Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([O:16]C)=[O:15])[S:7][N:6]=1)[CH3:4]>O.CO>[CH2:3]([C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([OH:16])=[O:15])[S:7][N:6]=1)[CH3:4]
Reactant: CCc1nsc(C(=O)OC)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nsc(C(=O)O)c1C(=O)OC
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of 14.9 g of NaOH in 120 ml of water and 150 ml of methanol is added dropwise to 85.5 g of dimethyl 3-ethylisothiazole-4,5-dicarboxylate in 300 ml of methanol, while cooling with ice. After 2 hours, the mixture is evaporated down, 1.5 l of water are added to the residue and the mixture is stirred, and extracted with ether. The aqueous phase is acidified with concentrated hydrochloric acid and extracted by shaking with dichloromethane. The organic phases are evaporated down to give 76.4 g of 3-ethyl-4-methoxycarbonylisothiazole-5-carboxylic acid of melting point 43°-45° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:16][CH3:17])(=[O:15])[C:9]#[C:10][C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C.O=O>CN(C)C(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]1[C:8]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Temperature: 115 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
A solution of aniline (3.91 ml, 43.0 mmol) and dimethyl but-2-ynedioate (5.28 ml, 43.0 mmol) in N,N-dimethylacetamide (DMA) (194 ml)/acetic acid (64.8 ml) was degassed with O2 for 5 min and treated with Pd(OAc)2 (0.964 g, 4.30 mmol). The reaction mixture was heated to 115° C. and placed under and atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of Celite™, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 220 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (5.5 g, 23.58 mmol, 54.9% yield) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ=9.32 (br. s., 1 H), 8.08 (d, J=8.2 Hz, 1 H), 7.48-7.44 (m, 1 H), 7.42-7.37 (m, 1 H), 7.29 (s, 1 H), 4.01 (d, J=2.0 Hz, 6 H); LCMS (m/z) ES+=234 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][C:3]=1[O:26][CH2:27][CH2:28][Cl:29].[N:30]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[Cl:29][CH2:28][CH2:27][O:26][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][OH:9])[CH:10]=[C:11]2[C:2]=1[NH:1][N:30]=[C:12]2[S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cc(OCCO)cc1OCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cc(OCCO)cc12
Temperature: 3 °C
Yield: 94.6 %

Procedure:
A mixture of 2-[4-amino-3- (2-chloroethoxy)-5-(naphthalene-1-sulfonylmethyl)phenoxy]ethanol (1.22 g, 2.8 mmoles) in THF and 4M HCl was stirred, under nitrogen, at 3° C., treated dropwise with a solution of sodium nitrite (0.20 g, 2.94 mmoles) in H2O, poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound (1.18 g, 2.65 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:62]=[CH:61][C:12]([C:13]([N:15]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:59]=[CH:58][C:35]4[N:36](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:37]=[N:38][C:34]=4[CH:33]=3)[CH:29]=[CH:28][C:27]=2[F:60])[CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH:36]1[C:35]2[CH:58]=[CH:59][C:32]([C:30]3[CH:29]=[CH:28][C:27]([F:60])=[C:26]([CH:31]=3)[CH2:25][N:15]([CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]3)[C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:62][CH:61]=3)=[CH:33][C:34]=2[N:38]=[N:37]1
Reactant: CC(C)N1CCC(N(Cc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)C(=O)c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(N(Cc2cc(-c3ccc4[nH]nnc4c3)ccc2F)C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
Trifluoroacetic acid (TFA, 0.25 mL) was added to a solution of 4-fluoro-N-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-N-(1-isopropyl-piperidin-4-yl)-benzamide (18 mg, 0.024 mmol) in 1 mL of dichloromethane and the resulting mixture stirred at ambient temperature for 3 h, when an additional 0.5 mL of TFA was added. This was stirred overnight and then the mixture was neutralized by the careful addition of 1M sodium carbonate. The layers were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered, and the volatiles were removed in vacuo to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 6.5 mg of product. LC/MS: Retention time, 2.25 min; (M+H)=490.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][C@@H:10]1[CH3:14])=[O:25]
Reactant: C[C@H]1CN(c2ccc(Cl)cc2)CCN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ccc(Cl)cc2)CCN1C(=O)CCl

