Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH:9][C:10]2[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([CH3:15])=[N:13][CH:14]=2)=[O:8])=[C:5]([NH2:22])[NH:4][N:3]=1.C(N(C(C)C)[CH:27]=[C:28]([F:31])[CH:29]=O)(C)C.C(O)(=O)C>C(O)(C)C.O>[NH2:22][C:5]1[C:6]([C:7]([NH:9][C:10]2[N:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:12]([CH3:15])=[N:13][CH:14]=2)=[O:8])=[C:2]2[N:1]=[CH:27][C:28]([F:31])=[CH:29][N:3]2[N:4]=1
Reactant: CC(C)N(C=C(F)C=O)C(C)C
Reactant: Cc1ncc(NC(=O)c2c(N)n[nH]c2N)n1-c1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: Cc1ncc(NC(=O)c2c(N)nn3cc(F)cnc23)n1-c1ccccc1
Temperature: 88 °C

Procedure:
To a mixture of 3,5-diamino-N-(2-methyl-3-phenyl-imidazol-4-yl)-1H-pyrazole-4-carboxamide (116 mg, 0.3902 mmol), 3-(diisopropylamino)-2-fluoro-prop-2-enal (67.59 mg, 0.3902 mmol) in isopropanol (0.58 mL) and water (0.58 mL) was added acetic acid (0.221 mL, 3.904 mmol) and the solution was heated to 88° C. for 2.5 h. The reaction mixture was partitioned between EtOAc and saturated sodium carbonate solution. Combined organic extract was dried (MgSO4), and concentrated in vacuo to give as a redish oil that was purified by fractionlynx. Clean fractions were freeze-dried to give 2-amino-6-fluoro-N-(2-methyl-1-phenyl-1H-imidazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. (16.4 mg, 8.5%). MS (ES+) 352.2.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14]([Mg]Br)[CH3:15]>C1COCC1>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([OH:7])[CH2:14][CH3:15])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: CC[Mg]Br
Reactant: COc1cc(C=O)cc(OC)c1Br
Solvent: C1CCOC1
Product: CCC(O)c1cc(OC)c(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
An oven-dried flask under argon was charged with 4-bromo-3,5-dimethoxybenzaldehyde (5.0 g, 20.4 mmol) and anhydrous THF (30 mL). The mixture was cooled over ice then a solution of ethyl magnesium bromide (3.0 M in diethyl ether, 8.2 mL, 24.5 mmol) was added dropwise from an addition funnel over a period of 45 min. After stirring for 20 min, the mixture was allowed to warm to room temperature and stirred for 19 hrs. After quenching with a solution of aqueous NH4Cl, it was diluted with H2O and EtOAc then cooled over an ice bath. After the mixture was cooled, the layers were separated. The organics were washed with H2O and brine then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo again to give 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-ol as a clear oil (5.43 g, 97% yield). The product was used without further purification.
Reaction SMILES: [CH:1]([N:4]=C=NC(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=2)[CH:19]([CH2:31][O:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH3:1][NH:4][C:28]([C:26]1[N:27]=[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH:19]2[CH2:31][O:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[S:24][CH:25]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C(=O)O)cs2)C(COc2cccnc2)C1
Reactant: CC(C)N=C=NC(C)C
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Diisoproylcarbodiimide (0.028 mL, 0.178 mmol) was added to a solution of 2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylic acid (68 mg, 0.162 mmol), methylamine hydrochloride (12 mg, 0.178 mmol), diisopropylethylamine (0.062 mL, 0.357 mmol), and N-hydroxybenzotriazole (24 mg, 0.178 mmol) in CH2Cl2 (2 mL). After stirring overnight, little reaction had taken place. TBTU (0.162 mmol) was added, and stirring was continued at rt. After 4 h, additional methylamine hydrochloride (20 mg, 0.296 mmol) was added, and the reaction was heated to 50° C. in a scaled vial overnight. Upon cooling to rt, the reaction mixture was quenched with 1 N NaOH (4 mL) and stirred for 1 h. The reaction mixture was diluted with EtOAc (20 mL) and was washed with 1 N NaOH (2×10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (40 to 90% EtOAc in hexanes gradient), yielding 35 mg (50%) of the title compound. LC-MS: RT=6.77 min, [M+H]+; =434.7. Rf=0.10 in 100% EtOAc.
Reaction SMILES: F[C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:19][O-:20].[Na+].CO>CN(C)C=O>[CH3:19][O:20][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Fc1c(OC(F)(F)F)cccc1C1CCNCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1c(OC(F)(F)F)cccc1C1CCNCC1

