (20 mL) was treated with potassium carbonate (0.773 g, 5.6 mmol) and 2-iodopropane (2 g, 11.76 mmol) and the resulting reaction mixture was refluxed for 3 days. It was cooled to ambient temperature, the solids were filtered off and the filtrate was evaporated in vacuo to an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 2-6% ethyl acetate in hexane as the eluent to afford the title product as (0.055 g, 15%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]([O:19][C:20](=[O:36])[NH:21][C@H:22]([C@@H:30]1[CH2:34][CH2:33][C:32](=[O:35])[O:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:18])([CH3:17])[CH3:16].Br[CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41]>C(=O)=O.CC(C)=O.O1CCCC1>[C:15]([O:19][C:20](=[O:36])[NH:21][C@H:22]([C@@H:30]1[CH2:34][C@@H:33]([CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])[C:32](=[O:35])[O:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)=CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a flame dried round bottom flask under a nitrogen atmosphere was added tetrahydrofuran (40 mL) followed by 1,1,1,3,3,3-hexamethyldisilazane (8 mL, 37.8 mmol). The mixture was cooled to 0° C. and n-butyl lithium (14.5 mL of a 2.5 M solution in hexanes, 36.0 mmol) was added. The mixture was stirred for 15 minutes, then cooled to −78° C. in dry ice/acetone bath. {1(S)-[5-Oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (5 g, 16.4 mmol) (prepared by the method of Fray, J. Org. Chem., (51) 4828 (1986)) dissolved in tetrahydrofuran (50 mL) was added dropwise via syringe and stirring continued for 30 minutes. A solution of 4-bromo-2-methyl-2-butene (2.07 mL, 18.0 mmol) in 40 mL of THF was added dropwise via syringe. Stirring was continued for 3 hours during which time the temperature rose to −60° C. The mixture was quenched by slow addition of saturated, aqueous ammonium chloride (25 mL). Upon warming to room temperature, the solution was diluted with ether (300 mL) and transferred to a separatory funnel. The organic phase was washed with saturated aqueous citric acid (2×100 mL), saturated aqueous sodium bicarbonate (NaHCO3)(2×100 mL), and 100 mL brine. The organic layer was dried over magnesium sulfate (MgSO4) and the solvent removed under reduced pressure. Thin layer chromatography in 1:2 hexane/diethyl ether (Et2O) revealed product with an Rf of 0.8. The resulting crude oil was chromatographed on silica gel (225 g) eluting with 2:1 hexanes/diethyl ether to provide 4.73 g (77%) of the title compound. TLC: 1:2 Hexanes/Et2O Rf: 0.8. 1H NMR (400 MHz, CDCl3): δ7.27 ppm (5H, m), 5.02 (1H, b), 4.52 (1H, d, J=9.3 Hz), Hz), 3.98 (1H, dt, J=8.5, 7.8 Hz), 2.93 (2H, m), 2.88 (1H, b), 2.68 (1H, m), 2.41 (1H, m), 1.92 (1H, m), 1.65 (3H, s), 1.58 (3H, s), 1.37 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]2)=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (3.1 g, 20.4 mmol), tert-butyl 4-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate (8.0 g, 21.7 mmol) and potassium carbonate (5.53 g, 40 mmol) in N,N-dimethylformamide (100 mL) was stirred at 60° C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a solid (7.12 g, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Cl:20])=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[Cl:20][C:11]1[CH:10]=[C:9]2[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8]2)=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)c([N+](=O)[O-])cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c2cc(Cl)c([N+](=O)[O-])cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A mixture of 12.0 g (40.5 mmol) of 7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (J. Med. Chem. 23, 1358 (1980)) and 60.0 mL of 2.5 N sodium hydroxide in 160.0 mL of ethanol is heated at reflux temperature for 1.5 hours. After allowing the reaction mixture to cool to room temperature, it is further cooled in an ice bath, brought to pH 4 with 4.0 N hydrochloric acid and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried in vacuo to yield 10.1 g of 7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a tan solid, mp 294–297° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([OH:18])[CH:11]=2)[CH2:6][CH2:5]1.C[O:20][C:21](=O)[CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]2[CH:32]=1.C(#N)C.N1CCCCC1>C1C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]2[N:26]([CH:32]=[C:23]([C:22]3[C:21](=[O:20])[O:18][C:12]4[C:13]([CH:14]=3)=[CH:16][CH:17]=[C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][F:1])[CH2:5][CH2:6]3)[CH:11]=4)[N:24]=2)[CH:27]=1
Reactant: O=Cc1ccc(N2CCN(CCF)CC2)cc1O
Reactant: COC(=O)Cc1cn2cc(Cl)ccc2n1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: O=c1oc2cc(N3CCN(CCF)CC3)ccc2cc1-c1cn2cc(Cl)ccc2n1
Temperature: 0 °C
Yield: 23.4 %

Procedure:
253 mg (1 mmol) 4-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-hydroxy-benzaldehyde and 450 mg (2 eq.) (6-chloro-imidazo[1,2-a]pyridin-2-yl)-acetic acid methyl ester refluxed in 15 mL benzene and 7.5 mL acetonitrile in the presence of 0.395 mL (4 eq.) piperidine for 21 h. The reaction mixture is cooled to 0° C. and the precipitated material filtered, washed with diethyl ether and dried under high vacuum, yielding 100 mg (23%) desired product as a yellow solid. M.p.=265° C. (decomposition).
Reaction SMILES: C1(=O)[N:5]([O:6][CH2:7][C:8]2[N:9]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:10]=[C:11]([O:15]C(C3C=CC=CC=3)C3C=CC=CC=3)[C:12](=[O:14])[CH:13]=2)C(=O)C2=CC=CC=C12.Cl>C(O)(=O)C>[NH2:5][O:6][CH2:7][C:8]1[N:9]([OH:29])[CH:10]=[C:11]([OH:15])[C:12](=[O:14])[CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cc(=O)c(OC(c2ccccc2)c2ccccc2)cn1OC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: NOCc1cc(=O)c(O)cn1O
Reaction time: 2 h

