Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8]Cl)(=[O:5])=[O:4].[I-:11].[Na+]>CC(=O)CC>[CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8][I:11])(=[O:5])=[O:4]
Reactant: [I-]
Reactant: CN(C)S(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: CN(C)S(=O)(=O)CCCI
Temperature: 80 °C

Procedure:
A mixture of 3-chloro-propane-1-sulfonic acid dimethylamide (1.06 g) and sodium iodide (2.57 g) in 2-butanone (20 mL) was heated at 80° C. for 16 h. After cooling to room temperature the solvent was reduced in vacuo. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was dried (MgSO4) and reduced in vacuo to give 3-iodo-propane-1-sulfonic acid dimethylamide as a yellow solid.
Reaction SMILES: [OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>O.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>[OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)=[CH:12][CH:11]=1
Reactant: CN1C(=O)C[C@H](c2ccc(I)cc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1C(=O)C[C@H](c2ccc(-c3ccc(F)cc3)cc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Yield: 50 %

Procedure:
(±)-(4R*,5R*)-5-[(1S*)Hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-iodophenyl)-1-methylpyrrolidin-2-one prepared as described in Example 21, step 1, (0.100 g, 0.204 mmol), Pd(PPh3)4 (0.025 g, 0.02 mmol) and 4-flourophenylboronic acid (0.037 g, 0.26 mmol) were stirred in anhyd. DME (1 mL). A 1M solution of Na2CO3 (0.55 mL, 0.55 mmol) in water was added and the resulting mixture was heated at the reflux temperature for 18 h. The reaction was cooled to room temperature and diluted with water. The resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (75% EtoAc/hex) to yield (±)-(4R*,5R*)-5-[(1S*)hydroxy(5-phenyl(2-thienyl))methyl]-4-[4-(4-fluorophenyl)phenyl]-1-methylpyrrolidin-2-one (0.046 g, 50%) as a yellow solid: mp 191-193° C.; 1H NMR (CDCl3) δ 2.29 (dd, J=14.5, 7.8 Hz, 1H), 2.96-3.06 (m, 1H), 3.30 (s, 3H), 3.85-3.89 (m, 1H), 4.23 (d, J=7.8 Hz, 1H), 4.50 (d, J=6.5 Hz, 1H), 5.99 (d, J=6.1 Hz, 1H), 6.88 (d, J=3.6 Hz, 1H).
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[BH3-][C:20]#N.[Na+]>CC(O)=O.CO>[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][CH3:20])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: [BH3-]C#N
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Formaldehyde (108 mg, 1.33 mmol, 37% wt solution in H2O) was added to a solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (318 mg, 1.33 mmol) and NaBH3CN (668 mg) in 10% CH3COOH/CH3OH (3 mL). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded on DOWEX™ 50W×2 column (10 mL) and washed with CH3OH (100 mL). Product was eluted off using 2 N NH3 in CH3OH (100 mL) and concentrated to afford 173 mg of crude 1-(4-chlorobenzyl)-4-{(methylamino)methyl}piperidine as a colorless oil used without purification.
