Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=2)[CH2:2]1.Cl.[CH3:17][S:18]([NH:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19].[OH-].[Na+].[P:38](=[O:42])([OH:41])([OH:40])[OH:39]>>[P:38](=[O:39])([OH:42])([OH:41])[OH:40].[OH:1][CH:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH2:2][N:31]1[CH2:32][CH2:33][N:28]([C:26](=[O:27])[C:25]2[CH:34]=[CH:35][C:22]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: COCCc1ccc(OCC2CO2)cc1
Agent: Cl
Agent: O=P(O)(O)O
Agent: [Na+]
Product: COCCc1ccc(OCC(O)CN2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
Add 2.64 g (.013 mol) of 1,2-epoxy-3-[4-(2-methoxyethyl)phenoxy]propane to a solution of 3.86 (12 mmol) 1-[4-[(methylsulfonyl)amino]benzoyl]piperazine hydrochloride in 50 mL MeOHand 13 mL 1 N NaOH. Heat the resultant solution at 50° C. for about 24 h. Cool the solution to room temperature and evaporate the solvents. Dissolve the resultant oil in ethanol and acidify with one equivalent of phosphoric acid. Remove the solvents to obtain the title compound.
Reaction SMILES: C[O:2][C:3]1[C:8](OC)=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=[CH:5][C:4]=1[C:15]1[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]2[C:27]3[N:28]=[C:29]([NH2:31])[S:30][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH:16]=1.B(F)(F)F.CCOCC>ClCCl>[NH2:31][C:29]1[S:30][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:4]4[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:3]=4[OH:2])[CH:16]=3)[C:27]=2[N:28]=1
Reactant: COc1c(-c2cc(Oc3cccc4sc(N)nc34)ncn2)ccc(C(F)(F)F)c1OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4O)ncn3)cccc2s1
Temperature: -78 °C

Procedure:
To a 100-mL, round-bottomed flask containing a solution of 4-[6-(2-methoxy-methoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 135(c)), (1.8 g, 3.9 mmol) in dichloromethane (39 mL) was added boron trifluoride diethyl etherate (1.5 mL, 12 mmol, Aldrich) with stirring at −78° C. The reaction mixture was then stirred at 0° C. for 1 h and at room temperature for 3 h. The mixture was quenched with satd sodium bicarbonate at 0° C. and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuum. The crude material was purified by silica gel chromatography (gradient: 0–3% 2 N ammonia in methanol/dichloromethane) to yield the title compound as an amorphous, white solid. MS (ESI, pos. ion.) m/z: 406 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23][C:24]([NH:26][C@H:27]([C:43](O)=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]([C:43](=[O:44])[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25])[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)CN(C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 69.3 %

Procedure:
By reacting 8.2 g of N-(indan-2-yl)glycine tert-butyl ester with 113 g of Nα -tert-butoxycarbonyl-Nε -carbobenzoxy-L-lysine as in Reference Example 5, there is obtained 14 g of Nα -tert-butoxycarbonyl-Nε -carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH:11]1([CH:17]([C:19]2[CH:20]=C(O)[CH:22]=[C:23]([CH:25]=2)[OH:24])[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:17]([C:19]2[CH:25]=[C:23]([OH:24])[C:22]3[C:2]4[CH2:6][CH2:5][S:4][C:3]=4[C:7](=[O:8])[O:9][C:10]=3[CH:20]=2)[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(c1cc(O)cc(O)c1)C1CCCCC1
Reactant: COC(=O)C1SCCC1=O
Product: CC(c1cc(O)c2c3c(c(=O)oc2c1)SCC3)C1CCCCC1

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(1-cyclohexylethyl)resorcinol to give 7-(1-cyclohexylethyl)-1,2-dihydro-9-hydroxy-4-oxo-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:17][CH2:16][CH:11]3[NH:12][CH2:13][CH2:14][CH:15]=[C:10]3[C:8]=2[CH:9]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[CH:27](=O)[CH2:28][CH3:29]>O.[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:17][CH2:16][C@H:11]3[N:12]([CH2:27][CH2:28][CH3:29])[CH2:13][CH2:14][CH2:15][C@@H:10]3[C:8]=2[CH:9]=1
Reactant: COc1ccc2c(c1)C1=CCCNC1CO2
Reactant: CCC=O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CCCN1CCC[C@@H]2c3cc(OC)ccc3OC[C@H]21
Reaction time: 16 h

