Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH:19]=[O:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1([Mg]Cl)[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([CH:19]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH:11]=2)[OH:20])[CH2:23][CH2:22]1
Reactant: Cl[Mg]C1CC1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C(O)C2CC2)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
1-(Phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.25 g, 0.87 mmol) was dissolved in dry THF (9 mL) and chilled to 0° C. Cyclopropylmagnesium chloride (2.6 mL of a 0.5M solution in THF, 1.5 eq.) was then added by syringe to the cold reaction mixture and stirred at 0° C. for 30 minutes. The mixture was then quenched with saturated ammonium chloride solution, extracted with EtOAc, extracts dried over sodium sulfate and concentrated to provide cyclopropyl(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanol (0.285 g, 98%). m/z (APCI-pos) M+1=329.1.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21]>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:18]([F:17])[CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: COc1ccc(N)cc1F
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Product: CCn1c(=O)ccc2cnc(Nc3ccc(OC)c(F)c3)nc21
Temperature: 175 °C
Yield: 41 %

Procedure:
A mixture of 8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (124 mg, 0.52 mmol) and 148 mg (1.05 mmol) of 3-fluoro-4-methoxyaniline was heated at 175° C. for 10 minutes. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate. Recrystallization from ethyl acetate and hexane provided 67 mg (41 %) of 8-ethyl-2-(3-fluoro-4-methoxyphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 196-198° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[N:40](C3CCCCO3)[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[NH:40][N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC[C@@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1F
Yield: 76.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide (126 mg, 0.187 mmol) prepared in Example 140a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (63 mg, 77%) as a colorless solid.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[O-]CC.[Na+].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=O)=[CH:13][C:12]=1[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[O:29])=[N:23]1>C(O)C>[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)=[CH:13][C:12]=1[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[C:30]2[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=2[F:36])=[N:23]1
Reactant: CC(N)=NO
Reactant: COC(=O)c1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(-c2ccc(Cl)c(Cn3ccc(NC(=O)c4c(F)cccc4F)n3)c2)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of acetamide oxime (89 mg, 1.20 mmol, GFS chemicals) in ethanol (2 ml) was added 4A activated molecular sieves (418 mg) (pre-dried in the oven overnight) and then 21% sodium ethoxide in ethanol (0.2 ml, 0.536 mmol, Alfa Aesar). To the reaction mixture was added methyl 4-chloro-3-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]benzoate (for a preparation see Intermediate 23)(105 mg, 0.259 mmol). The reaction was heated to reflux (100° C.) and stirred for 3 h under nitrogen. The reaction mixture was evaporated in vacuo and the residue dissolved in methanol (0.5 ml) and filtered through a hydrophobic frit. The residue was dissolved with DMSO (0.5 ml) and the sample was purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a white gum (6.1 mg);
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[NH2:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:31]3[CH:32]=[N:33][C:28]([NH2:27])=[CH:29][CH:30]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: Nc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Yield: 90.5 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxa zinan-2-one (1.6 g, 3.84 mmol) and 6-aminopyridin-3-ylboronic acid (1.0 g, 4.61 mmol), Pd(Ph3P)2Cl2 (150 mg), and aq Cs2CO3 solution (3.84 mL, 2 M) in 1,4-dioxane (150 mL) was stirred and heated to reflux for 2 h. The mixture was filtered and the filtrate was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.5 g, 90%), which was used for the next step without purification. 1H NMR (CDCl3): δ=1.51 (d, 3H), 2.17-2.31 (m, 3H), 2.54-2.60 (m, 2H), 2.90 (m, 1H), 4.46 (s, 2H), 4.99-5.09 (m, 2H), 5.65-5.71 (m, 2H), 6.54 (m, 2H), 6.88 (d, 2H), 7.03 (t, 2H), 7.21-7.27 (m, 3H), 7.58 (d, 1H), 8.22 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(CC#Cc1cccnc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC#Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of 49 (43 mg, 0.17 mmol) in CH2Cl2 (0.8 mL) at 0° C. was added TFA (1.5 mL, excess), the ice bath was removed and the resultant solution was stirred at ambient temperature for 1 h. The solvent and excess TFA were removed under a stream of argon and the residue was dissolved in HCl(aq) (1.0 M, 1 mL) and washed with CH2Cl2 (3×10 mL). To the aqueous fraction was added CH2Cl2 (8 mL) and water (8 mL) and the pH was adjusted to 10 with NaOH(aq) (10 N) while stirring. The organic fraction was collected and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 10/90, Rf=0.16) to afford the title compound 50 (13 mg, 53% yield) as an orange oil: 1H NMR (CDCl3) δ 8.65 (m, 1H), 8.51 (m, 1H), 7.07 (m, 1H), 7.23 (m, 1H), 3.64 (br s, 2H), 2.50 (br s, 3H); LRMS (ESI) m/z calcd for C9H11N2 [M+H]+ 147. found 147; LRMS (ESI) m/z calcd for C8H6N [M−NH(CH3)]+ 116. found 116; HRMS (ESI) m/z calcd for C9H11N2 [M+H]+ 147.0922. found 147.0921; HPLC>98% (tR=7.25 min, 60 (A):40 (B): 0.02 (C); tR=2.91 min, 60 (A):40 (B): 0.07 (C)).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:27][CH:26]3[CH:22]([N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25]3)[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:42]>C(Cl)Cl.CCOCC>[ClH:42].[Br:1][C:2]1[C:3]([N:20]2[CH2:27][CH:26]3[CH:22]([NH:23][CH2:24][CH2:25]3)[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CN(c3c(Br)cnc4[nH]cc(NC(=O)c5cccnc5)c34)CC21
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c[nH]c2ncc(Br)c(N3CC4CCNC4C3)c12)c1cccnc1
Yield: 28 %