Procedure:
Preparation according to preparation 34: 4-[2-fluoro-3-(trifluoromethoxy)phenyl]piperidine (1.23 g, 4.7 mmol), N,N-dimethylformamide (20 ml), sodium methoxide in methanol (30%, 2.35 ml, 13.2 mmol). Yield: 1.32 g.
Reaction SMILES: [CH2:1]([N:5]([C:7](SC)=[CH:8][N+:9]([O-:11])=[O:10])[CH3:6])[CH2:2][CH2:3][CH3:4].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH2:21])[CH:15]=1.P([O-])([O-])(O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([N:5]([C:7]([NH:21][CH2:20][C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)=[CH:8][N+:9]([O-:11])=[O:10])[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: NCc1cccnc1
Reactant: CCCCN(C)C(=C[N+](=O)[O-])SC
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCN(C)C(=C[N+](=O)[O-])NCc1cccnc1
Yield: 55 %

Procedure:
A mixture of 5.2 g of 2-(N-n-butyl-N-methylamino)-2-methylthio-1-nitroethylene, 2.84 g of pyridin-3-ylmethylamine and 3.69 g of disodium hydrogen phosphate in 30 ml of ethanol is refluxed for 1 hour. After removing the salt by filtration, the solvent is evaporated from the solution under vacuum and the residue is chromatographed through a column of silica gel with a 95/5 mixture of ethyl acetate/methanol. The product is eluated with ethylacetate/methanol (85/15). The solvent is removed by evaporation, affording 3.7 g of 2-(N-n-butyl-N-methylamino)-2-(pyridin-3-ylmethylamino)-1-nitroethylene as a viscous oil (Compound 3.2, Table 3).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:3]=1[O:4][C:5]1[C:10]([NH2:11])=[C:9]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:8]=[C:7]([CH3:18])[N:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([CH:13]([NH:12][C:9]1[CH:8]=[C:7]([CH3:18])[N:6]=[C:5]([O:4][C:3]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=2[CH3:1])[C:10]=1[NH:11][C:25](=[O:27])[CH3:26])[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2-(2,4,6-trimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,4-diamine (250 mg, 0.763 mmol), acetic anhydride (72 mg, 0.763 mmol) and triethylamine (77 mg, 0.763 mmol) in 5 ml of methylene chloride was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give 310 mg of the crude material. The crude material was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 250 mg (89% yield) of N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide as tan solid, mp 154–156° C. 1H NMR(CDCl3) δ 6.97(0.64H), 6.86(s,2H), 6.26(0.36H), 6.14(0.64H), 6.12(s,0.36H), 4.80(d,0.64H), 4.40(d,0.36H), 3.2–3.4(m,1H), 2.29(s,3H), 2.26(s,1.9H), 2.17(s,1.1H), 2.16(s,1.9H), 2.06(s,6H), 1.99(s,1.1H), 1.4–1.75(m,4H), 0.97(t,6H)ppm.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[C:71]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:79].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[C:71]([C:73]5[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=5)[CH:70]=[CH:69][N:68]=4)[C:56]=3[CH3:79])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cc(-c3ccccc3)ccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(-c3ccccc3)ccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.044 mmol), 2,5-dimorpholinopyridin-3-amine (0.086 g, 0.33 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-phenylpyridin-2-yl)quinoline (0.1 g, 0.27 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.066 g, 0.68 mmol) in toluene (2.7 mL) at 120° C. for 3.25 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-phenylpyridin-2-yl)-quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (1H, d, J=5.1 Hz), 8.10 (1H, s), 7.76 (3H, m), 7.64-7.61 (3H, m), 7.57-7.49 (3H, m), 7.03 (1H, ddd, J=13.5, 8.4, 2.5 Hz), 6.48 (1H, br. s.), 3.93 (4H, app t, J=4.8 Hz), 3.81 (4H, app t, J=4.5 Hz), 3.25 (4H, br. s), 3.09 (11H, app t, J=4.9 Hz), 2.25 (3H, s). Mass Spectrum (ESI) m/e=595.3 (M+1).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([O:50][CH3:51])[N:43]=1.NC(=C)C([O-])=O>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([O:50][CH3:51])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: COc1nc(N)c(F)cc1F
Agent: C=C(N)C(=O)[O-]
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(OC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 3 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.78 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 2-amino-3,5-difluoro-6-methoxypyridine until completion of the conversion into the aminoacrylate form was confirmed by monitoring the reaction by TLC. The solution was concentrated under reduced pressure, and to the residue were added 0.80 g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol to obtain 615 mg of the title compound as a pale brown powder.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[CH3:11][O-:12].[Na+].CO>CN(C=O)C>[CH3:11][O:12][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(I)nc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(I)nc1OC
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromo-3-methoxy-6-iodopyridine (4-3, 34 g, 108 mmol) in DMF (65 mL) was added sodium methoxide in methanol (37 mL, 162 mmol, 4.37M) and heated to 100° C. The mixture was stirred for 10 minutes and partitioned between saturated NaHCO3 and DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica (0 to 20% EtOAc in hexanes) to afford the title compound (4-4) as a white powder. ESI+MS [M+H]+ C7H8INO2: 265.8 found, 266.0 required.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:40][CH:39]2[CH2:41][C:42]([O:44]CC)=[O:43])=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62]>C1COCC1>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:40][CH:39]3[CH2:41][C:42]([OH:44])=[O:43])=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CC1c1ccc(O)cc1
