Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24]O>>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][N:10]1[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:19])=[O:18]
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Reactant: OCCCCBr
Product: O=S1(=O)N(CCCCBr)Cc2ccccc2N1c1ccccc1F
Yield: 66.3 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.75 g, 2.7 mmol) was reacted with 4-bromobutanol (0.83 mL, 5.2 mmol) to afford 3-(4-bromobutyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.74 g, 66%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]#[C:11][CH2:12][OH:13].[OH-].[Na+].[CH2:16]([SH:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN1CCCC1=O.C(OCC)(=O)C.O>[CH2:16]([S:28][CH:12]([OH:13])[CH:11]=[CH:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCS
Reactant: OCC#Cc1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCSC(O)C=Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
To a solution of 3-(2,4,6-trichloro-phenyl)-prop-2-yn-1-ol (1.0 g; 4.2 mmol) in N-methyl-2-pyrrolidone (10 ml) and ethyl acetate (2 ml) at 2° C. was added sodium hydroxide (grind to powder) (0.19 g; 4.7 mmol). At 5° C. was added dropwise dodecanethiol (1.4 ml; 6.0 mmol). The reaction mixture was allowed to warm at 22° C. and was stirred for 30 min. The mixture was poured in water and ethyl acetate was added. Organic layer was washed three times with brine, dried over sodium sulfate and evaporated. The crude oil obtained was subject to flash chromatography (eluant: c-hexane/ethyl acetate 99:1 to 80:20) to afford 0.60 g (32% of theory) of dodecylsulfanyl-3-(2,4,6-trichloro-phenyl)-prop-2-en-1-ol as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[N:17]=[N:18][C:19]([I:22])=[CH:20][CH:21]=1.ClC1N=NC(Cl)=CC=1>>[I:22][C:19]1[N:18]=[N:17][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:21][CH:20]=1
Reactant: Clc1ccc(I)nn1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: Clc1ccc(Cl)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(I)nn1
Yield: 81 %

Procedure:
As described for example 1, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (10.0 g, 53 mmol) was converted using 3-chloro-6-iodopyridazine (Goodman, A. J.; Stanforth, S. P.; Tarbit, B. Tetrahedron 1999, 55, 15067) instead of 3,6-dichloropyridazine to the title compound (16.9 g, 81%) which was contaminated with ca. 20% of 3-chloro-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine. The product was obtained as an off white solid. MS: m/e=394.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)C.C(OC([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=O)(C)(C)C>>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([CH:6]([N:43]2[C:44]3[C:40](=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:32]4[CH:31]=[CH:30][C:29]5[CH2:28][CH2:27][CH2:26][NH:25][C:34]=5[N:33]=4)=[CH:46][CH:45]=3)[CH:41]=[CH:42]2)[CH2:5][C:4]([OH:3])=[O:17])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1cnc2ccccc2c1
Product: O=C(O)CC(c1cnc2ccccc2c1)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Yield: 81 %

Procedure:
The title compound was synthesized from quinolin-3-yl-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 81% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 8.90 (m, 1H), 8.14 (m, 1.3H), 8.04 (m, 0.7H), 7.79 (m, 2H), 7.58 (m, 1H), 7.30 (d, 1H, J=7.6 Hz), 7.13 (m, 2H), 6.93 (m, 1.3H), 6.75 (m, 1.7H), 6.63 (d, 0.7H, J=3.2 Hz), 6.53 (d, 0.3H, J=3.2 Hz), 6.38 (s, 0.7H), 6.32 (s, 0.3H), 4.38 (m, 2H), 4.05 (m, 2H), 3.75 (t, 2H, J=6.4 Hz), 3.19 (t, 2H, J=6.4 Hz), 2.72 (t, 2H, J=6.4 Hz), 1.91 (m, 2H), 1.51 (s, 9H), 1.13 (t, 0.9H, J=7.0 Hz), 1.05 (t, 2.1H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][CH2:11]O)[CH2:2][CH3:3].S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH2:11][CH2:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCN1CCCCC1CCO
Solvent: ClCCl
Product: CCCN1CCCCC1CCCl

