Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:17]([O:21][C:22]([NH:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: COCCOc1ccc(C(=O)OC)c(O)c1
Product: COCCOc1ccc(C(=O)OC)c(OCC(C)(C)CNC(=O)OC(C)(C)C)c1
Yield: 85.6 %

Procedure:
Using a procedure similar to that of Example 26-B, methyl 2-hydroxy-4-(2-methoxyethoxy)benzoate (3.2 g, 14.14 mmol) is alkylated with 3-tert-butoxycarbonylamino-2,2-dimethylpropanol (2.88 g, 14.14 mmol) to afford methyl 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-methoxyethoxy)benzoate (4.982 g) after purification over silica gel, eluting with a gradient of 0-40% ethyl acetate in hexane.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N[C@@H]1c2ccccc2C[C@@H]1O
Reaction time: 0.5 h

Procedure:
To a mixture of (1R,2S)-1-amino-2-indanol (500 mg, 3.35 mmol) and triethylamine (0.51 mL, 3.69 mmol) in anhydrous CH2Cl2 at 0° C. was added chloroacetyl chloride (0.295 mL, 3.69 mmol) dropwise. The resulting mixture was stirred for 30 min, quenched with saturated aqueous NaHCO3 (15 mL) and then extracted with EtOAc (2×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc 70:30 to 0:100, to give the title compound. MS: m/z=226 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([CH:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]1.[Cl:46][C:47]1[N:56]=[CH:55][C:54]2[C:49](=[C:50](O)[CH:51]=[CH:52][CH:53]=2)[N:48]=1>C1COCC1>[Cl:46][C:47]1[N:56]=[CH:55][C:54]2[C:49](=[C:50]([O:36][CH:37]3[CH2:42][CH2:41][N:40]([CH:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]3)[CH:51]=[CH:52][CH:53]=2)[N:48]=1
Reactant: CC(C)N1CCC(O)CC1
Reactant: Oc1cccc2cnc(Cl)nc12
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2cccc3cnc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a 0.30M solution of triphenylphosphine (1.5 eq) in THF was added di-tert-butylazodicarboxylate (1.5 eq). The mixture was stirred 15 min at ambient temperature. 4-Hydroxy-1-isopropylpiperidine (4.0 eq) was added. The mixture was stirred 15 min at ambient temperature. 2-Chloroquinazolin-8-ol (1.0 eq) was added. The mixture was stirred an additional 2 h. The crude mixture was concentrated, purified by flash chromatography (EtOAc then 90:10:1 DCM:MeOH:NH4OH), and concentrated to give the desired product in 88% yield. ES/MS m/z 306 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([CH3:14])=[C:6]([CH:8]=[CH:9][C:10]=1[S:11][C:12]#N)[NH2:7].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].CI>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[C:5]([CH3:14])=[C:6]([CH:8]=[CH:9][C:10]=1[S:11][CH3:12])[NH2:7]
Reactant: COCc1c(SC#N)ccc(N)c1C
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: CI
Solvent: O
Product: COCc1c(SC)ccc(N)c1C
Yield: 92.7 %

Procedure:
29.1 g (0.14 mol) of 3-methoxymethyl-2-methyl-4-thiocyanoaniline was dissolved in 200 ml of ethanol and mixed with 100 ml of an aqueous solution containing 33.6 g of sodium sulfide nonahydrate at room temperature. Then, 21.9 g of methyl iodide was dropwise added thereto, and the mixture was reacted at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and water and chloroform were added to the residue. Then, the organic layer was separated and washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 25.6 g of the desired product as an oily substance.