Procedure:
A solution of tert-butyl 5-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (0.070 g, 0.13 mmol) in DCM (3 mL) was treated with TFA (1 mL) followed by 1M HCl in ether as described in Example 62, Step C, to provide N-(5-bromo-4-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (20 mg, 28% yield). 1H NMR (400 MHz, D2O) δ 9.15 (s, 1H), 8.84-8.83 (m, 1H), 8.78-8.75 (m, 1H), 8.24 (s, 1H), 8.00-7.96 (m, 1H), 7.43 (s, 1H), 4.15-4.11 (m, 1H), 3.97-3.92 (m, 1H), 3.73-3.69 (m, 1H), 3.65-3.61 (m, 1H), 3.54-3.50 (m, 1H), 3.27-3.23 (m, 2H), 2.91-2.87 (m, 1H), 2.00-2.94 (m, 1H), 1.88-1.86 (m, 1H); LCMS (APCI+) m/z 427, 429 (M+H)+.
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[O-][CH2:32][CH3:33].[Na+]>C(O)C>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([O:20][CH2:32][CH3:33])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC[O-]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 308.7 %

Procedure:
Single Aminoacid, Di- and Tripeptide-ketoesters (General Procedure). To a stirred solution of 8.53 g (15.0 mmol) of Z-Leu-Phe-EE in 40 ml anhydrous ethanol at room temperature was added dropwise a solution of sodium ethoxide (0.204 g; 3.0 mmol) in 20.0 ml anhydrous ethanol. The color of the reaction mixture change from colorless or pall yellow to deep yellow or orange dependent on enol-ester. Then the reaction mixture was stirred at room temperature for 4-5 hours, the ethanol was then evaporated in vacuo (rotavaporator) and the residue treated with 200 ml ethyl ether (or 200 ml ethyl acetate in the case of the tripeptide). The ether (ethyl acetate) solution was washed with 2×75 ml H2O, 2×75 ml satd. NaCl, decolorized with carbon and dried over MgSO4. After evaporation of solvent, the crude product 6.09 g (89.7%) was flash chromatographed on silica gel using CHCl3 : MeOH=50:1 v/v. Evaporation of solvent give pure Z-Leu-Phe-COOEt (4.08 g; 58.0%) as a thick oil. Single spot on TLC, Rf =0.60, A; 0.47, M. Mass spectrum, FB-MS [(M+1)/Z]=469.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CS(C)=O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-chloro-2-nitrobenzonitrile (7.828 g, 42.9 mmol) and morpholine (4.49 mL, 51.5 mmol) in DMSO (20.00 mL) was stirred at rt for 1 h, after which time LC-MS indicated a small amount of desired product formed. The reaction was heated to 100° C. After 24 h the reaction was equilibrated to rt and poured into 50 mL ea 1N aq. hydrochloric acid and EtOAc. The resulting orange precipitate was collected by filtration, rinsing with EtOAc, then dried under vacuum. Mass Spectrum (ESI) m/e=234.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(O)c(C)n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(C)n1
Temperature: 25 °C

