Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[N:3]=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B.O1CCCC1.O>C1COCC1>[NH2:3][CH:4]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CON=C(Cc1ccccc1)c1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: NC(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of the oxime geometric isomer mixture 9 (2.690 g, 10.36 mmol) in dry THF (50 ml, freshly distilled from sodium benzophenone ketyl) under nitrogen at room temperature was added borane-tetrahydrofuran solution (36.0 ml, 36.0 mmol, 1.0 M solution, Aldrich) by syringe. The resulting very pale orange solution was refluxed for 16 hours, and cooled in an ice bath. Water (80 ml) was added carefully to quench, followed by 20% NaOH (80 ml). The resulting colorless bi-phasic mixture was refluxed overnight with vigorous magnetic stirring. After cooling to room temperature, hexanes (50 ml) were added and the layers separated. The aqueous portion was washed with hexanes (1×30 ml), and the combined organic portions dried over potassium carbonate. Evaporation of the solvent afforded the pure amine as 2.392 g of a clear, pale yellow syrup (99% yield): Rf 0.22 (5% methanol in CHCl3): IR (CDCl3) 3376 (w), 3068 (w), 3031 (w), 2922 (w), 2850 (w), 1602 (m), 1493 (s), 1457 (m), 1409 (w); 1H NMR (CDCl3) δ7.40-21 (m, 7H), 7.19 (d, J=8.6 Hz, 2H), 4.21 (dd, J=8.4, 5.2 Hz, 1H), 2.98 (dd, J=13.2, 5.2 Hz, 1H), 2.81 (dd, J=13.2, 8.6 Hz, 1H), 1.43 (s, 2H); low resolution mass spec. 232 (M-1, 5.0), 230 (m-1, 11), 142 (M-91, 37), 140 (M-91, 100), 91 (28).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH:21]1([CH2:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)(Cl)(Cl)Cl>[Br:8][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:27](=[O:28])[CH2:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:30][CH:31]=1
Reactant: Cc1ccc(C(=O)CC2CCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CC1CCCC1)c1ccc(CBr)cc1
Temperature: 85 °C
Yield: 63.8 %

Procedure:
Add NBS (523 mg, 2.94 mmol) and AIBN (44 mg, 0.267 mmol) to a solution of 2-cyclopentyl-1-p-tolyl-ethanone (540 mg, 2.67 mmol) in carbon tetrachloride (80 mL) and heat overnight at 85° C. Add water and extract the aqueous phase with dichloromethane. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (98:2, 95:5) to obtain the desired intermediate as an oil (479 mg, 64%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]([NH2:36])([C:34]#[CH:35])[CH3:33]>>[NH2:36][C:32]([CH3:33])([CH3:31])[C:34]#[C:35][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[C:20]([OH:22])=[O:21])=[C:9]2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)N
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#CC(C)(C)N)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-(7-(3-Amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (85) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 2-methylbut-3-yn-2-amine. 1H-NMR: 400 MHz, (CD3OD) δ: 7.81 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.57 (m, 3H), 7.45 (d, J=8 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.62 (s, 3H), 1.68 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M—NH2]+ calcd for C28H28ClO3: 447.2; found: 446.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:21].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:21]
Reactant: OB(O)c1cccnc1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1C(Cc2c(Cl)cc(-c3cccnc3)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Temperature: 25 °C

Procedure:
Heat a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-[cis-1-(4-fluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 27) (0.346 g, 0.705 mmol), pyridine-3-boronic acid (0.173 g, 1.41 mmol), Pd(PPh3)4 (81 mg), 7 mL of 0.1 M Na2CO3 aq solution in 7 mL of dimethoxy ethane at 80° C. for 24 h. Cool the mixture to room temp and quench with 20 mL of 1N HCl. Dilute the mixture with 20 mL of EtOAc. Wash the organic layer with water, brine and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 421 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:30][C@H:31]2[C@@H:36]3[O:37]C(=O)[O:39][C@@H:35]3[C@@H:34]([O:41][CH3:42])[C:33]([CH3:44])([CH3:43])[O:32]2)=[CH:10][CH:11]=[C:12]2[C:17]=1[O:16][C:15](=[O:18])[C:14]([NH:19][C:20](=[O:29])OCC1C=CC=CC=1)=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57]1C(O)=O.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:8]1[C:9]([O:30][C@H:31]2[C@H:36]([OH:37])[C@H:35]([OH:39])[C@@H:34]([O:41][CH3:42])[C:33]([CH3:43])([CH3:44])[O:32]2)=[CH:10][CH:11]=[C:12]2[C:17]=1[O:16][C:15](=[O:18])[C:14]([NH:19][C:20]([C:57]1[NH:56][C:64]3[C:59]([CH:58]=1)=[CH:60][CH:61]=[CH:62][CH:63]=3)=[O:29])=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2ccc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2Cc2ccccc2)OC1(C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](Oc2ccc3cc(NC(=O)c4cc5ccccc5[nH]4)c(=O)oc3c2Cc2ccccc2)OC1(C)C
Reaction time: 12 h
Yield: 4.3 %