Reaction SMILES: [CH2:1]([CH2:6][CH2:7][NH2:8])[CH2:2][CH2:3][CH2:4][NH2:5].[C:9]([O:16][CH2:17][CH3:18])(=[O:15])[C:10]([O:12]CC)=O>C(O)C>[CH2:17]([O:16][C:9](=[O:15])[C:10]([NH:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:6][CH2:7][NH:8][C:10](=[O:12])[C:9]([OH:16])=[O:15])=[O:12])[CH3:18]
Reactant: NCCCCCCN
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=O)NCCCCCCNC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
The method of Example II in U.S. Pat. No. 2,343,808 was used. Molten HMDA (27.1 grams) was poured into a solution of diethyl oxalate (136 grams) in ethanol (127 mL) and stirred for 18 hours. The solid was collected by filtration, dissolved in CH2Cl2 (150 mL) and purified by flash column chromatography (EtOAc as the eluent). The resulting solid was boiled in MTBE (150 mL), cooled to ambient temperature, and then collected by filtration to obtain 19.8 grams of hexamethylene-bis-oxamic acid ethyl ester as white needles having a melting point in the range of 91.6 to 92.5° C. 1H NMR (CDCl3, 300 MHz) δ 7.13 (brs, 2H), 4.34 (q, J=7.2 Hz, 4H), 3.33 (q, J=6.9 Hz, 4H), 1.59-1.52 (m, 4H), 1.37 (t, J=7.2 Hz, 6H), 1.39-1.34 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][N:3]=1>[Pd].CCO>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1n[nH]c2ncc(N)cc12
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A 25 mL round bottom flask was charged with 3-methyl-5-nitro-1H-pyrazolo[3,4-b]pyridine (39 mg, 0.22 mmol) and 10% (wt.) Pd on activated carbon (12 mg, 0.011 mmol). EtOH (10 mL) was added, and then H2 was passed through the reaction mixture for 15 minutes. The vessel was left to stir under an H2 balloon for 4 hours, after which it was filtered through a 0.45 μm PVDF filter. The volatiles were removed to afford 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine as a solid (30 mg, 92% yield).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:28])([F:27])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[CH:10]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8].CO>C(Cl)Cl>[F:28][C:6]([F:5])([F:27])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:8]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(N1CCc2cc(O)ccc2C1c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 146.8 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.77 ml, 0.77 mmol) was added slowly to a solution of 2,2,2-trifluoro-1-(6-methoxy-1-phenyl-3,4-dihydro-1H-isoquinoline-2-yl)ethanone (0.172 g, 0.513 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The resulting yellow solution was stirred at 0° C. for 30 min, then warmed to rt and stirred at rt for 22 hr. MeOH (5 ml) was slowly added to the reaction mixture with stirring and the resulting solution was concentrated in vacuo to give 0.242 g of yellow oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 0.143 g (87% yield) of white solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:15]([CH3:17])[CH3:16])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[O:5][C:4](=[O:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:3]1[C:4](=[O:18])[O:5][C:6]([CH:15]([CH3:16])[CH3:17])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:7][C:2]=1[OH:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C1(CCc2nccs2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3nccs3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-2; 0.25 g, 0.95 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.42 g, 1.15 mmol), potassium carbonate (0.52 g, 3.76 mmol), and DMF (5 mL). The product was chromatographed on silica gel, eluting with 5% MeOH in CH2Cl2, to give the title compound, mp 108-110° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[CH:17]=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.[C:36](O)([C:38]([F:41])(F)F)=O>C(Cl)Cl>[F:41][C:38]1[CH:36]=[CH:17][CH:16]=[CH:15][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:32]#[N:33])[CH2:23][C:22](=[O:34])[NH:21][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K57) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (128 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[N:14][CH:15]=1)[CH3:9])=[O:6].[CH3:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O.CN(C)C=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:16][C:13]1[N:12]=[CH:11][C:10]([C@H:8]([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][O:28][CH3:27])[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)[CH:17]=2)=[O:6])[CH3:9])=[CH:15][N:14]=1
Reactant: COCc1ccccc1B(O)O
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccccc1-c1cc(C(=O)N[C@H](C)c2cnc(C)nc2)cc(-c2ccc(C)cn2)c1

Procedure:
In a 5 mL microwave vial, (R)-3-bromo-5-(5-methylpyridin-2-yl)-N-(1-(2-methylpyrimidin-5-yl)ethyl)benzamide (50.00 mg, 0.1216 mmol), 2-(methoxymethyl)phenylboronic acid (40.36 mg, 0.2431 mmol), cesium carbonate (198.0 mg, 0.6078 mmol), tetra-n-butylammonium iodide (44.90 mg, 0.1216 mmol), and POPd (6.100 mg, 0.01216 mmol) were dissolved in Water (0.09 mL, 5 mmol) and N,N-dimethylformamide (0.4 mL, 6 mmol). The reaction mixture was microwaved for 20 mins at 150 degrees. The reaction was purified directly by reversed phase HPLC (acetonitrile:water gradient) at pH10. The combined pure fractions were reduced in vacuo to afford the title compound as white solid.