Procedure:
Protocol S was followed using 1-(4-Chloro-phenyl)-3-(S)-methyl-piperazine, Et3N, chloroacetyl chloride and methylene chloride. Column chromatography afforded the title compound.
Reaction SMILES: C(OCC)(=O)C.Cl.[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:28][C:29]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@H]1COc2ccccc2NC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1COc2ccccc2NC1=O)OCc1ccccc1

Procedure:
To a mixture of 100 ml of ethyl acetate and 50 ml of water is added 1.5 of 3(S)-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride, and 1.5 ml of benzyloxycarbonyl chloride is added dropwise to the mixture at ice bath temperature with stirring. After stirring for 1 hour, the ethyl acetate layer separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue is added ethyl ether and the deposited crystals are collected by filtration to give 2 g of 3(S)-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one. This product is recrystallized from a mixture of ethyl acetate and ether to give colorless needles melting at 157°-159° C.
Reaction SMILES: CC(C1C=C(S[C@@H:16]2CCC[C@H:17]2[OH:21])C=C(C(C)(C)C)C=1)(C)C.[CH3:22][C:23]([C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[S:36][C@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[OH:42])([CH3:25])[CH3:24]>>[C:17]([O:42][C@@H:38]1[CH2:39][CH2:40][CH2:41][C@H:37]1[S:36][C:27]1[CH:28]=[CH:29][C:30]([C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:31][C:26]=1[C:23]([CH3:22])([CH3:24])[CH3:25])(=[O:21])[CH3:16]
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2O)cc(C(C)(C)C)c1
Reactant: CC(C)(C)c1ccc(S[C@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Product: CC(=O)O[C@@H]1CCC[C@H]1Sc1ccc(C(C)(C)C)cc1C(C)(C)C

Procedure:
The title compounds were prepared by the method described in Example 82, except that the title product of Example 79, Compound B, was substituted for the title product of Example 75, Compound A.
Reaction SMILES: [CH:1]([C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)=O.C(OC(=O)C)(=O)C.Cl[C:25](Cl)([F:30])[C:26]([O:28][CH3:29])=[O:27]>[Zn].[Cu]Cl.O1CCCC1>[F:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:1][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: O=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 31.5 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.16 g), molecular sieve 4A (1.1 g), tetrahydrofuran (18 ml), 1-formyl-1-(4-trifluoromethoxyphenyl)cyclopropane (1.08 g), acetic anhydride (0.6 ml) and methyl dichlorofluoroacetate (0.86 g) to yield the title compound (0.45 g, 34%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[H-].[Na+].I[CH3:35]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][CH3:35])[C:5]=1[N:12]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CI
Reactant: COC(=O)c1cccc(CO)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cccc(C(=O)OC)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 28 %

Procedure:
To a solution of 0.200 g (0.452 mmol) of the product of Example 336 in 5.0 mL of dry THF was added 0.022 g (0.543 mmol) of 60% sodium hydride followed by 0.028 mL of iodomethane. The reaction was stired at room temperature for 18 h and then diluted with ethyl acetate. The organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc to provide 0.057 g (28%) of the methyl ether as ayellow solid. Electrospray Mass Spec: 457.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C.[Pd](Cl)Cl.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>[C:12]1([C:18]#[C:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9](=[O:11])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)Cc1ccccc1C#Cc1ccccc1
Yield: 59 %

Procedure:
To a 3-necked, round bottom flask under nitrogen was added 4.0 g (18.8 mmole) of 2-bromophenyl-2-propanone in 40 ml of triethylamine, 2.5 ml (22.5 mmole) of phenylacetylene, 0.3 g (2 mole %) of bis-(triphenylphosphine) palladium dichloride and 0.14 g (4 mole %) of cuprous iodide. After refluxing for three hours another 0.5 ml (4.5 mmole) of phenylacetylene, 0.6 g (4 mole %) of bis (triphenylphosphine) palladium dichloride and 0.3 g (8 mole %) of cuprous iodide were added. Reflux was continued another 11/2 hours before 1.0 ml (9.0 mmole) of phenylacetylene and 10 ml of triethylamine were added. After an additional 21/2 hours at reflux the reaction was partitioned between ether and water, washed with brine, dried over MgSO4 and evaporated in vacuo to yield 55 g of crude reaction product. The mixture was flash chromatographed eluting with 1:19 ethyl acetate:hexane to give 2.6 g (59%) of 2-(phenylethynyl)phenyl-2-propanone as a dark oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.Cl[CH:17](Cl)[CH3:18]>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:18][CH2:17]2
Reactant: CC(Cl)Cl
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: O=S(Cl)Cl
Product: O=C1CCc2cc(F)ccc2C1
Temperature: 0 °C

