Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)#[CH:18]>>[CH3:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(C)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: Cc1cccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 59.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 3-ethynyltoluene (0.08 mL, 0.65 mmol) to provide 256 (80 mg, 60% yield) as a tan solid. LC-MS (M+H=311 obsd.=311).
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([CH2:33][O:34][C@H:35]3[O:43][C@H:42]([CH2:44][OH:45])[C@@H:40]([OH:41])[C@H:38]([OH:39])[C@@H:36]3[OH:37])[O:22][C@@H:15]([O:16][CH2:17][CH2:18][N:19]=[N+]=[N-])[C@@H:14]2[F:46])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]>O.[Pd]>[C@H:1]1([O:12][C@H:13]2[C@H:24]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:23]([CH2:33][O:34][C@H:35]3[O:43][C@H:42]([CH2:44][OH:45])[C@@H:40]([OH:41])[C@H:38]([OH:39])[C@@H:36]3[OH:37])[O:22][C@@H:15]([O:16][CH2:17][CH2:18][NH2:19])[C@@H:14]2[F:46])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: [N-]=[N+]=NCCO[C@@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@H]1F
Agent: [Pd]
Solvent: O
Product: NCCO[C@@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@H]1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-azidoethyl α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-4-O-benzyl-2-deoxy-2-fluoro-β-D-glucopyranoside (1.77 g, 2.66 mmol) and Pd/C (0.133 mmol) in water (30 mL) was allowed to stir under a balloon of H2 at rt for 16 h. The catalyst was filtered off and washed with H2O (3×10 mL). The Titrate was concentrated to give the title compound. UPLC Method B: calculated for C20H36FNO15 549.21, observed m/e: 550.29 [M+1]; Rt=0.86 min. 1H NMR (D2O) δ 5.16-5.14 (1H, m), 4.88-4.86 (1H, m), 4.80-4.76 (1H, m), 4.30-4.16 (1H, m), 4.06-4.03 (1H, m), 3.98-3.88 (4H, m), 3.86-3.72 (9H, m), 3.70-3.62 (5H, m), 2.94-2.88 (2H, m).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCCC1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 71 at rt but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as a white powder (3 mg, 5%). HPLC, Rt: 3.78 min. (purity 100%). LC/MS, M+(ESI): 405.3, M−(ESI): 403.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[CH2:33][C:34]([N:36]1[CH2:41][C@@H:40]([CH3:42])[N:39]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[CH2:38][C@@H:37]1[CH3:53])=[O:35]>CN(C)C=O.O1CCCC1.C(OCC)C>[CH3:53][C@H:37]1[CH2:38][N:39]([C:43]2[CH:44]=[CH:45][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:47][CH:48]=2)[C@H:40]([CH3:42])[CH2:41][N:36]1[C:34](=[O:35])[CH2:33][O:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:18]([F:19])([F:20])[F:21])[CH:6]=2)[CH2:12][CH2:13]1
Reactant: C[C@@H]1CN(C(=O)CCl)[C@@H](C)CN1c1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)CO[C@H]2CC[C@H](Nc3ccc([N+](=O)[O-])c(C(F)(F)F)c3)CC2)[C@@H](C)CN1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (118 mg, 0.39 mmol, prepared in accordance with Example 5) was placed under an inert atmosphere, dissolved in dry dimethylformamide (2 mL). A molar solution of lithium bis(trimethylsilyl)-amide (774 μL, 0.77 mmol) was added to the resulting mixture. The mixture was then stirred for 15 min at room temperature. Afterward, a solution of 2-chloro-1-[trans-2,5-dimethyl-4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (130 mg, 0.39 mmol, prepared in accordance with Example 3) in tetrahydrofuran (1 mL) was added. The resulting mixture was stirred at room temperature until the conversion stopped. Next, the mixture was diluted with diethylether (10 mL). The mixture was then washed with water (5 mL), and then saturated aqueous sodium hydrogencarbonate (5 mL). The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product isolated was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (24 mg, 10% yield). The structure was confirmed using Protocol II-A. Calculated mass=603; observed mass=603; HPLC retention time=4.69 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1cccnc1C
Solvent: CC(=O)O
Product: Cc1ccc[n+]([O-])c1C
Reaction time: 3 h

Procedure:
