Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl 3-[(aminooxy)methyl]piperidine-1-carboxylate 152 (0.312 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 153 (0.37 g, 84%) as a white foam.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.[NH:27]1[CH2:37][CH2:36][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][CH2:28]1>CS(C)=O>[CH2:34]([O:33][C:31]([CH:30]1[CH2:36][CH2:37][N:27]([C:11]2[CH:12]=[C:13]3[C:18](=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=4)[N:10]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)[CH2:28][CH2:29]1)=[O:32])[CH3:35]
Reactant: CSc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2cc3cccnc3c(-c3cccc(SC)c3)n2)CC1
Temperature: 60 °C
Reaction time: 23 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 8-(3-methylsulfanyl-phenyl)-[1,7]naphthyridin-6-yl ester (160 mg, 0.4 mmol) in DMSO (1 ml) is added ethyl isonipecotate (138 mg). The solution is stirred at 60° C. for 23 hours and then partitioned between ethyl acetate and water. The organic layer is separated and washed with brine 3×., then dried over magnesium sulfate and concentrated. The crude product is purified by flash chromatography on silica gel, eluting with 8% isohexane:DCM, increasing polarity to 2% methanol:DCM. The product is obtained as an amorphous solid. MS (ES+) 408.0893
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=1[NH:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.C(=O)(O)[O-].[Na+]>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]3[NH:1][C:33](=[O:35])[N:19]([CH2:20][C:21]([OH:24])([CH3:22])[CH3:23])[C:3]=3[CH:4]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:6]=2)=[CH:9][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(NCC(C)(C)O)c(N)c(-c2ccc(F)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2[nH]c(=O)n(CC(C)(C)O)c2c1
Temperature: 30 °C
Yield: 83.4 %

Procedure:
To a solution of methy 6-amino-4′-fluoro-5-[(2-hydroxy-2-methylpropyl)amino]biphenyl-3-carboxylate (180 mg, 0.542 mmol) in dichloromethane (16.2 mL) was added triethylamine (0.091 mL, 0.650 mmol) followed by triphosgene (80.0 mg, 0.271 mmol) in dichloromethane (5.42 mL). Reaction heated at 30° C. for 4 h. Reaction was cooled, diluted with saturated sodium bicarbonate and dichloromethane. Adjusted aqueous layer to pH=14. Wash aqueous with dichloromethane (5×). Combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% NOH) gave the title compound (81.0 mg): LC-MS [M+1]=359.2.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:10](N)=[O:11]>>[CH:10]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: NC=O
Product: O=CN[C@@H](CC(=O)O)C(=O)O

Procedure:
The process of claim 6 in which a slurry of L-aspartic acid in formamide is heated to form N-formyl-L-aspartic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:29][CH2:30][O:31][C:5]2=[CH:4][CH:3]=1.Cl[CH2:33][C:34]#[N:35]>>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([CH2:33][C:34]#[N:35])[CH2:27][CH2:28]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:29][CH2:30][O:31][C:5]2=[CH:4][CH:3]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCC1CCNCC1
Reactant: N#CCCl
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCC1CCN(CC#N)CC1