Procedure:
4-fluorophenylacetic acid (1 equivalent) was dissolved in dichloroethane (1.3 M) containing SOCl2 (3 equivalents), the mixture was refluxed for 90 minutes and the solvent was removed. Solution of this crude product in CH2Cl2 was added dropwise within 60 minutes to AICl3 (2 eq) in CH2Cl2 (0.4 M) while stirring at 0° C. Thereafter, ethylene was introduced at 0° C. over 45 minutes, whereupon the mixture was stirred further at room temperature for 1 hour, and thereafter was treated at 0° C. with ice-water. The organic phase was washed with 1N HCl (2×), NaHCO3 (sat. sol.), dried and evaporated. The residue was triturated with hexane, yielding the product as a bright yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Br:18]
Reactant: Cc1ccccc1-c1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1ccc2ccccc2c1
Yield: 78.5 %

Procedure:
105 g (0.48 mol) of 25 and 90 g (0.5 mol) of N-bromo-succinimide were dissolved in 2000 cm3 of tetrachloromethane at room temperature, 3 g of azobisisobutyronitrile were added, and the mixture was refluxed for 4 hours. The succinimide which precipitated was filtered off, the solvent was removed in vacuo, and the residue was purified by filtration through 1000 g of silica gel (hexane/methylene chloride 9:1), giving 112 g (79%) of 26 as a colorless lachrymatory oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:11]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OCC)c1
Yield: 33.1 %

Procedure:
Starting with 10.0 g of ethyl pyrrole carboxylate (72 mmol) and 33 ml (144 mmol) of dodecanoylchloride and following a procedure analogous to the one described above, 7.65 g (33% yield) of the desired product is obtained. 1H NMR (δ ppm, CDCl3): 9.66 (s, br, 1H, NH); 7.51 (dd, J=1.61, 3.40; 1H, α-pyrrolic); 7.26 (dd, J=1.61, 2.60; 1H ; β-pyrrolic); 4.33 (q, 2H, J=7.16 Hz, CO2Et); 2.73 (t, 2H, J=7.53; α-CO CH2); 1.68 (m, 2H, β-CO CH2); 1.35 (t, 3H, J=7.16; CO2Et); 1.23 (m, 16H, alkyl-CH2); 0.85 (t, 3H, J=7.02, end CH3). 13C NMR (δ ppm, CDCl3): 196.21; 160.96; 127.19; 125.88; 124.09; 114.68; 60.92; 39.81; 31.89; 29.60; 29.58; 29.49; 29.45; 29.41; 29.31; 24.62; 22.66; 14.34; 14.08. Exact mass calculated for C19H32NO3 (M+H)=322.238219, found=322.238983.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH:53]([CH3:56])[CH2:54][NH2:55])=[CH:49][CH:48]=1>CN(C=O)C>[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH:53]([CH3:56])[CH2:54][NH:55][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:22])=[CH:49][CH:48]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: COc1ccc(C(C)CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(C(C)CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-(4-methoxyphenyl)propylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-[2-(4-methoxyphenyl)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.40 min, MH+ 442.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:42][C:43]([F:46])([F:45])[F:44].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:42][C:43]([F:46])([F:45])[F:44])[N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)CI
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(F)(F)F)c4cc(F)ccc34)nc12
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a mixture of N-tert-Butyl-2-(6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 0.12 mmol) and potassium carbonate (100 mg, 0.72 mmol) in 10 mL of DMF was added 2-iodo-1,1,1-trifluoroethane (0.5 mL, 5.07 mmol). The reaction mixture was heated to 80° C. for 3 hours. After cooling to room temperature, 50 mL of water were added, and the mixture was extracted with ethyl acetate (2×50 mL), combined organics dried with sodium sulphate, filtered and concentrated to give N-tert-butyl-2-(6-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, crude). LCMS: (M+H)+=565; (M+Na)+=587. Crude material used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[N:4]=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH3:13]
Reactant: CCC(=O)c1ccccc1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(=Nc1c(C)cc(C)cc1C)c1ccccc1
Temperature: 200 °C