2,3-Dimethylpyridine(40g) was dissolved in glacial acetic acid(80ml). To the solution was added 35% hydrogen peroxide(46.5g), and the mixture was heated at 100°-110° C. to be reacted under reflux with stirring for 3 hours. After the reaction, to the reaction solution was added pformaldehyde(1.5 g); the mixture was heated at 100°-105° C. to decompose the residual hydrogen peroxide and then was concentrated to give 2,3-dimethylpyridine-1-oxide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[N:68][C:69]([O:72][CH3:73])=[CH:70][CH:71]=1>C(Cl)Cl>[CH3:73][O:72][C:69]1[N:68]=[CH:67][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:71][CH:70]=1
Reactant: COc1ccc(N)cn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.217 mmol) in methylene chloride (10 mL), HATU (Aldrich, 118 mg, 0.31 mmol) was added followed by the addition of DIPEA (0.15 mL, 0.86 mmol) and 3-amino-6-methoxy-pyridine (Aldrich, 43 mg, 0.34 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 0-5% MeOH/methylene chloride) to give a white solid. 73 mg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:11].O=P(Cl)(Cl)Cl.Cl.[OH-].[Na+]>O>[Cl:11][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc[n+]([O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccncc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound was prepared by a modified procedure based on the method of J. Rokach and Y. Girard, J. Heterocycl. Chem. 1978, 15, 683–684. 4-Cyanopyridine-N-oxide (250 g, 2.08 mol) was added portionwise to a stirred suspension of PCl5 (599.94 g, 2.88 mol) and POCl3 (800 mL, 8.71 mol) at 20° C. under nitrogen, in a reactor fitted with a reflux condensor. During the addition the temperature rose to 41° C. The mixture was stirred at 100° C. for 3 h then cooled to 95° C. and transferred to a mixture of 6M HCl (200 mL) and a 6:4 mixture of ice and water (5994 g) at such a rate that the temperature stayed below 15° C. (about 35 min). The resulting brown solution was cooled to below 5° C. and taken to pH 4.15 by adding 33% aqueous NaOH (about 4.5 L), keeping the temperature below 5° C. The resulting beige precipitate was filtered and washed thoroughly with water (4×500 mL), sucking as dry as possible. The residue was suspended in water (1.5 L) and n-heptane (7 L) and stirred at 30° C. for 1 h. The aqueous phase was separated and extracted further with n-heptane (2×2 L), stirring for 30 min each time at 30° C. The combined heptane layers were combined, dried (Na2SO4, 136 g), filtered and the resulting solution was concentrated under reduced pressure to a weight of 1.9 kg (about 3 L), at which point the product began to crystallise. The mixture was cooled to 0° C., stirred for 1.5 h then the product was filtered, washed with cold n-heptane (2×125 mL) and dried at room temperature in a circulating air drier to give the product (129.08 g, 44.8%) as a crystalline solid; m.p. 73.4° C.
Reaction SMILES: CN(CCN(C)C)C.C([Li])CCC.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN([CH:24]=[O:25])C>C1COCC1>[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Fc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccncc1F
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a solution of TMEDA (389 uL, 2.58 mmol) in THF (10 mL) at −78° C. was added a solution of n-butyl lithium in THF (2.5M, 1.03 mL, 2.58 mmol). After 30 minutes at −78° C., 3-fluoropyridine (221 μL, 2.57 mmol) was added. After another 2 hours at −78° C., DMF (219 μL, 2.83 mmol) was added. After a further 2 hours at −78° C., the reaction was quenched with saturated aqueous NaHCO3 (20 mL), extracted with ether (4×15 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the crude oil. Purification by column chromatography on silica gel (Hexanes:EtOAc 4:1) afforded the title compound as a pale yellow oil (120 mg, 37%). 1H NMR (CDCl3) 7.68 (t, 1H, J=5.2 Hz), 8.62 (d, 1H, J=4.7 Hz), 8.70 (s, 1H), 10.42 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH2:7](Br)[C:8]#[CH:9]>>[CH2:9]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])[C:8]#[CH:7]
Reactant: C#CCBr
Reactant: O=C1CCCN1
Product: C#CCN1CCCC1=O
Yield: 58 %

Procedure:
As in Example 6, 15 g (0.18 mol) of 2-pyrrolidinone and 18.65 mL (1 equivalent) of propargyl bromide were reacted, then distilled in vacuo (66˜71° C./0.1 mmHg) to obtain 11.94 g (58% yield) of 1-propargyl pyrrolidin-2-one.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].F[B-](F)(F)F.[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=[N+](C)C)=[C:23]1[O:35][CH2:36][CH3:37])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](/[CH:31]=[C:3](\[C:1]#[N:2])/[C:4]([NH2:6])=[O:5])=[C:23]1[O:35][CH2:36][CH3:37])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOc1c(C=[N+](C)C)c2ccccc2n1Cc1ccccc1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Product: CCOc1c(/C=C(\C#N)C(N)=O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.6 %

