Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:6]=1.[C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]>C(#N)C.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Y+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][CH:16]([CH3:17])[CH2:15][C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccc(N)cc2)cn1
Reactant: C/C=C/C(=O)NC(=O)OC(C)(C)C
Agent: O=[N+]([O-])[O-]
Agent: [Y+3]
Solvent: O
Solvent: CC#N
Product: Cc1cn(-c2ccc(NC(C)CC(=O)NC(=O)OC(C)(C)C)cc2)cn1
Temperature: 50 °C
Yield: 33 %

Procedure:
A mixture of 4-(4-methyl-1H-imidazol-1-yl)aniline (for a preparation see intermediate 64) (500 mg, 2.89 mmol), 1,1-dimethylethyl (2E)-2-butenoylcarbamate (for a preparation see intermediate 65) (615 mg, 3.32 mmol) and Yttrium(III) Nitrate hexahydrate (111 mg, 0.289 mmol) in acetonitrile (2 mL) was heated at 50° C. for 15 h. An extra portion of Yttrium(III) Nitrate hexahydrate (111 mg, 0.289 mmol) was added to the mixture which was stirred for 7 more hours before being cooled to room temperature. Half of the solvent was removed in vacuo and the residue was partitioned between AcOEt (40 mL) and a saturated NaHCO3 aqueous solution (20 mL). The layers were separated and the organic phase was washed with brine (15 mL). The combined aqueous phases were extracted with AcOEt (35 mL) and the combined organic were dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (gradient:4 to 8% MeOH in DCM) gave a residue which was further purified by flash chromatography on silica gel (gradient:60-95% AcOEt in Hexanes) to give 1,1-dimethylethyl (3-{[4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}butanoyl)carbamate (343 mg, 0.956 mmol, 33%) as a colourless sticky solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH2:15][CH:16]([N:18]1[C:23](=[O:24])[C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)=[C:21]([CH2:40][CH2:41][CH3:42])[N:20]2[N:43]=[C:44]([CH3:46])[N:45]=[C:19]12)[CH3:17]>C(OCC)(=O)C>[CH3:13][O:14][CH2:15][CH:16]([N:18]1[C:23](=[O:24])[C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[NH:3][C:4](=[O:7])[O:5][N:39]=3)=[CH:28][CH:27]=2)=[C:21]([CH2:40][CH2:41][CH3:42])[N:20]2[N:43]=[C:44]([CH3:46])[N:45]=[C:19]12)[CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)COC)c2nc(C)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)COC)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2-methoxy-1-methylethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.39 g, 55%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]>CC#N.CCOC(C)=O.O>[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[S:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1nc2cc(N(Cc3ccc(C#N)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Cyanobenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[C@H:5](OC1C=C(NS(C2N=CN(C)C=2)(=O)=O)N=C(S[CH2:25][C:26]2[CH:31]=C[CH:29]=[C:28](F)[C:27]=2F)N=1)C)[CH3:2].[BH4-].[Li+]>C1COCC1>[CH3:2][CH2:1][O:3][CH2:4][CH3:5].[CH3:29][CH2:28][CH2:27][CH:26]([CH3:31])[CH3:25]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2cn(C)cn2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(C)C
Product: CCOCC

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using 2-[[2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of step i) (0.28 g), THF (8 mL) and 2 M lithium borohydride in THF (0.81 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase). The resulting oil was triturated with toluene, methanol, then ether/iso-hexane to give the title compound as a white solid. Yield: 0.12 g
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CN(C=O)C.O.C(OCC)(=O)C>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cccnc1OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 1.00 g (6.35 mmol) of 2-chloronicotinic acid is slowly added to a suspension of 635 mg (15.9 mmol) of 60% sodium hydride in 25 ml of DMF, and the mixture is then stirred at 0° C. for 30 min. 1.15 g (6.98 mmol) of 5-phenyl-1-pentanol are dissolved in 5 ml of DMF and slowly added dropwise to the above reaction solution. The solution is stirred at room temperature for 3.5 hours. It is then heated at 75° C. and stirred overnight. The substance is taken up in water, ethyl acetate is then added and the aqueous phase is acidified using 1M HCl. The mixture is then extracted with ethyl acetate and the extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH3:19])[CH2:3][NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:19][C:2]1([CH3:1])[O:20][C:29](=[O:31])[N:4]([C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH2:3]1
Reactant: CC(C)(O)CNc1ccc(C#Cc2ccccc2)nn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CN(c2ccc(C#Cc3ccccc3)nn2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 2-methyl-1-(6-(phenylethynyl)pyridazin-3-ylamino)propan-2-ol (Example 152, step 1) (90 mg, 337 μmol) and triethylamine (102 mg, 141 μl, 1.01 mmol, 3 equiv.) in 4 ml of THF was cooled to 0-5° C. and then triphosgene (99.9 mg, 337 μmol, 1 equiv.) was added and the reaction was stirred for 1 hour at 0-5° C. The mixture was quenched with 5 ml of 5% sodium bicarbonate solution and worked up with ethyl acetate/water. The crude material was adsorbed onto silicagel and purified by flash chromatography over a heptane to 50% ethyl acetate in heptane gradient to yield the title compound (51 mg, 52% yield) as a crystalline light yellow solid, MS: m/e=294.2 (M+H+).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[C:6]([CH2:8][C:9]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][N:21]4[C:24]([C:27]5[CH:28]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[O:35])[CH:30]=[CH:31][CH:32]=5)=[CH:25][N:26]=[C:20]4[CH:19]=3)[CH:15]=[N:14]2)[CH2:12][NH:11][CH2:10]1)#[N:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:6]([CH2:8][C:9]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][N:21]4[C:24]([C:27]5[CH:28]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:40])([F:41])[F:39])=[O:35])[CH:30]=[CH:31][CH:32]=5)=[CH:25][N:26]=[C:20]4[CH:19]=3)[CH:15]=[N:14]2)[CH2:10][N:11]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:12]1)#[N:7]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(CC2CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Cyclopropanecarboxaldehyde (4.2 mg, 0.060 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (15 mg, 0.030 mmol) in methanol (1.0 mL). After stirring at r.t. for 20 min, sodium triacetoxyborohydride (13 mg, 0.060 mmol) was added. The reaction mixture was stirred at r.t. for 4 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=550.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1cccc(F)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=466.1, tR (minutes, Method F)=2.67. [α]D20=+28.57 (c=0.56 mg/mL,CHCl3)
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Br:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:32][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(Br)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.5 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-bromophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] the desired product (0.70 mg, 9.6% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.48 (m, 2H), 7.30–7.20 (m, 5H), 7.20 (m, 3H), 6.97 (apparent d, 1H, J=8.5 Hz), 6.73 (apparent d, 2H, J=8.5 Hz), 5.22 (apparent dd, 1H, J=4.9, 7.8 Hz), 3.15 (m, 2H), 2.65 (m, 2H), 2.51 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30–2.10 (m, 6H), 1.82 (m, 2H) 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 535.1 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[Na+].O.Cl.[CH3:10][CH:11]([CH3:15])[C:12]([NH2:14])=[NH:13]>C(OCC)C>[CH3:5][O:4][C:2]([NH:14][C:12](=[NH:13])[CH:11]([CH3:15])[CH3:10])=[O:3]
Reactant: CC(C)C(=N)N
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COC(=O)NC(=N)C(C)C
Yield: 86 %

Procedure:
165 parts of methyl chloroformate and 141.8 parts of sodium hydroxide in 590 parts of water are added via two inlets to 221 parts of 2-methylpropionamidine hydrochloride in 1,000 parts of diethyl ether, at from 25° to 30° C., in the course of 40 minutes, while stirring. The mixture is stirred at room temperature for one hour, and the organic phase is separated off. The aqueous phase is extracted again with 200 parts of diethyl ether, and the solvent is removed from the combined organic extracts to give 223 parts (86% of theory) of N-methoxycarbonyl-2-methylpropionamidine of melting point 127°-130° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C@H:31]1[CH2:35][O:34]C(C)(C)[O:32]1)[CH2:9][C:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([O:19]C)[C:13]=2[N:12](COCC2C=CC=CC=2)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>Cl.CO>[CH2:1]([N:8]([CH2:9][C:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([OH:19])[C:13]=2[NH:12][CH:11]=1)[CH2:30][C@H:31]([OH:32])[CH2:35][OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ncnc2c(CN(Cc3ccccc3)C[C@H]3COC(C)(C)O3)cn(COCc3ccccc3)c12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: OC[C@@H](O)CN(Cc1ccccc1)Cc1c[nH]c2c(O)ncnc12
Yield: 59.4 %

Procedure:
(S)—N-benzyl-1-(5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methanamine (1.1 g, 2.189 mmol) was heated to 100° C. in HCl (15 ml, 37%) for 3 h. Tlc (CH2Cl2-6M NH3 in MeOH, 9:1) showed reaction over. The solvent was evaporated and the residue dissolved in MeOH, neutralized with Amberlyst A21 resin, filtered and the solvent evaporated. The residue was chromatographed (CH2Cl2-6M NH3 in MeOH, 9:1 then 85:15) to give (S)-3-(benzyl((4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)amino)propane-1,2-diol (0.427 g, 1.3 mmol, 59.4% yield) as a colourless solid. [α]D20 12.7 (c 0.715, MeOH). The 1H NMR and 13C NMR were identical to that of compound 3.4. +ESMS Found 329.1618 C17H21N4O3 (M+H) requires 329.1614.
Reaction SMILES: CN(C=O)C.CC#N.C(Cl)(=O)C(Cl)=O.[NH:15]1[C:19]([C:20]([O-:22])=O)=[N:18][N:17]=[N:16]1.[K+].[K+].N1C(C([O-])=O)=NN=N1.[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([OH:56])[CH2:38][N:39]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=2[F:55])=[CH:44][CH:43]=1)[NH2:40])[CH3:34].N1C=CC=CC=1>>[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([OH:56])[CH2:38][N:39]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=2[F:55])=[CH:46][CH:47]=1)[NH:40][C:20]([C:19]1[NH:18][N:17]=[N:16][N:15]=1)=[O:22])[CH3:34]
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C([O-])c1nnn[nH]1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nnn[nH]1
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a stirred solution of DMF (734 μL, 9.5 mmol) in MeCN (2 mL, 50 mmol) at 0° C., was slowly added a solution of oxalyl chloride (257 μL, 3.0 mmol) in MeCN (500 μL, 9 mmol). After 10 minutes, dipotassium 1H-tetrazole-5-carboxylate (249 mg, 1.3 mmol) was added and after stirring for a further 15 minutes, was added to a solution of (R)-3-[N-(5′-chloro-2′-fluoro-biphenyl-4-ylmethyl)-hydrazino]-2-hydroxy-propionic acid ethyl ester (300 mg, 0.8 mmol) in MeCN (2 mL, 40 mmol) and pyridine (661 μL, 8.2 mmol). The mixture was stirred at 0° C. for 10 minutes then evaporated under reduced pressure and purified (Interchim reverse phase chromatography column; elute from 55-75%, both peaks coeluted together) to yield the title compound (280 mg). A portion (80 mg) was further purified by preparative HPLC to yield the title compound as a TFA salt (33 mg; purity 98%). MS m/z [M+H]+ calc'd for C20H20ClFN6O4, 463.12. found 463.4.