Reactant: CNc1cccc(CCO)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CNc1cccc(CCOc2ccc(C3CC3CC(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
To a solution of 2-[6-(methylamino)pyridin-2-yl]ethanol (1 g, 6.6 mmol) and PPh3 polymer bound (1.4 g, 9.9 mmole) in dry THF (50 mL) was added ethyl [(+)-2-(4-hydroxyphenyl)cyclopropyl]acetate (1.4 g, 6.6 mmol) from example 1 step 1, followed by diisopropyl azodicarboxylate (1.5 ml, 7.7 mmol). The reaction mixture was stirred at room temperature. After 18 hours, PPh3 polymer was filtered through celite and washed with excess THF. Filtrate was concentrated. The concentrated residue was dissolved in 1:1/acetonitrile:water (40 ml) and treated with LiOH (1 g). Reaction was heated two hours at 55° C. then cooled to room temperature. Reaction was acidified by adding TFA and purified on reverse phase HPLC twice to give 0.45 g (15%) of title compound. 1H NMR (400 MHz, CD3OD) δ 7.8 (m, 1 H), 7.0 (d, 2 H, J=8.6 Hz), 6.9-6.6 (m, 4 H), 4.26 (t, 2 H, J=6 Hz), 3.21 (t, 2 H, J=6 Hz), 3.0 (s, 3 H), 2.35-2.33 (m, 2 H), 1.71-1.67 (m, 1 H), 1.21-1.18 (m, 1 H), 0.89-0.76 (m, 2 H). HRMS calcd for C19H22N2O3 (M+H): 327.1703. found 327.1677.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:28])[CH2:13][NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH:17]=1.C=O.[CH3:31]C(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:28])[CH2:13][NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:31])[CH:17]=1
Reactant: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(C2CCCN2)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCCC1c1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyrrolidin-2-yl)benzamide (20 mg, 0.13 mmol) in MeOH (20 mL) was added HCHO (1 mL) and AcOH (0.05 mL). The reaction mixture was stirred at room temperature for 30 min at which time NaBH3CN (200 mg, 3.22 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the crude product was purified by prep-HPLC to give the desired product (8.5 mg, Yield 16.8%). 1H NMR (CD3OD, 400 MHz): δ 7.80 (brs, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.35-7.41 (m, 1H), 7.09-7.15 (m, 3H), 7.09-7.15 (m, 1H), 7.02-7.08 (m, 1H), 4.10-4.16 (m, 1H), 3.73-3.81 (m, 2H), 3.49-3.58 (m, 2H), 3.20-3.28 (m, 1H), 3.08-3.16 (m, 1H), 2.84-2.97 (m, 4H), 2.64-2.75 (m, 2H), 2.33-2.40 (m, 1H), 2.20-2.27 (m, 1H), 2.16 (s, 3H), 1.95-2.05 (m, 1H), 1.77-1.93 (m, 2H). LCMS (m/z): 394.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A degassed solution of 6-bromoindole (1.0 g, 5.1 mmol), 4-fluorobenzeneboronic acid (0.928 g, 6.63 mmol), potassium phosphate (2.7 g, 153 mmol) and palladium (0)tetrakis-(triphenylphosphine) (0.294 g, 0.255 mmol) in dimethylacetamide (50 mL) was heated at 120° C. for 14 hours. After cooling to room temperature, the mixture was diluted with water. The suspension was filtered, the solid washed with water and then dissolved in ethyl acetate (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:4) to give 0.411 g (38.2%) of the title compound as a white crystalline solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH3:33][O:32][C:31]1[C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccnc1Br
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: COc1cccnc1NC[C@@H]1[C@H](C)CCCN1C(=O)c1cc(C)ccc1-c1cnn(C)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone and 2-bromo-3-methoxypyridine. ESI-MS (m/z): 434 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[C:5]2[O:14][CH3:15].[H-].[Na+].[CH3:19][C@@H:20]1[CH2:22][O:21]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[C:3]([CH3:16])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C@H:20]([OH:21])[CH3:22])[CH:6]=[C:5]2[O:14][CH3:15]
Reactant: COc1c(C(=O)O)[nH]c2ccc(F)c(C)c12
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cn(C[C@@H](C)O)c2ccc(F)c(C)c12
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A suspension of 1.98 g of 5-fluoro-3-methoxy-4-methylindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 0.5 hour and, after cooling to 0°, diluted with 44 ml of tetrahydrofuran. 0.33 g of sodium hydride dispersion was added and the mixture was stirred for one hour. Subsequently, 1 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 90 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium surfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with toluene and toluene-ethyl acetate (9:1). 1.69 g (80%) of (R)-1-(5-fluoro-3-methoxy-4-methylindol-1-yl)-propan-2-ol were obtained as a pale brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:2]=1.[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([N:21]=[C:22]=[S:23])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([NH:21][C:22](=[S:23])[NH:10][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])[N:14]=1
Reactant: COc1nc(N=C=S)nc(OC)n1
Reactant: NS(=O)(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1nc(NC(=S)NS(=O)(=O)c2cccnc2)nc(OC)n1
Yield: 75.8 %