Procedure:
To a solution of 2-(1-propyl-piperidin-2-yl)-ethanol (0.150 g, 0.875 mmol) in dichloromethane (5 mL) was added thionyl chloride (1.0 mL, 13.70 mmol) at room temperature and the reaction mixture was refluxed for 3 h. The solvent and excess thionyl chloride was removed under reduced pressure. The product was dissolved in dichloromethane and evaporated to dryness. The product was used for the next step without further purifications. GC-MS m/z 189.00.
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[CH2:8][CH2:9][NH2:10].[ClH:14]>>[ClH:14].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:1][NH:10][CH2:9][CH2:8]2
Reactant: COc1cccc(CCN)c1
Reactant: C=O
Agent: Cl
Product: COc1ccc2c(c1)CCNC2
Yield: 61 %

Procedure:
Formaldehyde solution (20%) (50 g) was added dropwise with stirring to 3-methoxyphenethylamine (50 g, 0.33M) over 15 minutes. The reaction was then heated for 1 hour on a steam bath. Excess concentrated hydrochloric acid was added and the mixture was then evaporated to dryness in vacuo. The residual solid was recrystallised from MeOH:isopropanol:ether to yield 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (41 g, 61%), m.p. 234°-5° C. (lit.* 233°-4° C.).
Reaction SMILES: [OH-].[K+].Cl.O.[NH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[CH3:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1>CO>[CH3:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:8]3[CH2:7][CH2:6][NH:5][CH2:10][CH:9]=3)=[CH:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 92.7 %