Procedure:
A mixture of 14 g of 9-methoxy-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, 140 ml of ethanol, and a solution of 2.95 g of sodium carbonate in 10 ml of water and 3 g of 10% palladium on carbon catalyst is hydrogenated at 3 atm. pressure and 50° for 16 hours. After the addition of 15 g of propionaldehyde the hydrogenation is continued for an additional 16 hours under the same conditions. After filtration, the solvent is removed in vacuo. The residue is dissolved in ethanol and acidified with ethanolic hydrogen chloride to afford trans-9-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, m.p. 252°-254° (the compound of Example 2a).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH:16]([NH2:18])[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:33]=[CH:32][C:24]2[O:25][C@H:26]([C:29](O)=[O:30])[CH2:27][O:28][C:23]=2[CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([CH:16]([NH:18][C:29]([C@H:26]3[O:25][C:24]4[CH:32]=[CH:33][C:21]([C:20]([F:35])([F:19])[F:34])=[CH:22][C:23]=4[O:28][CH2:27]3)=[O:30])[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: O=C(O)[C@@H]1COc2cc(C(F)(F)F)ccc2O1
Reactant: CC(N)c1ccc2c(cnn2C2CCCCO2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)[C@@H]1COc2cc(C(F)(F)F)ccc2O1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethanamine (66 mg, 0.27 mmol), (5)-6-trifluoromethyl-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid (60.6 mg, 0.25 mmol), 4-dimethylaminopyridine (2.5 mg, 0.02 mmol) and N,N-diisopropylethylamine (153 μL, 0.88 mmol) in anhydrous DMF (4 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (102 mg, 0.27 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. The residue was dissolved in methanol (20 mL) and 2N HCl (5 mL) was added. The reaction mixture was heated at 60° C. for 2 hours, then cooled and the methanol removed under vacuum. The remaining aqueous product was poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 3% MeOH in DCM over 30 minutes) gave the product (23 mg) as a solid.
Reaction SMILES: Br.C(O)(=O)C.CC1N=CSC=1C([O-])=O.C(OC([NH:25][C@H:26]1[C@H:31]([NH:32][C:33]([C:35]2[NH:36][C:37]([CH2:41][CH3:42])=[C:38]([Cl:40])[N:39]=2)=[O:34])[CH2:30][CH2:29][N:28]([C:43]2[S:44][C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:46]([CH3:48])[N:47]=2)[CH2:27]1)=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[NH2:25][C@H:26]1[C@H:31]([NH:32][C:33]([C:35]2[NH:36][C:37]([CH2:41][CH3:42])=[C:38]([Cl:40])[N:39]=2)=[O:34])[CH2:30][CH2:29][N:28]([C:43]2[S:44][C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:46]([CH3:48])[N:47]=2)[CH2:27]1
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](NC(=O)OCc3ccccc3)C2)nc1C
Agent: Br
Agent: Cc1ncsc1C(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](N)C2)nc1C
Reaction time: 0.42 h
Yield: 105.8 %

Procedure:
Hydrobromic acid/acetic acid solution (1 mL) was added to ethyl trans(±)-2-(3-{[benzyloxy)carbonyl]amino}-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained by the method described in Example (79e) (62 mg, 0.11 mmol), and the mixture was stirred for 25 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction solution. Purification by reverse phase silica gel chromatography (elution solvent: distilled water, distilled water/THF=70/30, 60/40) gave 51.3 mg of the title compound (100%).
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([Cl:24])=[C:20]([CH3:23])[CH:21]=3)[O:16][C:15](=[O:25])[C:14]=2[CH2:26][C:27](O)=[O:28])[CH:10]=[CH:11][CH:12]=1.S(Cl)(Cl)=O.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[C:42]([F:45])([F:44])[F:43]>O1CCCC1.O.C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([Cl:24])=[C:20]([CH3:23])[CH:21]=3)[O:16][C:15](=[O:25])[C:14]=2[CH2:26][C:27]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[C:42]([F:45])([F:43])[F:44])=[O:28])[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cc2c(-c3cccc(Br)c3)c(CC(=O)O)c(=O)oc2cc1Cl
Reactant: Nc1ccc(F)cc1C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc2c(-c3cccc(Br)c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
N,N-Dimethylformamide (0.2 ml) was added to a solution of [4-(3-bromophenyl)-7-chloro-6-methyl-2-oxo-2H-chromen-3-yl]acetic acid (13.5 g) in tetrahydrofuran (135 ml), and then thionyl chloride (5.12 g) was added dropwise to the resulting mixture with passing nitrogen through the reaction vessel at 25° C. After completion of the addition, the mixture was warmed to 40° C. and stirred for 1.5 hours. Then, 2-amino-5-fluorobenzotrifluoride (6.53 g) was added thereto, and the mixture was warmed to 60° C. and then stirred for 2.5 hours. Acetonitrile (67.5 ml) and water (67.5 ml) were added dropwise successively thereto at 40 to 50° C. The resulting mixture was stirred at 40° C. for 1 hour and at 5° C. for 1 hour. Crystals precipitated was collected by filtration, and washed with cold tetrahydrofuran/acetonitrile/water (2/1/1, 40.5 ml). The resulting crystals (17.3 g) were dissolved in acetone (173 ml) by heating. Activated charcoal (0.865 g) was added to the solution, and the mixture was stirred for 10 minutes. The activated charcoal was removed by filtration, and washed with acetone (86.5 ml). The combined filtrate and washings were kept at 40° C., and water (51.9 ml) was added dropwise thereto with stirring. The mixture was cooled to 5° C. and stirred for 1 hour. Crystals were collected by filtration and washed with cold acetone/water (5/1, 51.9 ml) to obtain the title compound (16.1 g, yield 85.7%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].I[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>[Cu]I.O1CCOCC1>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([CH:3]=1)[O:1][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: N#Cc1cccc(I)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(C=O)cc1Oc1cccc(C#N)c1
Temperature: 100 °C
Yield: 43.7 %