Procedure:
A mixture of 1.58 g of 3-pyridinesulfonamide, 2.04 g of 4,6-dimethoxy-2-isothiocyanato-1,3-5-triazine and 1.5 g of anhydrous potassium carbonate was stirred in 75 ml of acetone for 60 hours at ambient temperature. The reaction mixture was then poured into 500 ml of cold water, acidified with hydrochloric acid and the precipitated product was removed by filtration to yield 2.7 g of the desired compound, m.p. 158°-160°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>CC1C=CC=CC=1C>[CH2:26]([O:25][C:23]([C:22]1[CH:28]=[N:17][C:14]2[C:15]([C:21]=1[OH:20])=[N:16][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:12][CH:13]=2)=[O:24])[CH3:27]
Reactant: COc1ccc(-c2ccc(N)cn2)cc1OC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cnc2ccc(-c3ccc(OC)c(OC)c3)nc2c1O
Temperature: 250 °C

Procedure:
A mixture of 6-(3,4-dimethoxy-phenyl)-pyridin-3-ylamine (Stage 249.1.4, 2.0 g, 8.69 mmol) and diethyl ethoxymethylenemalonate (Aldrich, Buchs, Switzerland, 2.087 ml, 10.42 mmol) in o-xylene (22 ml) was heated by microwaves at 150° C. for 45 min and at 250° C. for 9 h. The RM was cooled to rt and crystallized with diethylether. The suspension was filtered and the cake was triturated again in hot EtOAc and cooled after in the freezer. The suspension was filtered again. The cake was washed with EtOAc and dried in the vacuum oven to give the title compound as a brown solid. Used for next step without further purification. (HPLC: tR 2.58 min (Method A); M+H=355 MS-ES)
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:16]=[C:17]([CH:25]([OH:28])[C:26]#[CH:27])[CH:18]=[C:19]([Cl:24])[C:20]=1[N:21]([CH3:23])[CH3:22])([CH3:14])([CH3:13])[CH3:12]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:11]([C:15]1[CH:16]=[C:17]([CH:25]([OH:28])[C:26]#[C:27][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:18]=[C:19]([Cl:24])[C:20]=1[N:21]([CH3:22])[CH3:23])([CH3:14])([CH3:13])[CH3:12]
Reactant: C#CC(O)c1cc(Cl)c(N(C)C)c(C(C)(C)C)c1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)c1c(Cl)cc(C(O)C#Cc2ccc(C(=O)O)cc2)cc1C(C)(C)C
Yield: 87.5 %

Procedure:
In a manner analogous to example 1 f, the process is carried out by a reaction of 200 mg (0.8 mmol) of 4-iodobenzoic acid with 300 mg (1.1 mmol) of 1-(3-tert-butyl-5-chloro-4-dimethylaminophenyl)prop-2-yn-1-ol in the presence of 8 mg (0.04 mmol) of copper iodide and 16 mg (0.02 mmol) of bis(triphenylphosphine)palladium chloride. 270 mg of 4-[3-(3-tert-butyl-5-chloro-4-dimethylaminophenyl)-3-hydroxyprop-1-ynyl]benzoic acid are obtained in the form of a whitish solid (Mp=120° C., yield=87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:19]=1)=[O:17].O[Li].O>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:19]=1)=[O:17]
Reactant: CCOC(=O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3ccccc3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3ccccc3)cc3ccccc23)c1

Procedure:
Compound 6b was synthesized from 5b (0.27 mmol) and LiOH.H2O (0.81 mmol) using the procedure according to the above Method E.