Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2].[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:27][N:26]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:29]=3)[CH2:31][CH2:32]2)=[O:18])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncncc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ncncc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl (4-ethoxypyrimidin-5-yl)carbamate (315 mg, 1.00 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (246 mg, 1.00 mmol), diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (290 mg, 70.6%) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[H-].[Na+].[CH:20]1([N:25]2[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.CC(OC)(C)C.O.[OH-].[Na+]>[CH:20]1([N:25]2[CH2:30][CH2:29][CH:28]([O:17][C:14]3[CH:15]=[CH:16][C:11]([C:5]4([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]4)=[CH:12][CH:13]=3)[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: CS(=O)(=O)OC1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OC3CCN(C4CCCC4)CC3)cc2)CCOCC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (487 mg, 2.07 mmol) in DMF (2 ml) was added to a solution of NaH (100 mg, 2.5 mmol) in DMF (2 ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-cyclopentyl-piperidin-4-yl ester (409 mg, 1.65 mmol) in DMF (1.5 ml) was slowly added. The reaction was heated to 75° C. and stirred for 6 hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20 ml), water (10 ml) and 5M NaOH solution (10 ml). The organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude reaction was purified by column chromatography, eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white solid (78 mg, 12%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.28 (m, 1H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.89-2.76 (m, 2H), 2.52 (p, 1H), 2.40 (s, 2H), 2.37-2.25 (m, 2H), 2.14-1.94 (m, 4H), 1.96 (s, 6H), 1.93-1.77 (m, 6H), 1.76-1.34 (m, 6H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][NH:16][C@@H:17]([CH3:27])[C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[OH:19])=[CH:11][CH:10]=2)O1.Br[C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]=1[CH2:41][CH3:42].[F-].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH2:41]([C:33]1[CH:34]=[C:35]([C:36]([OH:38])=[O:37])[CH:39]=[CH:40][C:32]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][NH:16][C@@H:17]([CH3:27])[C@H:18]([OH:19])[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[CH:28][CH:29]=1)[CH3:42]
Reactant: CCc1cc(C(=O)O)ccc1Br
Reactant: C[C@H](NCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CCc1cc(C(=O)O)ccc1-c1ccc(OCCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 23.7 %

Procedure:
A mixture of 4-((1R,2S)-2-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethylamino}-1-hydroxypropyl)phenol (0.04 g), 4-bromo-3-ethylbenzoic acid (0.044 g), tetrakis(triphenylphosphine)palladium (0.011 g), cesium fluoride (0.088 g), 1,4-dioxane (0.6 mL), ethanol (0.12 mL) and water (0.2 mL) was stirred at 140° C. for 5 min in a sealed tube. After being cooled to room temperature, the reaction mixture was purified by SCX ion exchange column chromatography (2 g, preconditioning: tetra hydrofuran, washing solvent: tetra hydro-furan, eluent: 2 mol/L ammonia in methanol), followed by reverse phase column chromatography (Shiseido Capcell Pak C18 ODS, 5 μm, 120 Å, 20×50 mm, linear gradient 0.1% aqueous formic acid/acetonitrile=90/10-60/40) to afford the title compound (0.010 g) as a white amorphous. The structure and physical data were shown in table 3.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:28][CH2:27]2)[N:10]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.2 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt (66.3 mg, Example 11) in methylene chloride (3 mL) were added triethylamine (0.09 mL, 0.617 mmol, Aldrich) and methanesulfonyl chloride (8.9 mg, 0.0774 mmol, Aldrich) at 0° C. After stirring for 0.5 to 1 hour at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give [4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone (19.2 mg). HRMS, observed: 406.1546; Calcd for (M+H)+: 406.1544.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:35])[O:30][CH2:31][CH2:32][O:33][CH3:34]>C(Cl)Cl>[CH3:34][O:33][CH2:32][CH2:31][O:30][C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:35]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: COCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml), was added triethylamine (188 μl, 1.35 mmol) and 2-methoxyethyl carbonochloridate (63 μl, 0.54 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc, and the organic phase was washed with water and brine, dried over Na2SO4 and evaporated to dryness, obtaining (R)-quinuclidin-3-yl 2-((2-methoxyethoxy)-carbonylamino)-2-phenylacetate (73.0 mg; 45% yield).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)S(O[CH2:34][C:35]([CH2:46]OS(C(F)(F)F)(=O)=O)([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])(=O)=O>CC#N>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[N:1]3[CH2:46][C:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:34]3)[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: CCOC(=O)C(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)C(=O)OCC
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)CN([C@@H]2CCc3c(-c4noc(-c5ccc(OC(C)C)c(C#N)c5)n4)cccc32)C1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (247 mg, 0.62 mmol) in CH3CN (2 mL) at −10° C., under N2, was added diethyl 2,2-bis((((trifluoromethyl)sulfonyl)oxy)methyl)malonate INT-26 (3 mL of 0.25 mmol solution in CH3CN). The resulting mixture was warmed to room temperature over 30 min, then heated to 70° C. for 18 h. The mixture was concentrated, dissolved in DCM, and washed with water. The organic layer was dried over Na2SO4 and concentrated to provide 93 mg (28%) of crude (R)-diethyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3,3-dicarboxylate INT-27, which was used in the next step without further purification. LCMS-ESI (m/z) calculated for C30H32N4O6: 544.6; found 545.2 [M+H]+, tR=3.03 min.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[C:15](=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:20])[C:7]=2[CH:6]=1)=[N+]=[N-].[H][H]>CN(C=O)C.[Pt]>[NH2:1][CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[C:15](=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:20])[C:7]=2[CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CN(C)C=O
Product: NCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Yield: 75.9 %