Reaction SMILES: [N+](C1C=CC(S(OC[C@H]2O[C@@H](N3C4N=CN=C(NC(=O)C5C=CC=CC=5)C=4N=C3)[C@H](OC)[C@@H]2O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1)([O-])=O.Cl[CH2:59][C@H:60]1[O:64][C@@H:63]([N:65]2[C:82]3[N:81]=[CH:80][N:79]=[C:69]([NH:70][C:71](=[O:78])[C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[C:68]=3[N:67]=[CH:66]2)[C@H:62]([O:83][CH3:84])[C@@H:61]1[O:85][Si:86]([C:99]([CH3:102])([CH3:101])[CH3:100])([C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1.[Li][N:104]=[N+:105]=[N-:106]>CS(C)=O>[N:104]([CH2:59][C@H:60]1[O:64][C@@H:63]([N:65]2[C:82]3[N:81]=[CH:80][N:79]=[C:69]([NH:70][C:71](=[O:78])[C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[C:68]=3[N:67]=[CH:66]2)[C@H:62]([O:83][CH3:84])[C@@H:61]1[O:85][Si:86]([C:99]([CH3:102])([CH3:101])[CH3:100])([C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[N+:105]=[N-:106]
Reactant: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CCl)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Reactant: [Li]N=[N+]=[N-]
Agent: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Solvent: CS(C)=O
Product: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CN=[N+]=[N-])O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
(FIG. 8C) The above mixture of 14 and 15 (3.9 g) was dissolved in dry DMSO (30 mL) and LiN3 (1.18 g, 24 mmol) was added. The reaction mixture was stirred at 80° C. overnight, then concentrated in vacuo (oil pump). After standard work up and column chromatography using 1-2% gradient MeOH in CH2Cl2 16 was obtained as a colorless foam (2.55 g), 1H NMR δ8.92 (br s, 1H, NH), 8.72 (s, 1H, H2), 8.15 (s, 1H, H8), 8.02-7.36 (m, 15H, 3×Ph), 6.14 (d, J1′,2′=3.4, 1H, H1′), 4.44 (app t, J3′,4′=5.1, 1H, H3′), 4.27 (m, 1H, H4′), 4.01 (app t, J2′,1′=3.4, J2′,3′=4.9, 1H, H2′), 3.53 (dd, J5′,4′=3.2, J5′,5″=13.3, 1H, H5′), 3.37 (dd, J5″,4′=4.5, J5″,5′=13.3, 1H, H5″), 3.29 (s, 3H, OMe), 1.13 (s, 9H, t-Bu).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(O)CO>[Cu]I.C(O)CCC>[CH2:9]([NH:16][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1Br
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: OCCO
Product: O=C(O)c1ccccc1NCc1ccccc1
Temperature: 100 °C
Yield: 52.8 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-iodobenzoic acid (248 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). After heated for a specified duration, the reaction was allowed to reach room temperature. Water and diluted HCl (10%) was added until ˜pH 3. Diethyl ether (2 mL) was added and the organic layer was analyzed by tlc. The reaction mixture was further extracted by diethyl ether (4×10 mL) and the combined organic phase was washed with brine and dried over Na2SO4. The solvent was rotary evaporated and the yellowish-brown residue was purified by column chromatography using a solvent mixture (diethyl ether/ethylacetate=1/1, Rf=0.3) to afford 2-(N-benzyl)aminobenzoic acid (161 mg, 71% isolated yield) as light yellow solid. For aryl bromide substrate: copper(I) iodide (19 mg, 0.101 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μl, 1.20 mmol), 2-bromobenzoic acid (201 mg, 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 1-butanol (1.0 mL) was used and heated to 100° C. The above workup procedures was followed and obtained 2-(N-benzyl)aminobenzoic acid (120 mg, 53% isolated yield) as light yellow solid. For aryl chloride substrate: copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μl, 1.20 mmol), 2-chlorobenzoic acid (157 mg, 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 1-butanol (1.0 mL) was used and heated to 100° C. The above workup procedures was followed and obtained 2-(N-benzyl)aminobenzoic acid (109 mg, 48% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and indicated >95% purity. See Chang, M. R.; Takeuchi, Y.; Hashigaki, K.; Yamato, M. Heterocycles 1992, 33, 147-152. Moore, J. A.; Sutherland, G. J.; Sowerby, R.; Kelly, E. G.; Palermo, S.; Webster, W. J. Org. Chem. 1969, 34, 887-892.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([S:10]([Cl:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[C:2]([F:1])([F:14])[F:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
64.6 g (0.25 mol) of 3-trifluoromethyl-4-methylbenzenesulphonyl chloride are taken up in 500 ml of carbon tetrachloride and, after addition of 44.5 g (0.25 mol) of N-bromosuccinimide and 0.4 g of ABN, the mixture is heated under reflux for 24 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography with petroleum ether/toluene (4:1), 50 μm particle size, gives 33.9 g (40% of theory) of the title compound. Rf : 0.41 (petroleum ether/toluene 3:1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][CH:18](O)[CH3:19].C1C[O:24]CC1>>[C:1]([O:8][CH2:19][CH2:18][Cl:17])(=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)Cl