Procedure:
Using an analogous procedure to that described in Example 12, 4-(6-chloro-2,3-methylenedioxyanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline was reacted with 2-chloroacetonitrile to give the title compound as a solid; NMR Spectrum: (DMSOd6) 1.65 (m, 2H), 2.1 (m, 2H), 2.2 (m, 1H), 3.15 (m, 2H), 3.6 (m, 2H), 4.05 (s, 3H), 4.15 (m, 2H), 4.55 (s, 2H), 6.15 (s, 2H), 7.05 (d, 1H), 7.15 (d, 1H), 7.4 (s, 1H), 8.15 (s, 1H), 8.9 (s, 1H); Mass Spectrum: M−H− 480 and 482.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])(=[S:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:15][S:3][C:1](=[N:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH3:2]
Reactant: CC(=S)NC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CSC(C)=NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A mixture of N-(thioacetyl)-2,4-dichlorobenzamide (400 mg, 1.6 mmol) and K2CO3 (445 mg, 3.22 mmol) in anhydrous acetonitrile (20 mL) was stirred at ambient temperature. Iodomethane (458 mg, 0.2 mL, 3.22 mmol) was added and the reaction mixture was then stirred for 2.5 h. Solvent was removed in vacuo and the residue was partitioned between ether and water. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil (406 mg): NMR (CDCl3,300 MHz): δ 7.86 (d, 1H, J=8), 7.47 (d, 1H, J=2), 7.32 (dd, 1H, J=8, 2), 2.40 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]=[C:9]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[C:10]1[CH:32]=[CH:31][C:13]([C:14]([O:16][C@@H:17]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:18])=[O:15])=[CH:12][CH:11]=1.[Br-:38].[Li+]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]=[C:9]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[C:10]1[CH:32]=[CH:31][C:13]([C:14]([O:16][C@@H:17]([CH2:19][Br:38])[CH3:18])=[O:15])=[CH:12][CH:11]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)OC(=O)c2ccc(C(=N)N3CCCC3)cc2)cc1
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](CBr)OC(=O)c1ccc(C(=N)N2CCCC2)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
(2R)-3-{[(4-methylphenyl)sulfonyl]oxy}-2-propyl 4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate (45.1 mg, 0.083 mmol) obtained in Step 1 was dissolved in DMF (2 ml), lithium bromide (72 mg, 0.83 mmol) was added thereto, and the mixture was stirred at 50° C. for 2 days. The solvent was evaporated under reduced pressure, and the obtained residue was purified by reversed-phase HPLC in the same manner as in Step 4 of Example 1 to give the title compound.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:22]=[N:23][CH:24]=1>>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][O:25][C:21]2[CH:22]=[N:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)[CH2:29][CH2:30]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1ccc(C#N)s1
Reactant: Clc1cncc(OCCN2CCNCC2)c1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cncc(Cl)c2)CC1)c1ccc(C#N)s1

Procedure:
The title compound was synthesized in accordance with Example 77 from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl iodide and 1-[2-(5-chloro-3-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:16])([CH3:15])[CH3:14])[C:6]=2[N:5]=1.Br[CH2:18][C:19]1[CH:38]=[CH:37][C:22]2/[C:23](=[C:33](/[CH3:36])\[C:34]#[N:35])/[C:24]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:25]=3[O:26][CH2:27][C:21]=2[CH:20]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:24]2=[C:25]([CH:28]=1)[O:26][CH2:27][C:21]1[CH:20]=[C:19]([CH2:18][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:16])([CH3:14])[CH3:15])[C:6]=4[N:5]=[C:4]3[CH2:3][O:2][CH3:1])[CH:38]=[CH:37][C:22]=1/[C:23]/2=[C:33](/[CH3:36])\[C:34]#[N:35]
Reactant: COCc1nc2c(C(C)(C)O)cccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: COCc1nc2c(C(C)(C)O)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 99.6 %

Procedure:
[step 2] Using 2-[2-(methoxymethyl)-1H-benzo[d]imidazol-4-yl]propan-2-ol (74 mg, 0.34 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (166 mg, 99%) was obtained.
Reaction SMILES: [OH:1][C@@H:2]([CH2:12][C:13]([N:15]1[CH2:22][CH2:21][C:18]2([CH2:20][CH2:19]2)[C@H:17]([OH:23])[CH2:16]1)=[O:14])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][C@@H:6]([CH3:10])[C:5]1=[O:11].[Cl:24][C:25]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[CH:28]=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>>[Cl:24][C:25]1[CH:30]=[C:29]([NH:31][C:32]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:12][C:13]([N:15]3[CH2:22][CH2:21][C:18]4([CH2:19][CH2:20]4)[C@H:17]([OH:23])[CH2:16]3)=[O:14])[C:5](=[O:11])[C@@H:6]2[CH3:10])=[O:33])[CH:28]=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: C[C@@H]1NCCN(C[C@@H](O)CC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(C[C@@H](O)CC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 36 %

