Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:23]([CH2:6][C@@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+:24]=[N-:25]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])CC1CCCCC1
Temperature: 80 °C
Yield: 68.8 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (23.3 g, 0.070 mol) in anhydrous DMF (300 mL) was added solid NaN3 (13.5 g, 0.21 mol). The reaction mixture was heated at 80° C. overnight. After cooling to rt, the reaction solution was diluted with EtOAc (1200 mL) and water (400 mL). The organic phase was separated and washed with brine (3×300 mL), dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel to give (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate as a clear oil (13.6 g, 69%). 1H NMR (400 MHz, CDCl3): 4.45 (d, J=8.0 Hz, 1H), 3.84 (m, 1H), 3.45 (m, 1H), 3.31 (m, 1H), 1.81-1.60 (m, 5H), 1.45 (s, 9H), 1.40-0.78 (m, 8H). MS (E/Z): 383 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1.C(O)(=O)C>[CH:13]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC2CCCCC2)cc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of ethyl 4-aminobenzoate (20.00 g, 0.120 mol) and cyclohexanone (17.80 g, 0.180 mol) in tetrahydrofuran (100 ml) and acetic acid (10 ml) was added sodium triacetoxyborohydride (38.50 g, 0.180 mol) at room temperature, and the mixture was stirred for 2 hr. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and hexane was added to the obtained residue. The precipitated solid was collected by filtration and washed with hexane. The obtained solid was dried in vacuo to give ethyl 4-cyclohexylaminobenzoate (25.20 g, yield 84%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH:17]([C:16]1[CH:19]=[CH:20][C:13]([CH2:12][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[CH3:1])=[CH:14][CH:15]=1)=[CH2:18]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: C=Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Cn2c(C)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
This Example illustrates the synthesis of polymeric blocked developer PBD1. First, 1-(4-vinylbenzyl)-2-methylbenzimidazole was prepared. A suspension of 2-methylbenzimidazole (25.0 g, 0.19 mol), 4-chloromethylstyrene (31.8 g, 0.21 mol), powdered potassium hydroxide (10.6 g, 0.19 mol), and potassium carbonate (13.1 g, 0.1 mol) in 200 mL of dry tetrahydrofuran was stirred at 25° C. for 5 d. The reaction mixture was filtered, and the solid residue extracted with additional tetrahydrofuran. The combined liquids were concentrated at reduced pressure, and the resulting brown oil was triturated with ligroin and held at −15° C. for a few hours to induce crystallization. The ligroin was decanted from the product, which was then purified by recrystallization from 70% methanol/30% water. A cream colored solid product (43.2 g, 92%) was obtained after drying. 1H NMR (CDCl3) δ 2.61 (s, 3H), 5.28 (d, J=11.0, 1H), 5.33 (s, 2H), 5.75 (d, J=17.6, 1H), 6.7 (m, 1H), 7.05 (d, J=8.1, 2H), 7.25 (m, 2H), 7.37 (d, J=8.2, 2H), 7.78 (d, J=7.3, 1H). Electrospray mass spectrometry (ES-MS) m/e 249+ (M+1).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21].[OH-].[K+].O.CO>C1COCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[C:4]([CH:9]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(Br)ccc1CCc1cccc(OC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cccc(CCc2ccc(Br)cc2C(=O)O)c1C
Yield: 98 %

Procedure:
The crude 5-bromo-2-[2-(3-methoxy-2-methylphenyl)-ethyl]-benzoic acid methyl ester 6 was stirred with 50% KOH solution (5 mL), water (30 mL), methanol (12 mL), and THF (30 mL), heated at reflux temperature for three hours and concentrated in vacuo to remove the organic solvents. The resultant aqueous suspension was acidified using 1.0 N HCl solution and filtered. The filtercake was dried over night to give the benzoic acid 7 as a white solid, 4.74 g; 98% yield.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16](Br)[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:15]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(N2CCC3(CC2)OCCO3)c1

Procedure:
A mixture of 2,2′-Bis(diphenylphosphino)1,1′-binaphthyl[BINAP] (54.35 mg, 0.085 mmol) and Palladium(II)acetate[Pd(OAc)2] (6.95 mg, 0.028 mmol) in dry toluene (3 ml) was stirred vigorously and nitrogen was bubbled through the suspension for 30 minutes. To this, 1,4-Dioxa-8-aza-spiro[4.5]-decane (100 mg, 0.699 mmol), 3-Bromo-4-methyl-benzoic acid methyl ester (192.1 mg, 0.839 mmol) and dry Cesium Carbonate (683.5 mg, 2.09 mmol) was added. Nitrogen was bubbled through for another 30 minutes; the mixture was allowed to reflux overnight. The mixture was cooled, diluted with ethylacetate, water was added and the layers separated. The aqueous layer was extracted with ethyl acetate) and the two organic extracts were combined. The organics were washed with brine, then dried (sodium sulfate), filtered and concentrated. Further purification by silica gel chromatography using 5-10% ethyl acetate/Hexane as eluent provided 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-benzoic acid methyl ester [11] as a yellow solid [150.5 mg, 61.7%]
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[F:29][C:30]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40](I)[S:41][C:34]=12.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl.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>[F:29][C:30]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40]([C:18]3[CH:17]=[N:16][N:15]([CH2:14][CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:19]=3)[S:41][C:34]=12
Reactant: COCCN(CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
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: ClCCl
Solvent: COCCOC
Product: COCCN(CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1)C(=O)OC(C)(C)C

Procedure:
A mixture of 78 (369.3 mg, 0.93 mmol), 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US 2006/0287343 A1] (466.6 mg, 1.12 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol) and Na2CO3 (305 mg, 2.8 mmol) in DME (1.9 mL) was heated to reflux overnight under nitrogen. It was then diluted with DCM, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluents EOAc/Hex 1:1, EtOAc, 5% MeOH in DCM affording title compound 79 (203 mg, 39%) as brown syrup. MS (m/z): 558.2 (100%) (M+H).
Reaction SMILES: CC1OC(C2C=CC=CC=2)=NC=1CCO.CC1OC(C2C=CC=CC=2)=NC=1CC(OCC)=O.OC1C=CC(C=O)=CC=1.[CH3:43][C:44]1[O:48][C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N:46][C:45]=1[CH2:55][CH2:56][O:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62][OH:63])=[CH:60][CH:59]=1.P(Br)(Br)[Br:67]>C(Cl)Cl.CO>[CH3:43][C:44]1[O:48][C:47]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[N:46][C:45]=1[CH2:55][CH2:56][O:57][C:58]1[CH:59]=[CH:60][C:61]([CH:62]=[O:63])=[CH:64][CH:65]=1.[Br-:67]
Reactant: BrP(Br)Br
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO)cc1
Agent: CCOC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: Cc1oc(-c2ccccc2)nc1CCO
Agent: O=Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Product: [Br-]
Reaction time: 2 h

Procedure:
The procedure of Example 1, Part A was used to prepare 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol from ethyl 5-methyl-2-phenyl-4-oxazoleacetate. 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde was prepared following the procedures of Preparation 2, herein, using para-hydroxybenzaldehyde instead of 3-hydroxybenzaldehyde and 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol instead of 2-(2-phenyl-4-oxazolyl)ethanol. The aldehyde was reduced to 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl alcohol following the procedures of Example 22, Part A. A solution of 3 gm (0.01M) of 4-[2-(5-methyl-2-phenyl-4-oxazlyl)ethoxy]benzyl alcohol in 30 mL CH2Cl2 was treated with 1 mL of PBr3 and kept at ambient temperature for 2 h. The solution was treated cautiously with 2 mL of MeOH and evaporated in vacuo. The residue was dissolved in EtOAc, the solution washed with cold H2O, then with 20% NaHCO3, then with H2O, then with brine, and finally dried over MgSO4. Removal of solvent in vacuo afforded the solid bromide (2 g, 6 mM). The solid bromide was dissolved in 20 mL THF and and the solution was added drop-wise to a solution prepared by the reaction of 0.42 g of 60% NaH/oil dispersion (10 mM NaH), 1.6 gm (5.2 mM) of N-CBZ Diethylaminomalonate hydrochloride and 30 mL of EtOH. The subsequent reaction was allowed to proceed at ambient temperature for 12 h, during which time a precipitate had formed. TLC demonstrated the consumption of starting materials. The mixture was treated with 20 mL H2O and NaOH (1.1 g), stirred, and heated to reflux for 1 h. The cooled mixture was acidified to pH 2, diluted with H2O and extracted with EtOAc. The combined EtOAc extracts were washed with H2O, thwn with brine, and finally dried with MgSO4. Removal of solvent afforded a yellow taffy which crystallized from EtOAc/Hexane to provide the product as a white powder (0.78 g, 16% overall).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]([O-:20])=O)[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+].F[C:25]1C=CC(COC2C=C3C(C=C(C(OCC)=O)C=N3)=CC=2)=CC=1.[OH-].[Na+]>CO.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](=[O:20])[CH3:25])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:21][CH:22]=1
Reactant: O=C([O-])c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Reactant: CCOC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium 7-((4-fluorobenzyl)oxy)quinoline-3-carboxylate. To a solution of ethyl 7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2, 430 mg, 1.32 mmol) in MeOH (2 mL) and THF (2 mL) was added NaOH (95 mg, 2.38 mmol) in H2O (2.0 mL). The reaction was stirred for 15 minutes at ambient temperature. The crude reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J=2.0 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.63 (dd, J=5.5, 8.6 Hz, 2H), 7.50 (d, J=2.7 Hz, 1H), 7.35-7.25 (m, 3H), 5.31 (s, 2H). [M+H]=298.2
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>CCOC(C)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][N:11]1[CH2:24][CH2:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(COCc2ccccc2)nc1
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN1CC(C(=O)OCC)CCC1COCc1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 12.7 %

Procedure:
To an EtOAc solution (0.9 mL) of 14c (271 mg, 1.0 mmol) was added 2 M ethereal HCl (3.6 mL), and then the solvent was removed in vacuo and the residual 14c.HCl salt was dissolved in MeOH (5.4 mL) and PtO2 (14 mg) was added. The mixture was hydrogenated under 1 atm of H2 (1 h). The catalyst was filtered, and the solvent was removed in vacuo. The residue was dissolved in aqueous 1 N NaOH (3.5 mL) and extracted with EtOAc (3×15 mL). The organic extracts were combined, dried (Na2SO4), concentrated, and then dissolved in ethyl acrylate (1.1 mL, 10 mmol) and stirred at 80° C. (20 h). The reaction was concentrated to dryness and the residue was separated