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCCCl)c1ccccc1
Reaction time: 1 h
Yield: 99 %

Procedure:
20.0 g (142 mM) of benzoyl chloride and then additionally 14.4 g (142 mM) of triethylamine were added dropwise with vigorous stirring at room temperature to a solution of 11.5 g (142 mM) of chloroethanol in 200 ml of THF (exothermic reaction). After stirring for 1 h, the mixture was concentrated on a rotary evaporator, and the residue was partitioned between methylene chloride and water and acidified with 10% strength hydrochloric acid. The aqueous phase was reextracted twice with methylene chloride and the organic phase was then concentrated after drying with sodium sulfate. 26.0 g (99%) of 2-chloroethyl benzoate were isolated.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH:17]=[CH:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.C(O)(=O)C>[Pd].C(O)C>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])=[CH:39][CH:40]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A suspension of diethyl N-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoyl)-L-glutamate (0.16 g, 0.29 m,ol) and 10% palladium on carbon (0.10 g) in ethanol (100 ml) was shaken under hydrogen (40 psi) overnight. Ethanol (80 ml) and acetic acid (20 ml) were added and the mixture was hydrogenated (40 psi) for 1 day. The solution was filtered, concentrated in vacuo, and the residue and catalyst were recombined in acetic acid (40 ml) and hydrogenated over the weekend. The solution was filtered, concentrated in vacuo and the product twice filtered from a small volume of methanol to give diethyl N-(4-(2-(1, 2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)ethyl)benzoyl)-L-glutamate (0.10 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.16 (t, J=7 Hz, 3H, ester CH3), 1.19 (t, J=7 Hz, 3H, ester CH3), 1.90-2.18 (m, 2H, gluCH2), 2.43 (s, 3H, C3—CH3), 2.44 (t, J=7.5 Hz, 2H, gluCH2), 3.03-3.22 (m, 4H, ArCH2's), 4.04 (q, J=7 Hz, 2H, ester CH2), 4.10 (q, J=7 Hz, 2H, ester CH2), 4.37-4.47 (m, 1H, gluCH), 7.40 (d, J=8 Hz, 2H, Ar), 7.54 (dd, J=8, 1.5 Hz, 1H, Ar), 7.57 (d, J=8.5 Hz, 1H, Ar), 7.80 (d, J=8 Hz, 2H, Ar), 7.95 (d, J=8 Hz, 1H, Ar), 8.20 (d, J=9 Hz, 1H, Ar), 8.65 (d, J=7.5 Hz, 1H, gluNH), 9.72 (s, 1H, Ar), 12.51 (br s, 1H, N2H). Mass spectrum (CI—CH4): 544 (M+1, 4.2%). Anal. Calculated for C31H33N3O6.1/10 H2O: C, 68.27; H, 614; N, 7.70. Found: C, 68.34; H, 6.10; N, 7.68.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=C3C[N+:8]([O-])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:6]=2[CH:24]=1.[C:25]([O:28][C:29](=[O:31])[CH3:30])(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([OH:28])(=[O:27])[CH3:26].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:30]3[CH:29]([OH:31])[N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:24]=1
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2O

Procedure:
A stirred mixture of 1.0 g of 8-chloro-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-5-oxide (III), 5 ml. of acetic anhydride and 3 ml. of acetic acid is warmed on the steam bath, under nitrogen, for 30 minutes and concentrated in vacuo. The residue is suspended in water, neutralized with sodium carbonate and extracted with methylene chloride. The extract is dried, concentrated and chromatographed on silica gel eluting with ethyl acetate to yield 8-chloro-4-hydroxy-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH:6]=[C:5]2[CH:24]=[O:25].[CH:26]1([NH:29][C:30](=[O:48])[C:31]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[C:34]([CH3:46])=[C:33]([F:47])[CH:32]=2)[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:30](=[O:48])[C:31]2[CH:36]=[C:35]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=3)[CH:6]=[C:5]4[CH:24]=[O:25])[C:34]([CH3:46])=[C:33]([F:47])[CH:32]=2)[CH2:27][CH2:28]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)c1ccc(Cn2cc(C=O)c3cc(Br)ccc3c2=O)cc1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(C=O)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 60 step iii) using product of Example 103 step ii) and N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25]([CH:26]=O)=[C:24]([CH3:28])[N:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:53]CCCl>>[ClH:53].[CH3:20][C:21]1[C:25]([CH2:26][N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:13][CH:12]=[CH:11][N:10]=3)[CH2:19][CH2:18]2)=[C:24]([CH3:28])[N:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:22]=1