Procedure:
In analogy to the procedure described in Example 30, (S)—(S)-1-[2-hydroxy-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 25) and 1.2 eq. of 2-chloro-4-isocyanato-1-trifluoromethyl-benzene (intermediate 16) gave the titled compound in 36% yield as white powder. MS: 547.19 (MH+, Cl).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[F:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[C:22]([CH3:29])[N:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[C:20]([F:19])=[N:21][C:22]([CH3:29])=[CH:23][CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: Cc1ccc(B(O)O)c(F)n1
Product: Cc1ccc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c(F)n1
Yield: 60.8 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (61 mg, 0.20 mmol) and 2-fluoro-6-methylpyridine-3-boronic acid (62 mg, 0.36 mmol) were reacted. After purification the title compound (41 mg, 60% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (bm, 1H), 7.92 (a t, J=7.5 Hz, 2H), 7.85 (m, 1H), 7.75 (a t, J=7.7 Hz, 1H), 7.18 (a d, J=7.5 Hz, 1H), 2.96 (m, 1H), 2.58 (s, 3H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=338, HPLC 2.17 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[C:3]1=[O:24]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[C:3]1=[O:24]
Reactant: CN1C(=O)N(c2nccc(C(F)(F)F)n2)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2nccc(C(F)(F)F)n2)CC1C(=O)O
Yield: 102.7 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloro-4-(trifluoromethyl)pyrimidine (547 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated at reflux under argon for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylate (506 mg, 49%). LC/MS [M+H]+=347. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylate (506 mg, 1.46 mmol) in TFA/DCM (1:2, 9 ml) was stirred at room temperature for 16 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylic acid (assume ˜1.5 mmol) which was used in the next step. LC/MS [M+H]+=291.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:18]2[O:32][C@H:31]([CH2:33][O:34]C(C3C(C)=CC=CC=3)=O)[C@@H:20]([O:21]C(C3C(C)=CC=CC=3)=O)[CH2:19]2)[C:4]2[C:9]([C:10]=1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[CH:8][C:7]([Cl:16])=[C:6]([Cl:17])[CH:5]=2.C[O-].[Na+].CO.C(Cl)(Cl)Cl>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:18]2[O:32][C@H:31]([CH2:33][OH:34])[C@@H:20]([OH:21])[CH2:19]2)[C:4]2[C:9]([C:10]=1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[CH:8][C:7]([Cl:16])=[C:6]([Cl:17])[CH:5]=2
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2c(Cl)c(-c3ccco3)c3cc(Cl)c(Cl)cc32)C[C@@H]1OC(=O)c1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OC[C@H]1O[C@@H](n2c(Cl)c(-c3ccco3)c3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
2,5,6-Trichloro-3-(2-furyl)-1-(3,5-di-O-toluoyl-2-deoxy-β-D-ribofuranosyl)indole (4.76, 142 mg, 0.22 mmol) was suspended in dry MeOH (10 mL) to which was added sodium methoxide (30 mg, 0.56 mmol). The suspension was stirred at room temperature for 45 min, until the solids were completely dissolved. The solvent was then removed under vacuum, and the residue suspended in brine (50 mL). The aqueous suspension was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over MgSO4, filtered and evaporated to yield a clear oil. The oil was dissolved in CHCl3 (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a pale yellow solid which was recrystallized from 10% MeOH/CHCl3 and hexane to yield 67 mg (75%) of 4.78 as a white crystalline solid: mp 140-141 C; Rf 0.5 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 6.88 (d, 1H), 6.68 (s, 1H), 6.47 (dd, 1H), 5.42 (d, 1H, D2O exch.), 5.23 (s, 1H, D2O exch.), 4.45 (d, 1H), 3.89 (d, 1H), 3.73 (s, 2H), 2.55 (m, 1H), 2.13 (m, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 146.54, 142.25, 132.30, 125.61, 124.39, 124.09, 122.64, 120.75, 114.98, 111.51, 106.91, 104.87, 87.25, 85.04, 69.98, 60.91, 38.97. HRMS (EI) m/z calcd. for C17H14Cl3NO4 400.9988. found 400.9986. Anal calcd for C17H14Cl3NO4.¼H2O: C, 50.15; H, 3.59; N, 3.44. Found: C, 50.17; H, 3.65; N, 3.43.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH2:26])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.Cl.CON(OC)CCCN=C=NCC>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH:26][C:7]([CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[O:6]3)=[O:9])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C1CC[C@@H](C(=O)O)O1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Agent: CCN=C=NCCCN(OC)OC
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C1CCC(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (0.23 g, 1.7 mmole in anhydrous dichloromethane (30 mL) was slowly added to a solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) in anhydrous dichloromethane (100 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then a solution of 1-[3-(dimethoxyamino)propyl]-3-ethylcarbodiimide hydrochloride (0.37 g, 1.9 mmol) in anhydrous dichloromethane (50 mL) was added dropwise. The reaction mixture was stirred at ambient temperature overnight and then filtered to remove solids. The filtrate was washed twice with 10% sodium hydroxide and then with brine, dried, and then concentrated under vacuum to provide 0.3 g of crude product. This material was purified by column chromatography (silica gel eluting with dichloromethane) followed by recrystallization from acetonitrile to provide 0.1 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxotetrahydro-2-furancarboxamide as a white powder, m.p. 153-154° C. Analysis: Calculated for C20H24N6O3: %C, 60.59; %H, 6.10; %N, 21.19; Found: %C, 60.34; %H, 6.14; %N, 21.13. HRMS (EI) calcd for C20H24N6O3 (M+) 396.1909 found 396.1905
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:25]([C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[C:36]([CH:37]=O)=[CH:35][N:34]=[CH:33]2)=[CH:29][CH:28]=1)#[N:26].CCOC(C)=O>ClCCCl>[C:25]([C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:32]2[C:36]([CH2:37][NH:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:35][N:34]=[CH:33]2)=[CH:39][CH:40]=1)#[N:26]
Reactant: NCCCc1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CNCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-phenylpropylamine (0.202 mL, 1.42 mmol) in 5 mL of 1,2-dichloroethane at 0° C. was added 4Å powdered molecular sieves (0.38 g), followed by sodium triacetoxyborohydride (301 mg, 1.42 mmol g). The aldehyde 6 from Step 5 of Example 1 (200 mg, 0.947 mmol) was added, and the reaction was allowed to warm to room temperature. After 2 days, the reaction was poured into EtOAc, washed with sat. aq. NaHCO3, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in 12 mL of 20% CH2Cl2 /propylamine, stirred for 12 hours, concentrated in vacuo, and purified by preparative HPLC. Thus, the product was taken up in water/MeOH solution and was injected directly onto a Delta-Pak (C-18, 100A, 15 mm, 40 mm×100 mm) prep HPLC column using a gradient with 0.1% trifluoroacetic acid/water and 0.1% trifluoroacetic acid/acetonitrile as solvents. A portion of the pure fractions was then partitioned between methylene chloride and water, and the organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product 10 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 16.3 g. of ethyl 4-[3-(p-chlorophenyl)propylamino]benzoate, 16.3 g. of potassium hydroxide and 200 ml. of 95% ethanol is refluxed for 3 hours. The mixture is diluted with 100 ml. of water and brought to pH 6 with concentrated hydrochloric acid. Chilling and filtering gave 15 g. of white crystals. Recrystallization from ethanol gave 8.6 g. of white crystals, m.p. 191°-192° C.
Reaction SMILES: [C-:1]#[N:2].C([Al+]CC)C.[CH3:8][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]=[O:11].[NH4+].[Cl-].O>C1(C)C=CC=CC=1>[C:1]([CH:10]([OH:11])[C@@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:8])#[N:2]
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Temperature: -78 °C
Reaction time: 6 h