Procedure:
To a solution of potassium hydroxide (16 g) in methanol were added at 5° C. 4-piperidone hydrate hydrochloride (30 g) and a solution of 6-methyl-1H-indole (10 g) in methanol (50 ml). The mixture was refluxed for 16 hours. After cooling precipitated inorganic salts were filtered off. Methanol was evaporated and the remaining oil was dissolved in ethyl acetate (200 ml) and subsequently washed with brine (2×100 ml). After drying (anh. MgSO4) the solvent was evaporated leaving 15 g of crude 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole, which was used without further purification. The pure tetrahydropyridyl derivative crystallized from diethyl ether. Mp: 150°-152° C. To a solution of 1-(2-chloroethyl)-3-(2-propyl)-2-imidazolidinon (32 g) in MIBK (500 ml) were added 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (15 g), potassium carbonate (16 g) and potassium iodide (5 g). The mixture was refluxed for 19 hours and finally filtered while still hot. MIBK was evaporated and the resulting oil was dissolved in ethyl acetate (500 ml) and washed with brine (2×100 ml). After drying (anh. Na2SO4) ethyl acetate was evaporated. The remaining oil was stirred with diethyl ether (200 ml) and the precipitated, crystalline 3-[1-[2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl]-1,2,3,6-tetrahydro-4-pyridyl]-6-methyl-1H-indole was filtered off. Yield: 14.5 g. Mp: 170°-174° C. To a solution of the thus prepared imidazolidinon derivative (14 g) in acetic acid (300 ml), was added PtO2 (600 mg). This mixture was hydrogenated in a Parr apparatus at 3 atm. for 72 hours. The catalyst was filtered off and most of the acetic acid was evaporated in vacuo. The remaining oil was dissolved in H2O and pH was adjusted to 9-10 by addition of dil. NaOH solution. The title compound 14a was extracted with dichloromethane (2×200 ml) and isolated as above. The crude product was purified by eluting (eluent:ethyl acetate/dichloromethane/ethanol/triethylamine (40:40:20:5) through silica gel. Yield: 4.5 g. Mp: 185° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][CH2:29][CH2:30][N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].S([O-])(O)=O.[Na+]>ClCCl>[I:25][CH2:28][CH2:29][CH2:30][N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: II
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CN(CCCI)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Dry dichloromethane (40 ml), triphenylphosphine (3.28 g), imidazole (1.05 g) and iodine (3.85 g) were combined in that order. A solution of tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (1.90 g, J. Org. Chem., 1988, 53(10), 2229) in dichloromethane (10 ml) was added and the resulting reaction mixture stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen sulphite (6 g in 100 ml of water) was then added and the organic layer separated. The latter was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with iso-hexane:ether (7:3) to give tert-butyl N-(3-iodopropyl)-N-methylcarbamate (2.54 g) which was used immediately. Caesium carbonate (0.655 g) was added to a suspension of N-(3-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.453 g, Example 26) in acetonitrile (35 ml) and the mixture heated at 100° C. for 10 minutes. After cooling to room temperature a solution of tert-butyl N-(3-iodopropyl)-N-methylcarbamate (0.600 g) in acetonitrile (5 ml) was added and the reaction heated at reflux for 90 minutes. The reaction was concentrated under reduced pressure and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give a solid that was dissolved in methanol (10 ml). A solution of hydrogen chloride (generated by slow addition of acetyl chloride (12 ml) to methanol (15 ml) at 0° C. CARE—Very Exothermic) was then added to the latter solution and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give a gum that was scratched under ether:hexane (1:1) (20 ml) to give the title compound as a pale yellow powder (0.477 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.CCCCCCC.C([Mg]CCCC)CCC.CCCCCC.C([Li])CCC.[C:43]([N:62]1[CH:66]=[C:65]([CH:67]=[O:68])[N:64]=[CH:63]1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[Cl-].[NH4+]>O1CCCC1>[OH:68][CH:67]([C:65]1[N:64]=[CH:63][N:62]([C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:66]=1)[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCCC[Mg]CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCCCCC
Product: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: -13 °C
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (1.0 g, 3.79 mmol) was added to tetrahydrofuran (25 mL), and then 1.0 mol/L dibutylmagnesium heptane solution (2.0 mL) was added dropwise thereto at room temperature. The obtained solution was cooled to −13° C., 1.6 mol/L n-butyllithium hexane solution (2.6 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 1.5 hr. A solution of 1-trityl-4-formyl-1H-imidazole (1.4 g, 4.2 mmol) in tetrahydrofuran (15 mL) was added dropwise to the reaction mixture at −11° C., and the mixture was stirred at the same temperature for 5 hr. The reaction mixture was allowed to warm to 6° C. over 2.5 hr, and 20 w/v % aqueous ammonium chloride solution (30 mL) was added dropwise thereto. The organic layer was separated, and quantified to give 6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (1.2 g, 2.24 mmol). yield 71%.
Reaction SMILES: [F:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.[Cl:7][C:8]1[CH:9]=[C:10]([N:15]2[C:19](=[O:20])[CH2:18][NH:17][C:16]2=[O:21])[CH:11]=[CH:12][C:13]=1[CH3:14].C(N(CC)CC)C>C(OC(=O)C)C>[Cl:5][C:2]([Cl:6])([F:1])[S:3][N:17]1[CH2:18][C:19](=[O:20])[N:15]([C:10]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]1=[O:21]
Reactant: FC(Cl)(Cl)SCl
Reactant: Cc1ccc(N2C(=O)CNC2=O)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=O)CN(SC(F)(Cl)Cl)C2=O)cc1Cl
Reaction time: 3 h