Procedure:
In a 350 mL pressure vessel equipped with a stir bar was placed 3-hydroxy-4-methoxy-benzaldehyde (15) (1.5 g, 9.86 mmol), 3-iodo-benzonitrile (3.39 g, 14.8 mmol), cesium carbonate (3.21 g, 9.86 mmol), N,N-dimethylglycine (275 mg, 1.97 mmol), copper(I) iodide (188 mg, 0.986 mmol) and 1,4-dioxane (55 mL). The mixture was heated to 100° C. for 46 hours. The reaction was cooled to room temperature, quenched with water (300 mL) and then extracted with ethyl acetate (3×200 mL). The organic portions were combined, washed with brine (300 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 35%, 50%, 75% ethyl acetate/hexanes to produce 1.09 g (42% yield) of (16) as a white solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: c1ccc(CN2CC[C@@H](OC3CCCCO3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C1CCC(O[C@@H]2CCNC2)OC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 122.8 %

Procedure:
A mixture of 1-benzyl-3-(R)-tetrahydropyranyloxypyrrolidine (8.78 g, 27.3 mmol) and Pearlman's catalyst (3.50 g) in MeOH (100 ml) was stirred under hydrogen atmosphere at rt for 4 h. After removal of the catalyst by Celite filtration, the filtrate was concentrated to give 5.74 g of clear light brown oil. This was used for the next reaction without purification.
Reaction SMILES: [OH-].[Li+].FC(F)(F)C(O)=O.C([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]4[CH:37]=[CH:38][C:39]5[NH:45][C:44](=[O:46])[CH2:43][CH2:42][C:41]([CH3:48])([CH3:47])[C:40]=5[CH:49]=4)[N:29]=3)=[C:23]([N:50]3[CH:54]=[CH:53][CH:52]=[N:51]3)[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])C.CO.Cl>O>[Cl:34][C:33]1[C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C:13]([OH:14])=[O:12])[CH2:16][CH2:17]3)=[CH:22][C:23]=2[N:50]2[CH:54]=[CH:53][CH:52]=[N:51]2)=[N:29][C:30]([NH:35][C:36]2[CH:37]=[CH:38][C:39]3[NH:45][C:44](=[O:46])[CH2:43][CH2:42][C:41]([CH3:47])([CH3:48])[C:40]=3[CH:49]=2)=[N:31][CH:32]=1
Reactant: CCOC(=O)C1CCN(c2ccc(Nc3nc(Nc4ccc5c(c4)C(C)(C)CCC(=O)N5)ncc3Cl)c(-n3cccn3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCC(C(=O)O)CC5)cc4-n4cccn4)n3)cc21