Reaction SMILES: C(=O)(O[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)OC.[C:15]1([C@@H:21]([N:23]([C@H](C2C=CC=CC=2)C)P2OC3C=CC4C=CC=CC=4C=3C3C4C(C=CC=3O2)=CC=CC=4)C)[CH:20]=CC=C[CH:16]=1.CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir]>[CH2:21]([NH:23][C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=[CH2:5])[CH:15]([CH3:20])[CH3:16]
Reactant: C[C@@H](c1ccccc1)N([C@@H](C)c1ccccc1)p1oc2ccc3ccccc3c2c2c(ccc3ccccc32)o1
Reactant: COC(=O)OC/C=C/c1ccccc1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: C1=CCCC=CCC1
Solvent: CCO
Product: C=C[C@H](NCC(C)C)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of Methyl (2E)-3-phenylprop-2-en-1-yl carbonate (1.5 g) in THF (25 ml), was added N,N-bis[(1S)-1-phenylethyl]dinaphtho[1,2-f:2′,1′-d][1,3,2]dioxaphosphepin-4-amine (420 mg), and chloro(1,5-cyclooctadiene)iridium(I) dimer (105 mg) at RT under N2. The mixture was heated at reflux overnight. Evaporated material then redissoled in a 50:50 mixture of EtOH:THF. To this solution was added macro porous p-toluenesulfonic acid resin (10 g) and the mixture was gently agitated for 3 h. At this time the resin was washed completely with THF, THF:EtOH and EtOH. To a suspension of the resin in MeOH (75 ml) was added 7 N NH3.MeOH (75 ml). This mixture was gently agitated for 2 hours and filered, washing with MeOH, THF, THF:MeOH, and DCM. Evaporating this filtrate left a yellow oil (1.2 g). This oil was then distilled on a kuglerohr vacumme distilation aparatus. This left the title compound as a clear oil. (830 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 0.90 (d, 6H, J=6.6 Hz), 1.64-1.81 (m, 1H), 2.18-2.45 (m, 2H), 4.15 (d, 1H, J=6.9 Hz), 5.06-5.22 (m, 2H), 5.85-5.97 (m, 1H), 7.20-7.41 (m, 5H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH3:8][Si:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([O:14]CC)=O.[Cl-].[NH4+]>C1COCC1>[CH3:18][Si:9]([CH3:8])([CH3:17])[CH2:10][CH2:11][C:12]1([OH:14])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)CC[Si](C)(C)C
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCC1(O)CCCC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A flask was charged with 9.82 g of magnesium and 150 ml of THF, to which a solution of 43.5 g of 1,4-dibromobutane diluted with 50 ml of THF was added dropwise at 50° C. The solution was stirred for one hour at 65° C., after which 23.5 g of ethyl 3-trimethylsilylpropionate was added dropwise below 50° C. The solution was stirred for one hour at room temperature, after which an aqueous solution of ammonium chloride was added for hydrolysis. This was followed by ordinary post-treatments. Upon vacuum distillation, there was obtained 23.6 g (yield 94%) of 1-(2-trimethylsilylethyl)cyclopentanol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>CN(C=O)C>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][CH2:21][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[N:9]1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1ncc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C

Procedure:
A mixture of 6-nitro-1H-indazole (0.500 g, 3.07 mmol) and potassium carbonate (0.889 g, 6.44 mmol) in 15.3 mL of DMF was stirred for 30 minutes after which (3-chloro-propyl)-dimethyl-amine hydrochloride (0.553 g 3.50 mmol) was added. The reaction mixture was then heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.97 (m, 2 H), 2.10 (m, 6 H), 2.14 (m, 2 H), 4.58 (t, J=6.78 Hz, 2 H), 7.99 (m, 2 H), 8.32 (m, 1 H), 8.74 (m, 1 H); MS (DCI/NH3) m/z 249 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: COC(=O)c1cncc(C#Cc2cccc(N)c2)c1
Reactant: Cc1cccc(C(=O)O)c1
Product: COC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cccc(C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 5-((3-aminophenyl)ethynyl)nicotinate and 3-methylbenzoic acid are converted to the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=NC=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:39]3[CH:40]=[N:36][CH:29]=[CH:37][CH:38]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: BrCCc1cccnc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3cccnc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(2-bromoethyl)pyridine hydrobromide and isolated as light yellow gum. MS (m/e): 388.3 (MH+).