Procedure:
2,4,6-Trimethylaniline (11.5 mL, 82 mmol, Aldrich) was mixed with propiophenone (10 mL, 74.5 mmol, Aldrich) and p-TsOH (1.4 g, 7.3 mmol, Aldrich). The resulting mixture was heated for 2 h at 200° C. under a slow stream of Ar to remove H2O which formed. After cooling to RT the reaction mixture was poured into hexanes (100 mL), filtered, the precipitate washed with additional hexanes (2×100 mL) followed by the evaporation of the filtrate. The residue was filtered through a 9×4.1 cm plug of silica gel in hexanes/ether 10/1 (300 mL collected). After evaporation of the solvent the unreacted starting materials were distilled off under vacuum (45–50° C./0.4 mm). The residue was crystallized from methanol. Product was isolated as large orange-yellow crystals, 4.8 g, (25.6%). 1H NMR (CDCl3) 8.00–7.94 (m, 2H); 7.51–7.45 (m, 3H); 6.89 (s, 2H); 2.50 (q, 2H; J=7.7 Hz); 2.31 (s, 3H); 2.04 (s, 6H); 0.98 (t, 3H; J=7.7 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][NH2:18])[CH2:15][NH2:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[S:20](N)(N)(=[O:22])=[O:21]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:15][NH:16][S:20](=[O:22])(=[O:21])[NH:18][CH2:17]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(CN)CN)cc1
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1
Yield: 64.3 %

Procedure:
[4-(2-Amino-1-aminomethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester (as prepared in Example 4, step (b), 30.4 mg, 0.114 mmol) and sulfamide (15.4 mg, 0.802 mmol) in pyridine (0.7 mL) was heated at reflux for 4 h. The reaction mixture was concentrated in vacuo, and the residue was purified on silica (20%-70% EtOAc-hexane) to obtain the title compound (24 mg, 64%): 1H-NMR (DMSO-d6; 400 MHz): δ 9.35 (br s, 1H), 7.45 (m, 2H), 7.15 (m, 2H), 6.73 (m, 2H), 3.52 (m, 2H), 3.27 (m, 2H), 2.85 (m, 1H), 1.52 (s, 9H).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[O:3]C1=O.[NH3:13]>>[C:4]([NH2:13])(=[O:3])[C:5]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[SH:1]
Reactant: O=c1oc(=O)c2ccccc2s1
Reactant: N
Product: NC(=O)c1ccccc1S
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
An amount of 1.94 g of the compound of Example 1 was dissolved in 50 ml of ammonia saturated methanol, the solution was stirred at room temperature for 20 minutes, the methanol was evaporated, and an aqueous citric acid solution added followed by an extraction with ethyl acetate. After washing with aqueous sodium chloride, the mixture was dried over anhydrous magnesium sulfate, the ethyl acetate solution was concentrated, and the residue developed with methylene chloridemethanol (97:3) by silica gel column chromatography to obtain 1.63 g of the desired compound (yield 99.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([N:25]1[CH2:33][C:32]2([C:34]([O:36][CH3:37])=[O:35])[CH:27]([C:28](I)=[CH:29][CH2:30][C:31]2([CH3:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO.C1(C)C=CC=CC=1.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>[CH2:18]([N:25]1[CH2:33][C:32]2([C:34]([O:36][CH3:37])=[O:35])[CH:27]([C:28]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:29][CH2:30][C:31]2([CH3:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2(C)c1ccccc1
Reactant: COc1ccc(B(O)O)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: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(OC)cc1)=CCC2(C)c1ccccc1
Yield: 51.7 %

Procedure:
A solution of 20.1 g (0.132 mol) of 4-methoxyphenylboronic acid in 580 cm3 of methanol and 1170 cm3 of a 2N aqueous sodium carbonate solution were successively added to a solution of 58.6 g (0.12 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate and of 7 g of tetrakis(triphenylphosphine)palladium in 30 cm3 of toluene and then the mixture was brought to reflux for twenty-four hours. After returning to a temperature in the region of 20° C., the reaction mixture was extracted with ethyl acetate, washed with distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (98/02 by volume) mixture. 29 g (52%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4-methoxyphenyl)-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a brown powder, the characteristics of which were as follows: