Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH3:9])[CH2:4][CH2:3]1.[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=O)[O:19][C:17](=[O:18])[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11].C(=O)(O)[O-]>C(Cl)(Cl)Cl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[C:20](=[O:19])[C:15]3=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:23][CH:22]=[C:16]3[C:17]2=[O:18])[CH2:3][CH2:4]1)[CH3:9]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCN1CCC(N)CC1
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: CCN1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)CC1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
6.50 Grams (0.05 mole) of 4-amino-N-ethyl piperidine and 9.65 grams (0.05 mole) of 4-nitrophthalic anhydride were dissolved in 150 milliliters of chloroform and the solution was stirred for an hour at room temperature. The chloroform was evaporated and the solid dissolved in 50 milliliters of acetic anhydride and the solution was refluxed for an hour. The acetic anhydride was evaporated off and the dark red residue treated with isopropyl alcohol and the solvent evaporated. The residue which was a gum was repeatly subjected to treatment with isopropyl alcohol and evaporation of the solvent until a crystalline solid was produced. The solid was taken up in chloroform and this was washed with sodium bicarbonate solution, then water and then brine until the aqueous layer was neutral. The chloroform extract was dried with magnesium sulphate, filtered and evaporated to give a solid. Microanalysis showed this to be impure and the bicarbonate washing was repeated as outlined above. The dried chloroform extract was evaporated off and the residue treated with ether to give 2.5 grams of the title compound as a yellow solid, m.p. 153°-155°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:5]=[C:6]([CH:8]=O)[CH:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:25]=1[C:26]([NH2:28])=[O:27].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+].FC(F)(F)C(O)=O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:28][C:26](=[O:27])[C:25]3[C:24](=[CH:32][C:31]([O:33][CH3:34])=[CH:30][C:29]=3[O:35][CH3:36])[N:23]=2)[CH:5]=[C:4]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH:3]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(C=O)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(Cl)cc(N4CCNCC4)c3)nc2c1
Temperature: 110 °C
Yield: 29.3 %

Procedure:
A solution of tert-butyl 4-(3-chloro-5-formylphenyl)piperazine-1-carboxylate (3, 0.300 g, 0.918 mmol) and 2-amino-4,6-dimethoxybenzamide (4, 0.120 g, 0.612 mmol) in DMA (4 mL) was treated with p-TsOH (0.424 g, 1.46 mmol) and NaHSO3 (0.290 g, 1.84 mmol) and then heated at 110° C. for 16 h. The reaction mixture was cooled to room temperature, trifluoroacetic acid (5 mL) was added and the mixture was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH4OH and the precipitate filtered, washed with water, and dried under vacuum to afford the title compound (0.072 g, 29%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 7.60-7.70 (m, 2H), 7.08-7.12 (m, 1H), 6.78 (d, J=2.3 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.24 (t, J=5.2 Hz, 4H), 3.28 (t, J=5.2 Hz, 4H); ESI MS m/z 401 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]([C:37]#[N:38])=[C:30]2[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Br:46])[CH:41]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:46][C:42]1[CH:41]=[C:40]([NH:39][C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([NH:26][C:8](=[O:10])[C:7]#[C:6][CH2:5][O:4][CH2:3][O:2][CH3:1])[CH:28]=3)[N:33]=[CH:32][C:31]=2[C:37]#[N:38])[CH:45]=[CH:44][CH:43]=1
Reactant: COCOCC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCOCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of 0.51 g (3.54 mmol) of 4-(methoxymethoxy)-but-2-ynoic acid and 0.46 g (3.4 mmol) of isobutyl chloroformate in 12 ml of tetrahydrofuran was added at 0° C. with stirring 0.36 g (3.54 mmol) of N-methylmorpholine. After 15 min, 1.0 g (2.95 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile was added. After stirring 3 hr at room temperature, the mixture was poured into a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was dries over magnesium sulfate. The solvent was remove and the residue was purified by chromatography on silica gel eluting with chloroform-ethyl acetate mixtures to give 0.66 g of 4-methoxymethoxy-but-2-ynoic acid[4-(3-bromophenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow powder: ma of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile: mass spectrum (electrospray, m/e,): M+H 465.1, 467.0.
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25].CN1CCN(C)C1=O>O>[F:25][C:24]([F:26])([F:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=[N+]([O-])N=C1NCCN1C=Nc1ccccc1C(F)(F)F
Yield: 52.9 %

Procedure:
0.05 g of boron trifluoride ether complex was added under ice-cooling conditions to a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 3.47 g of o-aminobenzotrifluoride and 5 ml of 1,3-dimethyl-2-imidazolidinone. Immediately, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and concentrated. Ether was added to the resultant oily residue and the resultant crystals were removed by filtration, followed by washing with hot ethyl acetate to give 3.43 g of 1-(2-trifluoromethylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](C1C=CC=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>[Cu].O>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:2]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:30][CH:29]=1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: Cc1ccc(O)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(Oc2ccc(C)cc2C(=O)O)cc1

Procedure:
393 G. of 2-iodo-5-methyl-benzoic acid in 150 ml. of nitrobenzene are heated to 145° C. 138 G. of potassium carbonate are added thereto in small portions with stirring. Subsequently, 156 ml. of 4-methyl-phenol and 276 g. of potassium carbonate are added. To the resulting mixture, 3 g. of copper powder are carefully added, and the mixture is subsequently stirred at 165° C. for 20 minutes. After cooling, 1.25 liters of water are added to the mixture which is then extracted twice with ether. The aqueous phase is acidified with hydrochloric acid and extracted twice with ether. The ethereal solutions are washed with water, dried over sodium sulfate and concentrated in vacuo. The residue (brown crystals) is recrystallized from 1100 ml. of methanol and 700 ml. of water, and there is obtained 2-(4-methylphenoxy)-5-methyl-benzoic acid, which after repeated recrystallization from methanol/water, melts at 113°-115° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)cn2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OC(C)C)cn2)cc1

Procedure:
N-{3-[4-(5-Hydroxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide (50 mg, 166 μmol), 2-iodopropane (28 mg, 166 μmol) and cesium carbonate (135 mg, 416 μmol) were stirred in 3 ml of DMF at 50° C. for 3 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 35 mg (61%), M+H+: 343.16.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.[CH3:37]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>C(Cl)Cl.CO>[C:2]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)#[CH:37]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 21a (195 mg, 0.393 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (2 mL) was added. The Dess-Martin periodinane (184 mg, 0.433 mmol) was added and then the reaction was stirred at rt for 20 min. The reaction was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (2×20 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was placed in a 20 mL vial equipped with a stir bar and then MeOH (5 mL) was added. K2CO3 (163 mg, 1.18 mmol) was added and then dimethyl (1-diazo-2-oxopropyl)phosphonate (113 mg, 0.590 mmol) dissolved in MeOH (2 mL) was added. The reaction was stirred at reflux for 3 h. Additional K2CO3 (163 mg, 1.18 mmol)) and diazophosphonate (113 mg, 0.590 mmol) were added and the reaction was refluxed for 6 h. The reaction was cooled to rt and then the solvent was removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (3×10 mL) and then the combined organic extracts were washed with brine (20 mL), dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-60% ACN/DCM to afford compound 26a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.85 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.8, 2.4 Hz, 1H), 8.03 (d, J=5.6 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.08 (d, J=5.6 Hz, 1H), 3.95-4.03 (m, 4H), 3.88-3.95 (m, 4H), 3.60-3.68 (m, 4H), 3.50-3.60 (m, 4H), 3.28 (s, 1H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H31N7O3: 490.3 (M+H). Found: 490.3.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][CH:22]([CH:26]1[CH2:28][CH2:27]1)[C:23]([NH2:25])=[O:24].CO>CCCCCCC>[C:23]([CH:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH:26]1[CH2:28][CH2:27]1)(=[O:24])[NH2:25]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)C(N)C1CC1
Solvent: CCCCCCC
Solvent: CO
Product: NC(=O)C(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethyloxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/40% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 381.1734 (M+H)+, αD20 (MeOH)=−23.5°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][C@H:9]([CH2:12][OH:13])[CH2:8]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][C@H:9]1[CH2:10][CH2:11][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCN(c2ccccn2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCN(c2ccccn2)C1
Temperature: 25 °C

Procedure:
(S)-(1-(Pyridin-2-yl)pyrrolidin-3-yl)methanol (1.683 mmol, 0.3 g) and triethylamine (5.05 mmol, 0.702 ml, 0.511 g) were stirred in DCM (10 ml) at 0° C. Methanesulfonyl chloride (2.52 mmol, 0.195 ml, 0.289 g) was added and the reaction allowed to warm to room temperature over 1 hour. The reaction mixture was washed with water, dried over Na2SO4 and concentrated at reduced pressure to afford (S)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methyl methanesulfonate. (0.38 g)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(O)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30]>ClC(Cl)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCc1cccc(F)c1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: O[C@H](CNCc1cccc(F)c1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 3-fluorobenzylamine, and ethanol, essentially as described above in Example 57. Purity by LC/MS=96%, [M+H]+=411.
Reaction SMILES: C(O[C:4](=[O:6])C)=O.C(O)=O.[C@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>CCOCC>[C@H:10]1([NH:20][CH:4]=[O:6])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC(=O)OC=O
Solvent: O=CO
Solvent: CCOCC
Product: O=CN[C@@H]1CCCc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of acetic formic anhydride (0.056 mol) (prepared by stirring acetyl anhydride (7.36 ml, 78.0 mmol) and formic acid (2.94 ml, 78.0 mmol) at 50-60° C. for 2 h then cooling to room temperature) was added (r)-1,2,3,4-tetrahydro-1-naphthylamine (8.20 g, 55.7 mmol) dropwise with stirring at such a rate that the temperature never rose above 40° C. After stirring for 30 min, 300 mL of ether was added, and the solution was stirred at room temperature overnight. The reaction was diluted with ether, washed twice with water, twice with Sat. NaHCO3, with 5% HCl, and finally with water. The organic layer was dried with Na2SO4, filtered, and evaporated to dryness. flash chomatograph (SiO2, hexane/EtOAc=1:1 to pure EtOAc) afforded (R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)formamide as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH2:60][CH2:61][C:62]([O:64][CH3:65])=[O:63]>CN(C)C=O>[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH2:60][CH2:61][C:62]([O:64][CH3:65])=[O:63])[C:11]([C:7]1[N:6]=[C:5]2[N:4]=[C:3]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)[N:2]([CH3:1])[C:10]2=[CH:9][CH:8]=1)=[O:12]
Reactant: COC(=O)CCNc1ccccn1
Reactant: Cn1c(COc2ccc(C#N)cc2)nc2nc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CCN(C(=O)c1ccc2c(n1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
308 mg (1.0 mmol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-carboxyimidazo[4,5-b]pyridine were suspended in 5 ml of dimethylformamide and mixed with 303 mg (3.0 mmol) of N-methylmorpholine and 321 mg (1.0 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate. After 10 minutes at room temperature, a solution of 215 mg (1.2 mmol) of methyl N-(2-pyridyl)-3-aminopropionate in 2 ml of dimethylformamide was added, whereupon a clear solution was obtained. After 12 hours at room temperature, the reaction solution was stirred into ice-water. After extracting 3 times with ethyl acetate, the combined organic extracts were washed with a saline solution, dried over sodium sulfate, and evaporated down. The residue obtained was chromatographed on silica gel with dichloromethane/ethanol (90:1 to 25:1).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>COCCOC>[C:12]([NH:16][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC(C)(C)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
Combine 4-cyanobenzoic acid (30 mg, 2.07 mmol), tert-butylamine (0.5 mL, 4.13 mmol), triethylamine (0.4 mL, 2.89 mmol), and HATU (1.1 g, 2.89 mmol) in anhydrous DME (7 mL). Stir at ambient temperature for 17 h. Partition the reaction mixture between brine (15 mL) and diethyl ether (15 mL), separate the organic layer, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (0.4 g, 89%). MS (ES+) m/z: 203 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=O)=[C:4]([S:25][CH3:26])[N:3]=1.O.[NH2:28][NH2:29]>C(O)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=[N:28][NH2:29])=[C:4]([S:25][CH3:26])[N:3]=1
Reactant: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=O
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=NN
Temperature: 80 °C
Yield: 45.1 %

Procedure:
To a disposable sealed tube was added 2-(2-amino-5-formyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (100 mg, 0.25 mmol, 1.0 eq.), isopropanol (4.0 mL), and hydrazine monohydrate (0.048 mL, 0.96 mmol, 3.8 eq.). The tube was sealed and heated to 80° C. overnight. The reaction was then quenched with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with brine, dried with Na2SO4, and concentrated to give crude 2-(2-amino-5-hydrazonomethyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as an oil. The crude product was then precipitated out with 3 mL water and 0.5 mL of ACN, filtered and rinsed with 2 mL of H2O to give pure 2-(2-amino-5-hydrazonomethyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a yellow solid (45.0 mg, 45%). LC/MSD (HP Series 1100 MSD): Expected MW: 399, Observed M+H, 400.1, Retention time: 1.43 min. ANALYTICAL HPLC: >90%, Retention time: 3.89 min (8 minute run). 1H-NMR (d6-DMSO): 10.42 (s, 1H), 9.15 (t, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.80 (d, 1H), 7.58 (t, 1H), 7.42 (d, 1H), 6.45 (s, 2H), 5.25 (br s, 2H), 4.30 (d, 2H), 2.40 (s, 3H) ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1([NH:19][CH:20]=[O:21])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)=[O:6].[CH3:22]N(C=O)C.CI>C1COCC1>[CH3:3][O:4][C:5]([C:7]1([N:19]([CH:20]=[O:21])[CH3:22])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8]1)=[O:6]
Reactant: CN(C)C=O
Reactant: COC(=O)C1(NC=O)CCN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(N(C)C=O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
Sodium hydride (60% in oil) (10 mg, 0.25 mmol) was added to a solution of 3-Formylamino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2T) (50 mg, 0.183 mmol) in THF (3 ml). DMF (1 ml) was added and stirred for 1 hour. Methyl iodide (0.1 ml, 1.60 mmol) was added and the reaction was stirred overnight. The solvent was evaporated and the residue extracted with EtOAc (50 ml), washed with H2O (20 ml), dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 3% MeOH/MeCl2 yielding 3T (50 mg, 94%). LCMS (MH 287) Retention time=2.77 minutes.