Procedure:
9.5 g of 2-azidomethylanthraquinone are dissolved in 100 ml of DMF, 1.0 g of platinum-on-charcoal catalyst (5% by weight of Pt) is added and hydrogenation is carried out with hydrogen for 15 minutes. The catalyst is filtered off, 200 ml of water are added to the filtrate and the mixture is filtered. The red crystals which have precipitated are recrystallised from dioxane. 6.5 g (70.01% of theory) of 2-aminomethylanthraquinone are obtained; melting point: 170°-78° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17]CC=C(Cl)Cl)=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2].O>C1(C)C=CC=CC=1.C(OCC)C>[C:1]([C:4]1[C:5]([OH:17])=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCC=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Temperature: 85 °C
Reaction time: 6 h

Procedure:
6.1 g of 3-acetyl-2,5-bis-(3,3-dichloroprop-2-enyloxy)-1-chlorobenzene were dissolved in 160 ml of toluene. 7.79 g of magnesium dibromide/diethyl ether complex, dissolved in 25 ml of diethyl ether, were added to this solution, and the mixture was then stirred at 85° C. for 6 hours. After the reaction had ended according to TLC, the mixture was allowed to cool, about 300 ml of water were added and the organic phase was separated off. The aqueous phase was re-extracted twice with ethyl acetate, and the combined organic phases were then washed with saturated sodium chloride solution. After drying and concentration of the organic phase, the crude product was purified chromatographically. Yield: 2.86 g (64%)
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:22][CH:10]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][N:9]2[C:8]1=[O:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:22][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][N:9]2[C:8]1=[O:23]
Reactant: CC(C)(CO)CCCN1CC2CN(C(=O)OC(C)(C)C)CCN2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)CCCN1CC2CNCCN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(5-hydroxy-4,4-dimethyl-pentyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (Compound 69-B) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. The reaction mixture was stirred at rt for 1 hour and then the solvent was removed under vacuum to give the crude product 69-A, which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:13][CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.C(OC(O)C)C>C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:13][CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NCC1(O)CCCCC1
Reactant: Clc1c(Br)cnc2ccccc12
Agent: CCOC(C)O
Agent: Cl
Solvent: CCN(CC)CC
Product: OC1(CNc2c(Br)cnc3ccccc23)CCCCC1
Temperature: 0 °C

Procedure:
A mixture of 3-bromo-4-chloroquinoline (12.1 g), 1-aminomethyl-1-cyclohexanol.HCl (8.3 g), triethylamine (7.2 g) and 30 ml of ethoxyethanol was stirred at 120° C. for 5 hours and poured into 250 ml of ice water. The solid was filtered and recrystallized from acetone. The yield was 6.5 g, mp 130°-132° C.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[OH:18][NH:17][C:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 4-cyanopiperazine-1-carboxylate (1.22 g, 5.77 mmol) in anhydrous ethanol (10 mL) were added hydroxylamine hydrochloride (420 mg, 6.04 mmol) and triethyl amine (843 L, 6.06 mmol). The reaction was heated to reflux for 45 min, after which TLC showed complete consumption of the starting material. The mixture was allowed to cool to room temperature overnight, and the resulting precipitate was removed by filtration. The filtrate was concentrated, yielding 1.42 g of a yellow gel that was used directly in the next step.
Reaction SMILES: [CH2:1]([C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]#[N:17])[CH2:5]1)[CH:2]=C.[O:18]=[O+][O-]>ClCCl>[O:18]=[CH:2][CH2:1][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]#[N:17])[CH2:5]1
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC2(CCCCC2)O1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCCC2)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(2-propenyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile 4.26 g (19.42 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90 V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 5.6 g (21.36 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 4.04 g of pure (±)-cis-4-(2-oxoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:26]([Cl:34])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1)(C)(C)C.O1CCCC1.O>C(O)(=O)C>[Cl:34][C:26]1[CH:25]=[C:24]([C@@H:16]([CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:35])[CH:29]=[CH:28][C:27]=1[S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCO)n2)cc1Cl
Temperature: 25 °C
Yield: 98.4 %