Reaction SMILES: [Na].[Br-].[NH2:3][C:4]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=[CH:6][N+:5]=1[CH2:14][C:15]([O:17]CC)=O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([C:14]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:4]2=[N:3][C:15]1=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C[n+]1cccc(OC(C)C)c1N
Reactant: BrCc1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Product: CC(C)OC1=CC=CN2C1=NC(=O)C2(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Metallic sodium (81 mg) is added to 3.0 ml of absolute ethanol and is stirred for one hour at room temperature. Then, the reaction mixture was added with 586 mg (1.77 mmol) of 2-amino-3-isopropoxy-1-(ethoxy-carbonylmethyl) pyridiniumbromide and stirred at room temperature for one hour. Then, the reaction mixture was added with 605 mg (3.54 mmol) of benzylbromide at 0° C. and stirred at room temperature for 4 hours. Then, the resulting precipitates were filtrated out and dried. The obtained crystals were re-crystallized from ethanol to obtain 588 mg (yield: 92%) of the titled compound.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][CH2:5][CH3:6].[C:7]([CH:10]1[CH2:13][N:12]([C:14](=[O:28])/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:24](=[N:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)[CH2:11]1)(=O)[CH3:8]>CO.ClCCl>[O:28]=[C:14]([N:12]1[CH2:13][CH:10](/[C:7](=[N:2]\[O:3][CH2:4][CH2:5][CH3:6])/[CH3:8])[CH2:11]1)/[CH:15]=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:24](=[N:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reactant: CCCON
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCO/N=C(/C)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h

Procedure:
1-(Amino-oxy)-propane hydrochloride (32 mg, 0.29 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (61.3 mg, 0.20 mmol) in a mixture methanol/dichloromethane (8:2, 3.5 mL) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol (95:5) as eluent. The title product was obtained as a white solid (56.0 mg, 76%).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([C:28]([CH2:30][Br:31])=[O:29])=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[Br-:31].[C:14]1([P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:30][C:28](=[O:29])[CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(C=Cc1ccccc1)CBr
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 85.6 %

Procedure:
To a refluxed solution of triphenylphosphine (5.84 g, 22.3 mmol) in dry THF (25 mL) under nitrogen is slowly added bromomethyl styryl ketone (5.0 g, 22.3 mmol, in 25 ml THF). The reaction mixture is refluxed for 2 hrs. After cooling, the white precipitate is collected by filtration and washed with Et2O. Crystallization of the product with methanol gives triphenyl cinnamoylmethyl phosphonium bromide (9.3 g, 86%) as colorless needles, 1H NMR (400 MHz, DMSO-d6) d 8.02 (1H, d, J=16.0 Hz, β-CH═), 7.87, 7.76, 7.49 (20H, m, Ph), 7.00 (1H, d, J=16.0 Hz, a-CH═), 6.07 (2H, d, J=13.2 Hz CH2Br).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].CN(C=O)C.C([O-])(=O)C.[Na+].Br[CH2:16][C:17]([C:19]1[N:20]=[CH:21][C:22]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[N:23][CH:24]=1)=[O:18]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26]([NH:25][C:22]1[N:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][O:3][C:1](=[O:4])[CH3:2])=[N:20][CH:21]=1)=[O:31]
Reactant: CC(C)(C)C(=O)Nc1cnc(C(=O)CBr)cn1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A 500 mL round bottomed flask equipped with a magnetic stirrer, addition funnel, thermocouple probe and nitrogen inlet/outlet was charged with 4.40 mL (76.86 mmol) of acetic acid, 140 mL of DMF and 7.000 g (85.33 mmol) of sodium acetate. Then, 23.30 g (77.62 mmol) of the compound obtained in step 5 was added portionwise over 45 min. After stirring at room temperature for an additional 1 h, HPLC analysis indicated complete reaction. The reaction mixture was diluted with 350 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate was added with stirring. The organic layer was separated, washed with 3×100 mL of water and concentrated at 30° C./60 mmHg to a volume of ca. 60 mL. The resulting slurry was diluted with 200 mL of heptane, concentrated at 30° C./60 mmHg to a volume of ca. 150 mL, and stirred at 50° C. for 30 min. After cooling to room temperature, the solid was collected by filtration, washed with 40 mL of 10% ethyl acetate in heptane and dried by suction, then under reduced pressure (house vacuum) for 24 h, to give 19.52 g (90.0% yield) of the title compound as an off-white solid; 98.81% pure as determined by HPLC analysis (same conditions as in step 4, retention time 6.78 min).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[C@H:40]([OH:41])[CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@H:36]4[C@H:40]([OH:41])[CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c14) and commercially available tert-butyl (3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.