Reaction SMILES: [CH2:1]([CH2:8][C:9]([OH:11])=[O:10])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.O.[CH2:20]([O:27][C:28](ON1C(=O)CCC1=O)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCOCC1>[CH2:20]([O:27][C:28]([NH:7][CH:3]([CH2:2][CH2:1][CH2:8][C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCCC(=O)O)C(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)CCCC(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.8 %

Procedure:
A solution of L-2-aminoadipic acid (920 mg, 5.71 mmol), triethylamine (2.85 mL, 20.5 mmol) and water (3 mL) in 12 mL of dioxane was cooled to 0° C. and N-benzyloxycarbonyloxysuccinimide (Cbz-OSu: 1.71 g, 6.85 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours and at ambient temperature for 0.5 hours. The reaction mixture was washed with ethyl acetate and then acidified with aqueous potassium hydrogen sulfate. The acidic solution was extracted with ethyl acetate and the ethyl acetate solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.80 g of the title compound. MS (FAB+) m/e 296 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][CH:27]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: N#Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(C#N)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 51 mg (0.18 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 9 mg (0.22 mmol) of 60% sodium hydride, 44 mg (0.22 mmol) of 6-bromomethyl-pyridine-2-carbonitrile and 0.7 mL of N,N-dimethylformamide. Yield: 27 mg of a white solid: LC-MSD, m/z for C25H19N3O2 [M+H]+=394.1; HPLC retention time: 2.1 min.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9]([CH2:12][C:13]#[CH:14])[CH2:8][CH2:7]1)=[O:5].C(O)(=O)C.C(OC1(O[Si](C)(C)C)CC1)C.C([BH3-])#N.[Na+]>CO>[ClH:1].[CH:12]1([N:9]2[CH2:8][CH2:7][C:6]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)(=[O:17])=[O:16])([C:4]([NH:3][OH:2])=[O:5])[CH2:11][CH2:10]2)[CH2:14][CH2:13]1
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CC1
Agent: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NO)C1(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CCN(C2CC2)CC1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
Part A: To a solution of the amine hydrochloride salt of Example 6, part E (2.13 g, 5.0 mmol) in methanol (25 mL) was added 3A molecular sieves, acetic acid (2.86 mL, 50 mmol) and the solution was stirred for 5 minutes. To this solution was added ((1-ethyoxycyclopropyl)oxy)-trimethylsilane (6.08 mL, 30 mmol) followed by sodium cyanoborohydride (1.41 g, 22.0 mmol), and the solution was heated to reflux for 18 hours. The excess salts and sieves were collected by filtration and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1N NaOH, H2O and saturated NaCl, and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the cyclopropyl amine as a white solid (1.90 g, 86%).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].Cl.[OH:6][C:7]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])=[CH:21][CH:20]=2)=[O:18])[CH2:10][CH2:9]1>O.C(O)C>[OH:6][C:7]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])=[CH:21][CH:20]=2)[OH:18])[CH2:10][CH2:9]1
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Add sodium borohydride (0.105 g, 2.77 mmol) to a solution of sodium hydroxide (0.053 g, 1.33 mmol) in deionized water (2 mL) and add, by dropwise addition, to a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid hydrochloride (0.70 g, 1.31 mmol) in ethanol (30 mL). Stir at room temperature for 3.5 hours at pH 7-8. Evaporate the solvent in vacuo and stir the residue with methylene chloride (15 mL) and deionized water (15 mL). Dry (MgSO4), acidify to pH 3 with gaseous hydrogen chloride and evaporate the solvent. Add ether with stirring, filter the white solid and wash with additional ether. Dry to give the title compound.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[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:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@@H:18]3[C:23]([O:25][C:26](C)(C)C)=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[ClH:40]>C(OCC)C>[ClH:40].[F:36][C:2]([F:1])([F:37])[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:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][C@@H:18]3[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)[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: CO
Product: COC(=O)[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 22; 50 mg, 0,094 mmol), methanol (0.3 ml) and 1M HCl in diethyl ether was stirred at room temperature for 10 days and heated at reflux for 5 hours. The mixture was concentrated in vacuo to give the title compound as a white solid.