Procedure:
Palladium on carbon (10%, 46 mg) was added to 25e (230 mg, 0.38 mmol) in anhydrous THF (2.50 mL) and the solution was placed under an atmosphere of H2. After 12 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (177 mg, 99%). EDCI (61.5 mg, 0.32 mmol) and 1H-indole-2-carboxylic acid (41.4 mg, 0.26 mmol) were added to the amine (60.0 mg, 0.13 mmol) in 30% pyridine/CH2Cl2 (3.50 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 3:1 Hexane:Ether→40:1 CH2Cl2:Acetone) to afford a yellow solid, which was used without further purification (66.2 mg, 85%). Triethylamine (150 μL) was added to the carbonate (66.2 mg, 0.11 mmol) in MeOH (2.50 mL) and CH2Cl2 (2.50 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford 26m as a colorless amorphous solid (6.50 mg, 10%, 8.4% over 3 steps): 1H NMR (CD2Cl2, 500 MHz) 8.68 (s, 1H), 8.62 (s, 1H), 7.63-7.61 (m, 1H), 7.47 (dd, J=5.7, 3.3 Hz, 1H), 7.16-7.10 (m, 4H), 7.10-7.04 (m, 4H), 6.99 (t, J=8.2 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.43 (dd, J=8.1, 0.7 Hz, 1H), 5.31 (d, J=2.9 Hz, 1H), 4.17 (t, J=6.8 Hz, 1H), 4.01 (dd, J=8.5, 2.9 Hz, 1H), 3.90 (d, J=13.1 Hz, 2H), 3.45 (s, 3H), 3.16 (d, J=8.6 Hz, 1H), 2.43 (s, 1H), 2.21 (s, 1H), 1.25 (s, 3H), 0.95 (s, 3H); 13C NMR (CDCl3, 125 MHz) 166.8, 155.4, 153.8, 140.2, 131.6, 130.2, 128.0, 127.6, 127.5 (2C), 127.4 (2C), 126.9, 125.1 (2C), 115.2, 108.3 (2C), 105.8 (2C), 97.1 (2C), 83.3 (2C), 77.2, 70.2, 67.9 (2C), 65.0, 60.6, 21.9, 13.1, 13.0; IR (film) νmax 3333, 2961, 2926, 2854, 1717, 1601, 1466, 1261, 1090, 1076, 1041, 800, 750 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C33H32N2O8, 607.2056. found, 607.2056.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:42][C:43]([NH:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:42][C:43](=[O:44])[NH:45][C:46]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:20]([N:22]([CH2:32][C:33]2[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[S:36][CH:37]=2)[C@@H:23]([CH3:31])[CH:24]([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 60 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[C:12]1([CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1O
Reactant: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCc1cccc2ccccc12
Temperature: 100 °C
Yield: 43.2 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (2.30 g, 18.8 mmol) in DMF (20 mL) is added 1-(chloromethyl)-naphthalene (3.36 mL, 22.6 mmol) and K2CO3 (3.11 g, 22.6 mmol), and the reaction mixture is heated to 100° C. for 12 h. Once complete, the reaction mixture is cooled to room temperature and diluted with water (100 mL) prior to being poured into a separatory funnel containing ethyl acetate (250 mL). The organic layer is separated, washed with brine (2×) and dried over sodium sulfate prior to concentration. The crude product is purified by column chromatography (5% ethyl acetate in hexanes) to afford 2-(1-naphthylmethoxy)benzaldehyde (2.13 g, 43%) as a light yellow oil.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([O:9][CH2:10][C:11]#[C:12][CH3:13])[CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5]1)=[N+:2]=[N-:3]>C1(C)C(C)=CC=CC=1>[CH3:13][C:12]1[N:3]=[N:2][N:1]2[C:11]=1[CH2:10][O:9][C@H:8]1[CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C@H:4]21
Reactant: CC#CCO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: Cc1nnn2c1CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]12
Yield: 47.9 %

Procedure:
Example 54 can be prepared in the same manner as example 46 from (3S,4S)-tert-butyl 3-azido-4-(but-2-ynyloxy)pyrrolidine-1-carboxylate (115 mg, 0.41 mmol) and xylene (10 ml), afforded the titled compound (55 mg, 47%) as white solid. M.p. 195-196° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1([C:15]2[N:20]=[CH:19][C:18]([CH:21]=[CH:22][CH:23]=[O:24])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[N:11]1.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.ClCCl.C(OCC)(=O)C>[N:10]1([C:15]2[N:20]=[CH:19][C:18]([CH:21]=[CH:22][CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: O=CC=Cc1ccc(-n2cccn2)nc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCC=Cc1ccc(-n2cccn2)nc1
Reaction time: 2 h
Yield: 60.1 %