Procedure:
In a round bottom flask was placed (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (85 mg, 0.15 mmol), tetrahydrofuran (2 mL), water (0.5 mL) and acetic acid (2 mL). This solution was then stirred at 25° C. until all starting material is consumed (˜4 hr). The reaction was then diluted with water (10 mL) and transferred to a separatory funnel where it was extracted with ethyl acetate (3×10 mL). The organic layers were combined and then washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 100% ethyl acetate to 5% methanol/ethyl acetate) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (67 mg, 99%) as a white foam: [α]29589=−11.5° (c=0.13, methylene chloride); ES-HRMS m/e calcd for C20H24N3O5SCl (M+H)+ 454.1198, observed 454.1193; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.78-2.30 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.67 (q, J=5.4 Hz, 2H, OCH2), 3.96 (m, 1H, ArCHCO), 4.00 (m, 2H, NCH2), 4.84 (t, J=5.4 Hz, 1H, OH), 6.41 (d, J=2.1 Hz, 1H, Ar), 7.55 (d, J=2.1 Hz, 1H, Ar), 7.62 (d, Jo=8.3 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.85 (s, 1H, NH).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][N:16]1[CH2:20][CH2:19][C@@H:18]([OH:21])[CH2:17]1.[H-].[Na+]>O1CCCC1.CO.CCOC(C)=O>[CH3:15][N:16]1[CH2:20][CH2:19][C@@H:18]([O:21][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:17]1
Reactant: CN1CC[C@@H](O)C1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CC[C@@H](Oc2cc([N+](=O)[O-])ccc2C(F)(F)F)C1
Reaction time: 48 h
Yield: 45.6 %

Procedure:
A solution of 2-fluoro-4-nitrobenzotrifluoride (12.4 g, 59.3 mmol, 1.0 eq) and (R)-1-methyl-pyrrolidin-3-ol (6.0 g, 59.3 mmol, 1.0 eq) in anhydrous tetrahydrofuran (150 ml) was cooled to 0° C. then slowly treated with portions of 60% sodium hydride (4.7 g, 0.12 mol, 2 eq) over 5 min. Without removing the ice bath, the reaction was allowed to come to room temperature and stir for 48 hrs. Quenched with water (50 ml) and brine (100 ml) then extracted into diethyl ether (5×100 ml). Extracts dried over anhydrous magnesium sulfate and decolorizing charcoal for 1 hr. Filtered through Celite. The filtrate was treated with silica (35 g) then evaporated to give the crude product suspended on silica. Column chromatography on silica (1% MeOH/EtOAc→5% MeOH/EtOAc) gave the product (Rf≅0.3 in 1% MeOH/EtOAc) as an orange oil (7.85 g, 46%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:15][C:14]=1[OH:27])=[O:12]>CC(C)=O>[CH2:7]([O:27][C:14]1[CH:15]=[C:16]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:17]=[CH:18][C:13]=1[CH:11]=[O:12])[CH:8]=[CH2:9]
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1C=O
Reaction time: 2 h
Yield: 73.5 %

Procedure:
Potassium carbonate (1.6 g, 11.5 mmol) and allyl bromide (1 ml, 11.5 mmol) were added to a solution of trifluoro-methanesulfonic acid 4-formyl-3-hydroxy-phenyl ester (1.55 g, 5.7 mmol) in acetone (50 ml). The reaction mixture was stirred at 55 C for 2 h, filtered and evaporated in vacuo. The residue was chromatographed (silica gel, EA:Hex, 1:20) to give 1.3 g (73%) of trifluoro-methanesulfonic acid 3-allyloxy-4-formyl-phenyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(OC)=C(F)C=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COc1ccc(CBr)cc1F
Agent: COc1ccc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC3)cc1F
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F
Yield: 5.4 %

Procedure:
The title compound (0.021 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.35 g) using 3-fluoro-4-methoxybenzyl bromide (0.25 g) in place of benzyl chloride. The reaction sequence also provided 3-(4-chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H21ClFN3O, 385.14; found, m/z 386.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.47-7.42 (m, 2H), 7.06-7.02 (m, 1H), 6.90-6.86 (m, 2H), 5.29 (s, 2H), 3.84 (s, 3H), 3.35-3.29 (m, 2H), 2.94-2.92 (m, 4H), 2.88-2.85 (m, 2H), 2.80-2.77 (m, 2H). 13C NMR (125 MHz, CD3OD): 154.2, 152.2, 149.1, 148.1, 143.5, 134.2, 132.9, 131.1, 131.0, 130.5, 129.1, 123.3, 118.7, 115.0, 114.8, 114.4, 56.2, 52.4, 49.9, 28.8, 27.3.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: NCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine gives 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])(O)[CH3:7])=[CH:2]1.C[Si]([N:19]=[N+:20]=[N-:21])(C)C.B(F)(F)F.O>C1C=CC=CC=1>[N:19]([C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)([C:9]1[O:13][CH:12]=[N:11][C:10]=1[CH3:14])[CH3:7])=[N+:20]=[N-:21]
Reactant: Cc1ncoc1C(C)(O)c1ccoc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: O
Product: Cc1ncoc1C(C)(N=[N+]=[N-])c1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethanol (1 g) was suspended in benzene (4 ml). Trimethylsilylazide (822 μl) was added followed by borontrifluoride diethyletherate (770 μl). The mixture was stirred overnight at room temperature, then poured into water and extracted to give the title compound.