Procedure:
To a mixture of cyanoacetamide (4.60 g, 54.7 mmol) and NaOMe (0.5 M solution in MeOH, 80 mL, 4 mmol) was added a solution of (N-[(1-benzyl-2-ethoxy-1H-indol-3-yl)methylene]-N-methylmethanaminium tetrafluoroborate (v-a, 27.6 mmol) in MeOH (120 mL). The reaction was stirred at RT under an atmosphere of Ar. After 15 h, the reaction was cooled to 0° C. and was quenched by the addition of water. The insoluble product was filtered, triturated in MeOH and refiltered to yield a yellow solid (2E)-3-(1-benzyl-2-ethoxy-1H-indol-3-yl)-2-cyanoacrylamide (vi-a, 5.68 g, 60%). NH4OAc QC conditions. DAD Retention Time=1.78 min. M+H=346.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20]([C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[C:25]([NH:27][O:28][CH3:29])=[O:26])#[CH:21]>>[CH3:29][O:28][NH:27][C:25]([C:24]1[CH:23]=[C:22]([C:20]#[C:21][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=2)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: C#Cc1cccc(C(=O)NOC)c1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: CONC(=O)c1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described in Example 460 (step 2), (S)-5-bromo-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) and 3-Ethynyl-N-methoxy-benzamide (0.106 g, 0.442 mmol) were reacted to give the title compound yield (0.126 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:41][O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][C:47](Br)=[CH:46][CH:45]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:41][O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][C:47]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[CH:46][CH:45]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCc3c(-c4cnc(N(Cc5ccc(OC)cc5)Cc5ccc(OC)cc5)nc4)nc(N4CCOCC4)nc32)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
A solution of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg, 0.370 mmol), 4-bromobenzoic acid methyl ester (95 mg, 0.444 mmol), palladium acetate (10.0 mg, 0.0444 mmol), S-Phos (36.4 mg, 0.0888 mmol) and potassium phosphate (157 mg, 0.740 mmol) in dimethylformamide (3 ml) was degassed under ultrasonic irradiation, and stirred at 100° C. for 3 hours. To this, water was added, and the precipitate was filtered, which was subsequently dissolved in dichloromethane, and dried over sodium sulfate, followed by concentration under reduced pressure. Purification by silica gel column chromatography (dichloromethane/methanol=200/1) afforded 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid methyl ester as a yellow powder (143.5 mg, Yield 57%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1)([O-:20])=[O:19]
Reactant: CC(=O)Oc1ccc(Oc2ccccc2[N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(O)cc1
Yield: 99.7 %

Procedure:
To a solution of 4-(2-nitrophenoxy)phenyl acetate (6.32 g, 23.2 mmol) in methanol (100 ml) was added potassium carbonate (6.39 g, 46.3 mmol), followed by reflux for 3 hours. The reaction solution was poured into water, made acidic with hydrochloric acid and extracted with chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried. The solvent was evaporated under reduced pressure to give the title compound (5.35 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:10][CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:17]Br.[OH-].[Na+]>C(O)(=O)C>[Br:17][C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]([O:10][CH3:11])=[N:6][CH:7]=1