Procedure:
DIBAL (1.0 M solution in toluene, 3.10 mL, 3.10 mmol) was added dropwise to a suspension of the compound from step B (350 mg, 1.53 mmol) in toluene (10 mL) and dichloromethane (4 mL) at −78° C. and the mixture was stirred for 2 h at that temperature. MeOH (1 mL) was added and the mixture was poured into a stirring mixture of ethyl acetate (20 mL) and 10% aq. potassium sodium tartrate (20 mL) and stirred for 1 h at RT. The organic layer was washed with brine (20 mL), dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded 185 mg (59%) of the title compound. MS 202 (M+H)+.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][C:9]1[S:10][C:11]([C:15]2[CH:16]=[C:17]([NH:22][S:23]([C:26]3[S:30][C:29]([CH3:31])=[N:28][C:27]=3[CH3:32])(=[O:25])=[O:24])[C:18]([Cl:21])=[N:19][CH:20]=2)=[C:12]([CH3:14])[N:13]=1>COCCOC>[Cl:21][C:18]1[C:17]([NH:22][S:23]([C:26]2[S:30][C:29]([CH3:31])=[N:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[CH:16][C:15]([C:11]2[S:10][C:9]([NH:8][C:6]([NH2:5])=[O:7])=[N:13][C:12]=2[CH3:14])=[CH:20][N:19]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1nc(C)c(S(=O)(=O)Nc2cc(-c3sc(N)nc3C)cnc2Cl)s1
Solvent: COCCOC
Product: Cc1nc(C)c(S(=O)(=O)Nc2cc(-c3sc(NC(N)=O)nc3C)cnc2Cl)s1
Temperature: 115 °C

Procedure:
A mixture of trimethylsilyl isocyanate (0.032 mL), N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]-2,4-dimethylthiazole-5-sulfonamide (46 mg) and DME (1 mL) was placed in a sealed glass reaction vessel and heated to 115° C. in a microwave reactor for 18 hours. The resultant mixture was evaporated and the residue was purified by preparative HPLC on reversed-phase silica using a solvent gradient of 10% to 100% acetonitrile in water (containing 1% acetic acid) as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a solid (16 mg); 1H NMR Spectrum: (DMSOd6) 2.28 (s, 3H), 2.34 (s, 3H), 2.62 (s, 3H), 6.47 (br s, 2H), 7.71 (s, 1H), 8.34 (br s, 1H), 10.55 (s, 1H), 10:85 (br s, 1H); Mass Spectrum: M+H+ 459.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1)(=[O:19])[CH3:18]
Reactant: N[C@H]1C=C[C@@H](CO)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1C=C[C@@H](CO)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
25 g of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene hydrochloride were dissolved in 182 ml of acetic anhydride and, at 0° C., a solution of 18.25 g of triethylamine in 60 ml of acetic anhydride was added. The mixture was stirred at 80° C. for 3 h and then cooled to room temperature. The triethylamine hydrochloride was filtered off and washed with 120 ml of n-hexane. The filtrate was evaporated. The residue was mixed with 300 ml of toluene and stirred at room temperature in the presence of 5.2 g of active charcoal and 13 g of Celite for 20 min. After filtration and washing of the filter cake (3×40 ml of toluene), the solvent was completely evaporated off. The residue was mixed with 180 ml of methanol and 15.5 g of K2CO3 and stirred at room temperature for 10 h. The suspension was filtered and the filtrate was evaporated. The residue was suspended in 750 ml of isopropyl acetate and boiled in the presence of 0.5 g of active charcoal under reflux for 1.5 h. After the active charcoal filtration (70-80° C.), the filtrate was cooled at 0° C. overnight. The title compound was filtered, washed with 80 ml of cold isopropyl acetate and dried in vacuo. 17.2 g of product were obtained. The yield was 66%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]2[NH:18][CH2:17][CH2:16][NH:15]2)[CH:6]=[C:7]([O:11]C)[C:8]=1[O:9]C.[BrH:19]>>[BrH:19].[OH:11][C:7]1[CH:6]=[C:5]([N:13]=[C:14]2[NH:15][CH2:16][CH2:17][NH:18]2)[CH:4]=[C:3]([OH:2])[C:8]=1[OH:9]
Reactant: COc1cc(N=C2NCCN2)cc(OC)c1OC
Agent: Br
Product: Oc1cc(N=C2NCCN2)cc(O)c1O
Reaction time: 5 h
Yield: 78.6 %