Procedure:
To a room temperature solution of Lithium hydroxide (53 mg, 2.2 mmol) in Water (3 mL), was added 1-{4-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-7-ylamino)-pyrimidin-4-ylamino]-3-pyrazol-1-yl-phenyl}-piperidine-4-carboxylic acid ethyl ester; compound with trifluoro-acetic acid (47 mg, 0.063 mmol) followed by Methanol (12 mL). After 72 hours 1 N HCl (2 mL) was added to the reaction to neutralize the base, then the mixture was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC to yield the desired 1-{4-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-3-pyrazol-1-yl-phenyl}-piperidine-4-carboxylic acid as a lyophylate (20%); 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.39 (s, 1H), 9.32 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.97 (m, 1H), 7.83 (s, 1H), 7.57 (d, J=7.07 Hz, 1H), 7.42 (s, 1H), 7.12 (s, 1H), 6.97 (d, J=9.86 Hz, 1H), 6.79 (d, J=8.34 Hz, 1H), 6.54 (s, 1H), 3.75 (m, 2H), 2.8 (m, 2H), 2.6 (m, 1H), 2.15 (m, 2H), 1.99 (m, 4H), 1.70 (m, 2H), 1.2 (s, 6H); MS (m/e) 601.56 (M+H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C@@H:18]3[C:23]#[CH:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N:37]=[N+:38]=[N-:39])(C)C.[ClH:40]>C1(C)C=CC=CC=1.CCOCC>[ClH:40].[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][C@H:18]3[C:23]2[NH:39][N:38]=[N:37][CH:24]=2)[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:8]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#C[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3c2cnn[nH]2)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-ethynyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 98; 136 mg, 0.3 mmol) and trimethylsilylazide (0.1 ml, 0.8 mmol) in toluene were heated in a sealed tube at 130° C. for 48 hours. The mixture was allowed to cool and quenched with methanol and water. The mixture was concentrated in vacuo, and the residue purified by flash column chromatography, eluting with 5% methanol/dichloromethane. The debenzylated product was treated with 1.0 eq HCl in ether and the title compound isolated as a white crystalline solid (20 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][N:25]=[CH:24][CH:23]=2.FC(F)(F)C(O)=[O:33].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:33])[CH2:17][OH:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][N:25]=[CH:24][CH:23]=2
Reactant: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (44 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was brought to 0° C. Trifluoroacetic acid (0.4 ml) was added thereto, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 4 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (7 mg, yield 15%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][S:10][CH3:11])=[CH:4][N:3]=1.[N:12]#[C:13][NH2:14].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[F:8][C:7]1[CH:6]=[C:5]([CH2:9][S:10]([CH3:11])=[N:14][C:13]#[N:12])[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: N#CN
Reactant: CSCc1cnc(Cl)c(F)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CS(Cc1cnc(Cl)c(F)c1)=NC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of 2-chloro-3-fluoro-5-methylthiomethylpyridine (1.7 g, 8.9 mmol) and cyanamide (3.7 g, 8.9 mmol) in THF (15 mL) cooled to 0° C. was added iodobenzene diacetate (2.86 g, 8.9 mmol) in one portion and the resulting mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h. The solvent was removed in vacuo and the resulting mixture was purified on silica gel using 60% acetone in hexane to give 1.828 g of [1-(5-fluoro-6-chloropyridin-3-yl)methyl](methyl)-λ4-sulfanylidenecyanamide as an off-white solid in 89% yield. LC-MS calcd. for C8H7ClFN3S [M+1]+: 232.69. Found: 232.04.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[CH3:43])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[CH3:43])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccccc3F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (362 mg, 1.2 mmol) and 3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H8) (300 mg, 1.0 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (312 mg).
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](=[N:22][CH3:23])([NH2:21])=[O:20].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH:34][C:35](=[O:43])OC2C=CC=CC=2)[N:27]=1.C(O)(=O)C>C(#N)C.ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](=[N:22][CH3:23])([NH:21][C:35]([NH:34][C:28]1[N:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:26]([O:25][CH3:24])[N:27]=1)=[O:43])=[O:20]
Reactant: CN=S(N)(=O)c1ccccc1Br
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN=S(=O)(NC(=O)Nc1nc(OC)cc(OC)n1)c1ccccc1Br
Yield: 104.6 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.15 mL, 1.0 mmol) was added dropwise over one minute to a stirred solution of 2-bromo-N'-methylbenzenesulfonimidamide (0.25 g, 1.0 mmol) and phenyl (4.6-dimethoxypyrimidin-2-yl)carbamate (0.28 g, 1.0 mmol) in dry acetonitrile (5 mL) at room temperature. The solvent was evaporated, and the residue was dissolved in dichloromethane. Evaporation of this solvent left a pale yellow viscous oil (0.65 g). This was dissolved in CH2Cl2, and acetic acid (57 μL, 1.0 mol) was added. This solution was chromatographed on a column of silica gel using 1:1 dichloromethane-ether as eluant. Fractions containing the product were diluted with toluene. The solvent was evaporated leaving an oil. This was dissolved in dichloromethane, and the solvent was evaporated leaving 2-bromo-N-(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl-N'-methylbenzenesulfonimidamide as a hard amorphous foam (0.45 g) melting at 120°-125° C.