Reactant: CCOc1cccnc1OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1cc(Br)cnc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a stirred mixture of 3-ethoxy-2-methoxy-pyridine (2.7 g, 17.6 mmol, 1.0 equiv) and sodium acetate (1.74 g, 21.2 mmol, 1.2 equiv) in acetic acid (50 mL) at 10° C. was slowly added a solution of bromine (1.09 mL, 3.38 g, 21.2 mmol, 1.2 equiv) in acetic acid (10 mL). After the addition was completed the reaction mixture was stirred for 1 h at rt. The reaction mixture was poured on ice, neutralized with NaOH and the solution extracted with diethylether (3×50 mL). The combined organic phases were dried over MgSO4 and the solvent removed by evaporation under reduced pressure yielding 3.86 g (94%) of a mixture of 5-bromo-3-ethoxy-2-methoxy-pyridine and 6-bromo-3-ethoxy-2-methoxy-pyridine in the ratio 3:2 as indicated by 1H NMR, which was used directly in the next reaction step. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.0 Hz, 3H), 3.91 (s, 3H), 3.98 (q, J=7.0 Hz, 2H), 7.05 (d, J=1.9 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:26][CH2:27][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:29][CH:30]=3)=[CH:21][N:20]=2)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=1)(=O)C.[OH-].[Li+].O>C1COCC1.C(O)(C)C>[OH:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:26][CH2:27][N:28]([CH:31]4[CH2:32][O:33][CH2:34]4)[CH2:29][CH:30]=3)=[CH:21][N:20]=2)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4=CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(C3=CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
A mixture of 200f (260 mg, 0.39 mmol) and lithium hydroxide (92.4 mg, 3.85 mmol) in THF (9 mL), isopropanol (6 mL), and water (1 mL) was stirred at room temperature for 0.5 h. The mixture was extracted concentrated under reduced pressure and diluted with water (4 mL). It was then extracted with dichloromethane (2×10 mL) and the combined C dichloromethane extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 200 (53.1 mg, 20%) as yellow solid. MS-ESI: [M+H]+ 634.2. 1H NMR (500 MHz, DMSO-d6) δ 8.76 (d, J=1.5 Hz, 1H), 8.74 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.73-7.71 (m, 1H), 7.54 (d, J=2.5 Hz, 1H), 7.36 (d, J=5.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.58 (s, 1H), 6.11 (s, 1H), 4.97 (s, 1H), 4.57 (t, J=6.5 Hz, 2H), 4.38-4.49 (m, 4H), 4.08-4.26 (m, 3H), 3.86 (d, J=12.0 Hz, 1H), 3.61 (s, 3H), 3.54-3.45 (m, 1H), 2.95 (s, 2H), 2.68-2.54 (m, 2H), 2.48-2.46 (m, overlap, 6H),1.83-1.75 (m, 2H), 1.73-1.65 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].C([O-])([O-])=O.[Na+].[Na+].[CH3:17][C:18](C)=O>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH2:17][CH3:18]
Reactant: Oc1c(F)cc(Cl)cc1Br
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOc1c(F)cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a mixture of 30-2 (48.1 g, 214 mmol) and Na2CO3 (34 g, 321 mmol) in acetone (300 mL) was added a solution of Et2SO4 (39.6 g, 257 mmol) in acetone (100 mL) dropwise over 20 minutes and then the mixture was stirred at room temperature for one hour. The solid was filtered off and the filtrate was concentrated under vacuum to afford 30-3 (48.6 g, 90%) as a white solid. LRMS: calc 251.9 and found: 252.9 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][C:24]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)=[O:29])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([N:31]3[CH2:32][CH2:33][CH2:34][N:30]3[C:28]([O:27][C:24]([CH3:26])([CH3:25])[CH3:23])=[O:29])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCN1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CC(C)(C)OC(=O)N1CCCN1C(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 1-pyrazolidinecarboxylic acid 1,1-dimethylethyl ester (CAN 57699-91-9) as starting materials; MS (EI) 486.2 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6](=[O:26])[N:7]([C:15]1[CH:20]=[C:19](Br)[N:18]=[C:17]([NH2:22])[C:16]=1[N+:23]([O-:25])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]>C1COCC1>[CH2:3]([O:5][C:6](=[O:26])[N:7]([C:15]1[CH:20]=[C:19]([NH:2][CH3:1])[N:18]=[C:17]([NH2:22])[C:16]=1[N+:23]([O-:25])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(NC)nc(N)c1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
Methylamine (40% solution in water) (0.055 ml) was added to a solution of (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (50 mg) in THF (0.5 ml) at room temperature. The reaction was stirred under nitrogen for 16 hours then the solution pre-absorbed directly onto silica gel. The mixture was purified by chromatography on an Isco Companion, eluting with ethyl acetate:heptane, increasing the gradient linearly from 20:80 to 60:40 over several column volumes. The desired fractions were combined and evaporated to provide the title compound (30 mg) as a yellow gum.