Procedure:
Diethylaluminum cyanide (4.53 mL, 1M in toluene, 4.53 mmol) was added dropwise to a stirred solution of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry toluene (33 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. Saturated NH4Cl (20 mL) and water (10 mL) were added then the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1 mixture of diastereoisomers. Rf=0.63 (50% EtOAc in hexanes). LCMS calc.=257.1; found=257.1 (M+1)+. 1H NMR (500 MHz, CDCl3) major diastereoisomer: δ 7.39-7.31 (m, 5H), 5.11 (m, 2H), 4.60 br (s, 1H), 3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H), minor diastereoisomer: δ 7.39-7.31 (m, 5H), 5.14 (m, 2H), 4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:8]1=[O:17])[CH3:5])[CH3:2].C(N(CC)CC)C.[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:25]1([C:31]([N:9]2[C@@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[C:8]2=[O:17])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCOC(C)OC1C(=O)NC1c1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C)O[C@H]1C(=O)N(C(=O)N2CCOCC2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 30 mg (0.13 mmol) of 3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone 6 in 2 mL of CH2Cl2, 2 mg of DMAP and 0.05 mL of triethylamine was added at room temperature. After 5 min. 22.9 mg (0.15 mmol) of morpholinecarbonyl chloride was added. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with 20 mL of CH2Cl2 and the organic layer was washed two times with brine, dried over Na2CO3 and concentrated. The crude solid product was purified by chromatography on silica gel to yield pure 7f: 87%; pale yellow oil; 1H NMR (250 MHz, CDCl3) δ [0.90 (d, J=5.3 Hz), 1.01 (d, J=5.3 Hz) (3H)], [1.04 (t, J=7.1 Hz), 1.18 (t, J=7.1 Hz)] (3H), 3.20 (m, 4H), [3.28 (m), 3.53 (m), 3.67 (m) (2H)], 3.60 (m, 4H), [4.41 (g, J=5.3 Hz), 4.63 (q, J=5.3 Hz) (1H)], [5.07 (d, J=5.8 Hz), 5.08 (d, J=5.8 Hz) (1H], [5.29 (d, J=5.8 Hz), 5.32 (d, J=5.8 hz) (1H], 7.23-7.27 (m, 5H).