Procedure:
To a solution of 2,6-dimethyl-3-pyridinol (3 g, 24.35 mmol) in THF (30 ml) at r.t., were added Cs2CO3 (15.87 g, 48.71 mmol) and 3,4-difluoro-1-nitro-benzene (3.87 g, 24.35 mmol). The reaction mixture was heated at reflux for 2 h. After cooling to r.t. the solids were filtered off and the filtrate was evaporated to dryness. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D21 (5.88 g, 92%).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([CH:39]4[CH2:41][CH2:40]4)=[CH:34][N:33]=3)[CH2:28][CH2:27]2)=[O:25])=[C:20]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:19]=1>>[CH:39]1([C:35]2[CH:36]=[C:37]([CH3:38])[C:32]([N:29]3[CH2:30][CH2:31][N:26]([C:24]([C:21]4[CH:22]=[CH:23][C:18]([N:11]5[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]5(=[O:15])=[O:16])=[CH:19][C:20]=4[S:42]([CH3:45])(=[O:44])=[O:43])=[O:25])[CH2:27][CH2:28]3)=[N:33][CH:34]=2)[CH2:40][CH2:41]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3[C@H](CO)CCS3(=O)=O)cc2S(C)(=O)=O)CC1
Yield: 31 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (241 mg) described in Preparation Example 1 and (4-bromo-2-methanesulfonylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (478 mg) described in Preparation Example 126 and by the reaction and treatment in the same manner as in Example 32, the title compound (170 mg) was obtained.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:36])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:15]=1.CC(O)=O.C(Cl)Cl>CCCCCCC.CCOC(C)=O.[Zn]>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([CH:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:16]2[CH:15]=[C:14]([S:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:36])=[O:4])[CH:19]=[CH:18][CH:17]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(c1ccc(C(F)(F)F)cc1)c1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(c1ccc(C(F)(F)F)cc1)c1cccc(SCc2ccccc2C(=O)O)c1
Yield: 76.5 %

Procedure:
The titled compound was prepared according to the method described for example 1 above from 2-{3-[1-(4-Trifluoromethyl-phenyl)-ethoxycarbonylmethyl]phenylsulfanylmethyl}-benzoic acid 2,2,2-trichloro-ethyl ester (157 mg, 0.0.259 mmol), zinc (339 mg, 5.18 mmol), HOAc, 97% (1.48 mL, 25.9 mmol) and DCM (12 mL). The crude was submitted to flash chromatography using heptane and EtOAc (70/30-60/40) as eluent to give the titled compound (94 mg, 77%) as an oil; 1H NMR (400 MHz, CDCl3): δ 1.53 (s, 3H), 3.60 (dd, 2H), 4.54 (dd, 2H), 5.91 (m, 1H), 7.07-7.12 (m, 1H), 7.15-7.20 (m, 2H), 7.21-7.32 (m, 3H), 7.35-7.42 (m, 3H), 7.58 (d, 2H), 7.98 (d, 1H); Mass spectrum: M−H+ 473.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH:25]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=1
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)O)c1
Reactant: COC(=O)CNCC(=O)OC
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)N(CC(=O)OC)CC(=O)OC)c1