Procedure:
23.8 g of fluorodichloromethanesulphenyl chloride in 100 ml of acetic acid ethyl ester is added dropwise within 20 minutes at -10°C, with vigorous stirring, to a suspension of 22.5 g of 3-(3'-chloro-4'-methylphenyl)imidazolidine-2,4-dione in 400 ml of acetic acid ethyl ester, and after one hour there is also added dropwise, at 0°C in the course of 10 minutes, 14.2 g of triethylamine in 100 ml of acetic acid ethyl ester; the cooling bath is subsequently removed and stirring is continued for 3 hours at room temperature. The triethylamine hydrochloride that has precipitated is filtered off and then washed with 100 ml of acetic acid ethyl ester; the solvent is evaporated off in vacuo to obtain, after recrystallisation in methanol, Compound No. 1 which melts at 166° - 167°C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH3:14])[C:7]=1[B:15]([O:20]C(C)C)[O:16]C(C)C.Cl.[OH-].[Na+]>C1COCC1>[CH2:13]([O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:2]=[O:1])[C:7]=1[B:15]([OH:20])[OH:16])[CH3:14]
Reactant: CCOc1cccc(C2OCCO2)c1B(OC(C)C)OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cccc(C=O)c1B(O)O
Yield: 98.2 %

Procedure:
To the mixture of diisopropyl 2-(1,3-dioxolan-2-yl)-6-ethoxyphenylboronate (136 g, 0.42 mol) in THF (500 mL) was added diluted HCl (2N, 200 mL) slowly at room temperature with stirring. After stirred for 1.5 h at room temperature, the reaction mixture was basified with 20% aqueous solution of NaOH to pH=12 and then washed with EtOAc (2×100 mL). The aqueous layer was acidified by using the diluted HCl (2N) to pH=2 and then extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give the target compound as white solid (80 g, yield 83%). 1H NMR (400 MHz, DMSO-d) δ 9.93 (s, 1H), 7.92 (s, 2H), 7.45-7.48 (m, 2H), 7.23-7.28 (d, 1H), 4.01-4.06 (m, 2H), 1.69-1.20 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]#[CH:27])[CH:23]=[CH:24][CH:25]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:27]#[C:26][C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[NH2:19])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: C#Cc1cccc(N)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Nc1cccc(C#Cc2cccc(C(F)(F)F)c2)c1
Temperature: 65 °C
Yield: 70.5 %