Procedure:
A mixture of 8 gm (0.032 mol) of 2-(3,4,5-trimethoxy-phenylimino)-imidazolidine base and 150 ml of 48% of hydrobromic acid was refluced for 5 hours on an oil bath. Thereafter, the reaction mixture was evaporated in vacuo to half its original volume and allowed to stand overnight in the refrigerator. The amorphous precipitate which had formed was isolated and dried, yielding 7.3 gm (78.6% of theory) of 2-(3,4,5-trihydroxy-phenylimino)-imidazolidine hydrobromide, m.p. 204°-206° C., Rf -value 0.3 in mobile phase 75 parts sec.butanol, 15 parts formic acid, 10 parts water. Carrier: silicagel, visualization; potassium iodoplatinate.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:20]([OH:22])=[O:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.Cl.N1C=CC=CC=1.Cl>>[OH:2][C:3]1[CH:4]=[C:5]([C:20]([OH:22])=[O:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(=O)O)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To acid 23 (0.075 g, 0.250 mmole) was added pyridine-HCl (5.1 g, 43.3 mmole). After stirring at 200° C. for 30 minutes, the mixture was cooled to rt, poured into 2N HCl aq. and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 1:1) to afford 0.052 g (77%) of acid 24 as a white solid: Mp=260-262° C.; 1H NMR (DMSO-d6) δ 13.3 (br s,1 H), 9.79 (br s, 1 H), 9.46 (br s,1 H), 7.91 (d, 2 H, J=8.7 Hz), 7.30 (d, 1 H, J=2.4 Hz), 7.11 (s, 1 H), 7.08 (d, 1 H, J=2.4 Hz), 6.98 (d, 2 H, J=8.9 Hz); MS 269 (M−H)− Product was still contaminated with some 3-Cl compound.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][NH2:23])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1>>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][NH:23][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: C/C=C/C(=O)Cl
Product: C/C=C/C(=O)NCCn1c(CCCC)nc2c(N)nc3cccnc3c21
Yield: 81.1 %

Procedure:
Using the general method of Example 92, crotonyl chloride (68 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamide as a white powder, m.p. 198–200° C. Analysis: Calculated for C19H24N6O: % C, 64.75; % H, 6.86; % N, 23.85; Found: % C, 64.25; % H, 6.68; % N, 23.99. HRMS (EI) calcd for C19H24N6O (M+) 352.2011 found 352.1996.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[C:16](I)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(Cl)(Cl)Cl>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[C:16]([NH:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(I)c(C(=O)Nc2cccc(Cl)c2)n1
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2cccc(Cl)c2)n1
Temperature: 150 °C
Yield: 24.2 %

Procedure:
In a 5 ml microwave reaction vessel were dissolved 50 mg (0.134 mmol) 3-Iodo-6-methyl-pyridine-2-carboxylic acid (3-chloro-phenyl)-amide and 16 mg (0.168 mmol, 1.25 equiv.) of 3-aminopyridine in 2 ml of dioxane. Cesium carbonate (61 mg, 188 mmol, 1.4 equiv.) were added and argon was bubbled through the suspension for 3 min. Then Xanthphos (26 mg, 0.044 mmol, 0.33 equiv.) and Pd2(dba)3.CHCl3 14 mg (0.013 mmol, 0.1 equiv.) were added and the mixture was heated for 30 min at 150° C. under microwave irradiation. The mixture was diluted with methylene chloride, filtered and concentrated in vaccuo. The resulting dark brown oil (129 mg) was purified by flash chromatography (gradient: heptane/ethyl acetate 4:1 to 3:2) to yield the title compound as a yellow solid (total 11 mg, 24%), MS (ISP): m/e=339.1, 341.1 (M+H+).
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C(N(CC)CC)C.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30]>CC(C)=O>[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([O:1][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:40][CH:39]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([OH:15])=[O:14]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCCCC(CCCCCCCCCCC(=O)O)OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 12-Hydroxy stearic acid (450 grams, 1.5 moles), Triethylamine (313 ml, 2.35 moles) in Acetone (1 L) at 10-15° C., was added 4-Nitro Benzoyl Chloride (332 grams, 1.78 moles) and later stirred at room temperature for 10 hours. 75% of the solvent was distilled off. The resulting solution was cooled to room temperature and poured onto cold water. The pH of the solution was adjusted to 4-5 with dilute HCl, and resulting solid was filtered off and washed with chilled water. The solid was converted into slurry with 500 ml diisopropyl ether. The DIPE was filtered off and the resulting solid was dried in vacuum oven at 70-75° C. to yield pure 4-nitrobenzoic acid 11-carboxy-1-hexyl-undecyl ester product as white powder with a melting point of 98-101° C. The resulting compound was characterized by 1H NMR (DMSO-d6) δ 0.85 (t, 3H, CH3), 1.2-1.6 (m, 28H, 14×CH2), 1.8 (m, 2H, CH2), 2.32 (t, 2H, COCH2), 3.2 (m, 1H, CH) 8.1-8.25 (m, 4H, Ar).