Procedure:
The conversion of 3-(tetradecyloxy)benzoic acid to the acid chloride followed by treatment with dimethyl iminodiacetate as in Example 1 gave N-(2-methoxy-2-oxoethyl)-N-[3-(tetradecyloxy)benzoyl]glycine methyl ester, mp <23°. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:15](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:13]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCC1(c2ccc(Br)cc2)CC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC1(c2ccc(Br)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
[1-(4-Bromo-phenyl)-cyclopropyl]-methanol (11.42 g, 50.29 mmol) was dissolved in CH2Cl2 (171 mL) and the solution was cooled to −78° C. Triethylamine (8.41 mL, 60.35 mmol) was added followed by methanesulfonyl chloride (4.30 mL, 55.31 mmol) and the reaction stirred at −78° C. for 1 hour. The reaction was allowed to slowly warm to 0° C. while stirring for an addition 1.5 hours. The reaction was submitted to standard aqueous workup and was then diluted with DMF (90 mL) and evaporated to remove any residual CH2Cl2. Sodium cyanide (7.39 g, 150.8 mmol) and DMF (20 mL) were added and the reaction was heated to 70° C. for 3 hours. The reaction was cooled and submitted to standard aqueous workup to give the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccnc(S(C)(=O)=O)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Nc3ccnc(S(C)(=O)=O)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of N-tert-butyl-2-(2-(methylsulfonyl)pyridin-4-ylamino)-5-((2-(trimethylsilyl) ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (127 mg, 245 μmol) in dichloromethane was added trifluoroacetic acid (558 mg, 377 μL, 4.9 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (4 mL), methanol (2 mL) and ammonium hydroxide (0.7 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(2-(methylsulfonyl)pyridin-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (94 mg, 242 μmol, 99%) as an off white solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.51 (s, 1H), 10.36 (s, 1H), 8.39 (d, J=5.9, 1 H), 8.10 (s, 1H), 8.01 (s, 1H), 7.99 (dd, J=5.3, 2.3, 1 H), 7.83 (d, J=2.1, 1 H), 7.52 (s, 1H), 3.15 (s, 3H), 1.35 (s, 9H); MS (EI/CI) m/z: 389.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][NH:6]1)=[O:4].C(N(CC)CC)C.[CH:15]([S:18](Cl)(=[O:20])=[O:19])([CH3:17])[CH3:16]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:18]([CH:15]([CH3:17])[CH3:16])(=[O:20])=[O:19])=[O:4]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC(=O)C1CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of aziridine-2-carboxylic acid methyl ester (0.5 g) in dichloromethane (20 ml) at 0° C. were added triethylamine (0.95 g) and isopropylsulfonyl chloride (1.38 g). The mixture was warmed to room temperature and stirred for 3.5 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with brine. The organic phase was dried (MgSO4), filtered and evaporated to give the crude 1-(propane-2-sulfonyl)-aziridine-2-carboxylic acid methyl ester as a yellow oil.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.CN(CCN(C)C)C.[CH2:27]([N:29]([CH:39]([O:44][CH3:45])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[CH3:28].[CH3:46][Si:47](Cl)([CH3:49])[CH3:48]>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Si:47]([CH3:49])([CH3:48])[CH3:46])[C:31]=1[C:30]([N:29]([CH2:27][CH3:28])[CH:39]([O:44][CH3:45])[C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38]
Reactant: C[Si](C)(C)Cl
Reactant: CCN(C(=O)c1ccccc1Cl)C(OC)C(C)(C)C
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCN(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(OC)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 59.7 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (3.53 mL, 4.59 mmol) was added to a dry ice/acetone cooled solution of TMEDA (639 mL, 4.23 mmol) and N-ethyl-N-(1-methoxy-2,2-dimethylpropyl)-2-chlorobenzamide (1.0 g, 3.53 mmol) in THF (7 mL). The resulting mixture was stirred at -78° C. for 45 min, then TMSCl (671 mL, 5.29 mmol) was added in a single portion. The reaction was allowed to warm to 0° C., and partitioned between ether and 10% HCl. The ether solution was then extracted with sat aq NaHCO3, dried (MgSO4), and purified by RC with 1:49 EtOAc/hexanes to afford 750 mg of the title compound as a white solid, a 60% yield. m.p. 82-83° C.
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[CH2:14]([CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O[K])(C)(C)C.O>COCCOC.C(O)C>[CH2:14]([CH:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[C:11]#[N:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC1CCCC1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CCCCCCCC1CCCC1C#N
Temperature: 0 °C
Yield: 63.2 %

Procedure:
27.6 g of tosylmethyl isocyanide and 20 g of 2-heptylcyclopentanone were dissolved in 400 ml of 1,2-dimethoxyethane and 10 ml of ethanol. The solution was cooled to 0° C. with an ice-bath, and 29 g of tBuOK were added in 1 hour maintaining the temperature between 0 and 10° C. After completion of the reaction, the reaction mixture was poured into water and extracted with cyclohexane. The organic layer was washed 3 times with water until neutral pH. Purification by bulb-to-bulb distillation (150° C./0.06 mbar) gave 13.4 g of the pure 2-heptylcyclopentanecarbonitrile.