Reactant: Cc1nn(-c2ccccc2)c(C)c1C=O
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccc2)c(C)c1CN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
Dissolve 3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.200 g, 0.774 mmol) in DCE (10 mL). Add 3,5-dimethyl-1-phenylpyrazole-4-carboxaldehyde (0.186 g, 0.929 mmol), and stir at room temperature for 10 min. Add sodium triacetoxyborohydride (0.247 g, 1.16 mmol) followed by acetic acid (47 μL, 0.813 mmol). Stir at room temperature for 18 hr. Purify via SCX chromatography, followed by silica gel chromatography, eluting with 0:100 to 10:90 methanol:DCM, followed by reverse phase chromatography to give the free base of the title compound (221 mg, 65%). Dissolve the free base (0.099 g, 0.225 mmol) in methanol and add a solution of ammonium chloride (0.012 g, 0.225 mmol) in a minimal volume of methanol. Shake for 1 hr. at room temperature and concentrate to give the title compound (108 mg, 100%). MS (ES): m/z=443 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CCOCC>[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:1](=[O:5])[C:2]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:3])=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: O=C(C(=O)N1CCCC1)c1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
Add oxalyl chloride (11.6 g, 90.6 mmol) dropwise to a solution of 6-nitroindole (10.6 g, 65.4 mmol) in ether (100 mL). Stir at room temperature for 18 h, filter the precipitate formed, and dry. Dissolve the precipitate in CH2Cl2 (100 mL), cool to −20° C., and add pyrrolidine (16.0 mL, 191.5 mmol) dropwise. Warm to room temperature and stir for 2 h. Filter the solid from the reaction, wash several times with ether, and dry to give the title compound (8.5 g, 45%). MS (ES+) 288 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]([NH2:45])=[O:44])[CH2:39][CH2:38]1.[C:46]1([C:52]2([C:58]([OH:60])=[O:59])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(OCC)(=O)C>CO.ClCCl>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]([NH2:45])=[O:44])[CH2:39][CH2:38]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:55]3[CH2:54][CH2:53][C:52]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:58]([OH:60])=[O:59])[CH2:57][CH2:56]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: CN1CCN(C(N)=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid 4-methylpiperazine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with ethyl acetate, 3% methanol/dichloromethane, 6% methanol/dichloromethane, and then 10% methanol/dichloromethane, the title compound: Rf =0.41 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>O1CCCC1>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)Nc1ccccc1
Reaction time: 0.33 h
Yield: 57.9 %

Procedure:
Under a nitrogen atmosphere, phenyl isocyanate (52 μL, 0.48 mmol) was added to a suspension of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) in anhydrous tetrahydrofuran (60 mL). The reaction mixture was stirred for 20 minutes at which time it had turned homogeneous and thin layer chromatography indicated no starting material remained. Aminomethyl resin (280 mg of 1% cross linked, 100-200 mesh available from BACHEM, Torrance, Calif.) was added and the reaction mixture was allowed to stir for 0.5 hr. Silica gel (0.4 g) was added and the mixture was concentrated under vacuum to provide a solid. The solid was purified by flash chromatography eluting with 95/5 dichloromethane/methanol to give a white solid which was dried under vacuum at 60° C. to provide 0.12 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-phenylurea. Analysis: Calculated for C24H29N7O+⅕H2O: %C, 66.25; %H, 6.81; %N, 22.53; Found: %C, 66.27; %H, 6.63; %N, 22.83
Reaction SMILES: C(O)(C(F)(F)F)=[O:2].S(=O)(=O)(O)O.[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=3[Cl:35])=[C:22]([C:36]#[N:37])[CH:21]=2)[CH:17]=[CH:16][N:15]=1.N>O>[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][C:26]=3[Cl:35])=[C:22]([C:36]([NH2:37])=[O:2])[CH:21]=2)[CH:17]=[CH:16][N:15]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1cc(-c2ccnc(N)n2)[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of TFA (2.0 mL), water (0.480 mL) and 98% sulfuric acid (0.240 mL) was added to 5-(2-amino-pyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbonitrile (137 mg, 0.415 mmol). The mixture was allowed to stir for 8 h at 70° C. and then was diluted by drop wise addition of water (6 mL). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia under stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50° C. affording the title compound as a white solid (133 mg, 92%).