Procedure:
A multinecked round bottom flask fitted with a mechanical stirrer, reflux condenser, and thermometer was flushed and maintained under positive pressure of nitrogen. The flask was charged with 100.0 g (0.44 mol) of 3-bromobenzotrifluoride, 300 ml of dried, degassed triethylamine, 51.5 g (0.44 mol) of 3-aminophenylacetylene, 0.35 g (0.499 mmol) of bis(triphenylphosphine) palladium II chloride, 1.6 g (6.09 mmol) of (triphenylphosphine), and 0.1 g (0.52 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 20 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature followed by the addition of 200 ml of ether. Removal of the triethylamine hydrobromide salt by-product by suction filtration followed by concentration of the filtrate under reduced pressure gave the crude product as a light off-white solid. Short path distillation of the crude product under reduced pressure gave 81.0 g (0.31 mol, 71% yield) of the product as a colorless liquid which crystallized on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([CH3:23])[CH:15]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.[CH3:60][O:61][C:62]1[CH:63]=[C:64]([CH:66]=[CH:67][CH:68]=1)[NH2:65]>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].C(OC(=O)C)C.O.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:65][C:64]4[CH:66]=[CH:67][CH:68]=[C:62]([O:61][CH3:60])[CH:63]=4)[CH:3]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)=[CH:15][C:16]=1[CH3:23])[CH3:22]
Reactant: CCOc1ccc(C2(c3cccc(Br)c3)COC(N)=N2)cc1C
Reactant: COc1cccc(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C2(c3cccc(Nc4cccc(OC)c4)c3)COC(N)=N2)cc1C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A microwave tube was charged with 4-(3-bromo-phenyl)-4-(4-ethoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (Building Block M, 175 mg, 0.467 mmol, 1.0 eq), sodium tert-butoxide (89 mg, 0.933 mmol, 2.0 eq.), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′biphenyl (18 mg, 0.042 mmol, 0.042 eq.), tris(dibenzylideneacetone)dipalladium (10 mg, 0.012 mmol, 0.025 eq.) and 3-methoxyaniline (115 mg, 0.933 mmol, 2.0 eq.). After three vacuum-nitrogen cycles, toluene was introduced (1 mL), the tube was scaled and stirred at 100° C. for 16 hours. After cooling to room temperature, water (1 mL) and ethylacetate (1 mL) were added. The organic fraction of the reaction mixture was placed on an SCX column. This was then washed with dichloromethane/methanol. The desired product was obtained by eluting with 2 M ammonia in methanol. Fractions containing the compound were combined and the product purified further using preparative HPLC to yield 95 mg (30% yield) of the title compound as a white solid.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.[S:11]([N:21]1[C:25]2[N:26]=[CH:27][C:28]3[N:29]([C:30]([C@@H:33]4[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34]4)=[N:31][N:32]=3)[C:24]=2[CH:23]=[CH:22]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].CC([O-])=O.[Na+]>O.C(Cl)Cl>[N:38]1([C@H:35]2[CH2:36][CH2:37][C@@H:33]([C:30]3[N:29]4[C:24]5[CH:23]=[CH:22][N:21]([S:11]([C:14]6[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=6)(=[O:13])=[O:12])[C:25]=5[N:26]=[CH:27][C:28]4=[N:32][N:31]=3)[CH2:34]2)[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](n5cccc5)C4)n23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A solution of 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol) in water (3 mL) was heated at about 100° C. for about 1.5 h. The solution was cooled to ambient temperature. A suspension of (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentanamine hydro-chloride (0.10 g, 0.21 mmol, prepared using E from Preparation #B.1 and HCl) and NaOAc (0.05 g, 0.61 mmol) in DCM (5 mL) was added to the aqueous solution. The reaction mixture was stirred at ambient temperature for about 1 h followed by addition of additional 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol). The reaction mixture was heated to about 40° C. for about 15 h. Additional 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol) was added and the reaction mixture was stirred at about 40° C. for about 8 h then at about 35° C. for about 48 h. The reaction was diluted with DCM (10 mL) and water (10 mL). The layers were separated and the organic layer was washed with water (2×10 mL) and brine (10 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give 1-((1R,3S)-3-(1H-pyrrol-1-yl)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.095 g, 99%) as a yellow residue: LC/MS (Table 1, Method a) Rt=2.42 min; MS m/z: 447 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]([CH2:28][CH3:29])[C:12]1=[O:30])C.[OH-].[Na+]>C(O)C>[CH2:28]([N:13]1[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[C:12]1=[O:30])[CH3:29]
Reactant: CCOC(=O)CCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(-c2ccccc2)c(-c2ccccc2)n(CCCCCCC(=O)O)c1=O

Procedure:
The product is produced as described in example 18 from 12.3 g of 7-(3-ethyl-4.5-diphenyl-2-oxo-4-imidazolin-1-yl) enanthic acid ethyl ester and 1.16 g of NaOH in 60 cc. of ethanol. Further purification by chromatography on silicic acid gel using chloroform as eluant.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:9]=[CH:10][CH:11]=1.[I-].[Na+].ClC([SiH3])Cl>C(#N)C.CCOC(C)=O>[CH2:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC(c1ccccc1)c1cccc(C2OCCO2)c1
Agent: [I-]
Agent: [Na+]
Agent: [SiH3]C(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1cccc(Cc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
Combine (3-[1,3]dioxolan-2-ylphenyl)-phenyl-methanol (2.3 g, 8.7 mmol) and sodium iodide (5.3 g, 35.0 mmol) in acetonitrile (25 ml). Add dichloromethylsilane (2.1 ml, 17.4 mmol) via syringe. After 10 min, dilute with EtOAc and wash with water, saturated sodium bicarbonate, 10% sodium thiosulfate, and then brine. Dry the organic layers (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the title compound.