Procedure:
To 38.6 g of 2-phthalimidooxymethyl-1,5-dibenzhydryloxy-4-pyridone, 220 ml of glacial acetic acid and 48 ml of concentrated hydrochloric acid were added, and the mixture was reacted at 100° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated. To the concentrated solution, 240 ml of water was added, and insoluble matters were separated by filtration. The insoluble matters were washed with 80 ml of water, and the filtrate and the washing solution were put together. Then, a powder of sodium carbonate was added thereto to adjust the pH to 3.0, whereupon precipitates were collected by filtration. A powder of sodium carbonate was further added to the filtrate to adjust the pH to 5.2, and the mixture was stirred for 2 hours and then left to stand overnight in a refrigerator. Precipitated crystals were collected by filtration, and the crystals were washed with water and then dried to obtain 8.1 g of the above identified compound as a slightly yellowish white product. The IR and NMR spectra of the compound thus obtained, agreed with those obtained in Example 1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[CH3:24][O:25][C:26](=[O:67])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH2:63][CH3:64])([C:43]3[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]4([O:57][Si](C)(C)C)[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:45]([CH3:62])[CH:44]=3)[CH2:41][CH3:42])=[CH:36][C:35]=2[CH3:65])=[CH:30][C:29]=1[F:66].[Cl-].[NH4+]>>[CH3:24][O:25][C:26](=[O:67])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH2:63][CH3:64])([C:43]3[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]4([OH:57])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:45]([CH3:62])[CH:44]=3)[CH2:41][CH3:42])=[CH:36][C:35]=2[CH3:65])=[CH:30][C:29]=1[F:66]
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Reaction time: 0.67 h
Yield: 92.8 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.105 mL, 0.105 mmol) was added to (4′-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 97-(1); 54.0 mg, 0.0881 mmol), and the mixture was stirred for 40 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound (44.2 mg, 92%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]([CH2:21][CH2:22][CH2:23][NH2:24])[Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>O1CCCC1>[O:13]([CH2:21][CH2:22][CH2:23][NH:24][S:9]([CH3:8])(=[O:11])=[O:10])[Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.16 ml, 16 mmol), followed by methanesulfonyl chloride (Compound 19, 1.48 ml, 19.2 mmol) was added to a solution of 3-tert-butyldimethylsiloxy-1-propylamine (Compound 29, 2.80 g, 16 mmol) in tetrahydrofuran (60 ml) at 0° C. under argon. After stirring at room temperature overnight, the mixture was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate and brine. Evaporation of the dried (magnesium sulfate) organic phase gave the title sulfonamide. 1HNMR(CDCl3): 0.04 (s, 6H), 0.87 (s, 9H), 1.76 (p, 2H, J=6.4 Hz), 2.91 (s, 3H), 3.24 (q, 2H, J=6.2 Hz), 3.74 (t, 2H, J=5.52 Hz) and 5.05 (br t, 1H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@@H:44]5[CH2:45][CH2:46][CH2:47][NH:48][CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-Boc-3-aminopiperidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.95 (m., 14H) 2.52 (t, J=7.38 Hz, 2H) 2.92 (br. d., 1H) 3.07 (br. d., 1H) 3.39 (s, 3H) 3.81 (br. s., 1H) 3.94 (s, 3H) 4.06 (t, J=13.64 Hz, 2H) 4.45 (m, 1H) 7.34-7.55 (m, 2H) 7.90 (s, 1H) 8.03 (d, J=7.58 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H] calculated for C27H35F2N7O3, 544. found 544.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[C:11]([O:15][C:16](OC([O-])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([O:15][C:16]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Brc1ccc2c(c1)CCN2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Yield: 89 %

Procedure:
4 g (20 mmol) 5-bromo-indoline in 50 ml CH2Cl2 were treated with 4.4 g (20 mmol) di.-tert.-butyldicarbonate at RT over night. The reaction mixture was concentrated in vacuo and triturated with hexane to yield 5.3 g (89%) 5-Bromo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless solid, MS: 297 (M, 1Br).
Reaction SMILES: C(O)(=O)C.[BrH:5].C(O)(=O)C.C(O[C@@H:14]1[O:31][CH2:30][C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=O)C>C(Cl)(Cl)Cl>[C:17]([O:16][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[CH2:30][O:31][C@@H:14]1[Br:5])(=[O:19])[CH3:18]
Reactant: Br
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@@H]1Br
Temperature: 25 °C

Procedure:
Acetic acid (6 mL) and a 30% hydrobromic acid-acetic acid solution (25 mL) were put in a 100 mL round bottom flask containing 1,2,3,4-tetra-O-acetyl β-D-xylose (5.0 g, 15.7 mmol) and stirred at room temperature for an hour. Chloroform (100 mL) was poured into the reaction mixture. The resulting mixture was washed with water (100 mL×2) and with a saturated aqueous solution of sodium hydrogen carbonate (100 mL×1), and dried over calcium chloride for 10 minutes. The resulting mixture was concentrated to 20 mL. To the resulting mixture, diethyl ether (8 mL) was added, followed by stirring. Petroleum ether (5 mL) was quietly added to the resulting mixture, which was cooled in the freezer for crystallization. The crystals are filtered by suction, washed with cold ether and dried to give the title compound. White acicular crystals. Yield 4.6 g, 87%. The product was unstable at room temperature, and stored in the freezer.