by PTLC (EtOAc/hexanes=2/3) to give 15c (48 mg, 13%) and 17 (32 mg, 12%), respectively. Compound 15c: clear oil; Rf 0.57 (EtOAc/hexanes=1/1); IR (neat) 2978, 2935, 2862, 1731, 1454, 1372, 1181 cm−1; 1H NMR (CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.64-1.77 (m, 4H), 2.43-2.54 (m, 3H), 2.66 (dd, J=3.9, 12.2 Hz, 1H), 2.82-2.97 (m, 4H), 3.45 (dd, J=5.9, 9.6 Hz, 1H), 3.66 (dd, J=5.4, 9.6 Hz, 1H), 4.12 (q, J=7.2 Hz, 4H), 4.47 (1/2 AB, J=12.2 Hz, 1H), 4.52 (1/2 AB, J=12.2 Hz, 1H), 7.27-7.34 (m, 5H), 13C NMR (CDCl3) 14.1, 14.2, 23.3, 25.9, 33.1, 40.6, 50.1, 50.3, 57.6, 60.1, 60.2, 69.3, 73.2, 127.4, 127.5 (2C), 128.3 (2C), 138.3, 172.7, 174.1 ppm; MS (+CI) 378 [M+1]+; Mr (+CI) 378.228 63 [M+1]+ (calcd for C21H32NO5 378.228 05). Compound 17 (King et al., “Substituted Benzamides with Conformationally Restricted Side Chains. 5. Azabicyclo[xyz] Derivatives as 5-HT4 Receptor Agonists and Gastric Motility Stimulants”, J. Med. Chem. 1993, 36, 683-689) (cis- and trans-mixture): yellow oil; Rf 0.44 (EtOAc/hexanes=1/1); IR (neat) 2974, 2924, 2814, 1735, 1455, 1377 cm−1; 1H NMR (CDCl3) δ 1.00 (d, J=6.6 Hz, 1.4H), 1.10 (d, J=6.6 Hz, 1.6H), 1.23-1.28 (m, 6H), 1.40-2.01 (m, 4H), 2.18-2.31 (m, 1H), 2.42-2.59 (m, 4H), 2.67-2.88 (m, 2H), 3.03-3.10 (m, 1H), 4.08-4.17 (m, 4H), 13C NMR (CDCl3) 13.7 (2C), 14.2 (2C), 19.9 (2C), 23.1 (2C), 27.4 (2C), 32.7, 33.8, 41.2, 42.2, 48.8, 49.6, 49.8, 53.3, 54.1, 55.1, 60.2 (2C), 60.3 (2C), 172.8 (2C), 174.1 (2C) ppm; MS (+CI) 272 [M+1]+; Mr (+CI) 272.186 63 [M+1]+ (calcd for C14H26NO4 272.186 18).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]([CH2:19][CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C1(C)C=CC=CC=1>B(F)(F)F.CCOCC.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:13]([CH2:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(=CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Yield: 77.1 %

Procedure:
In a 500-ml flask, 4-trifluoromethylaniline (80.6 g, 0.5 mol), methyl 3-oxopentanoate (65.1 g, 0.5 mol) and toluene 400 ml were placed. To this solution was added boron trifluoride etherate (1.42 g, 10 mmol), and the resulting mixture was heated under a reduced pressure of 8 kPa. The reaction mixture was heated for 5 hours under reflux, while water produced was removed out of the reaction system by using a Dean-Stark trap. Then, the heating was discontinued and nitrogen was leaked. After cooling, the solvent was removed by distillation by using a rotary evaporator. The residue was then distilled under reduced pressure to give 105.3 g of the title compound. The yield was 77.1%.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([CH2:15][CH3:16])([F:14])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:50][C:45]2[CH:46]=C[CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([CH2:15][CH3:16])([F:14])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:50][CH:45]5[CH2:44][N:49]([CH3:48])[CH2:46]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CCC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CN(C)C4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71-0.95 (m, 1 H) 0.89 (t, J=7.3 Hz, 3 H) 1.07-1.92 (m, 12 H) 2.29 (s, 3 H) 3.03 (t, J=7.1 Hz, 2 H) 3.26 (s, 3 H) 3.51-3.76 (m, 1 H) 3.58 (t, J=7.2 Hz, 2 H) 3.76-3.87 (m, 1 H) 3.95 (s, 3 H) 4.44 (m, 1 H) 7.49 (d, J=8.3 Hz, 1 H) 7.52 (s, 1 H) 7.78 (s, 1 H) 8.11 (s, 1 H) 8.33 (d, J=8.6 Hz, 1 H) 8.63 (d, J=6.8 Hz, 1 H). [M+H] calc'd for C28H38FN7O3, 540; found 540.
Reaction SMILES: [CH3:1][C:2]1([CH3:49])[O:6][C:5]2[C:7]([CH:16]([C:33]3[C:43]4[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=4[CH:41]=[C:35]4[O:36][C:37]([CH3:40])([CH3:39])[O:38][C:34]=34)[C:17]3[C:27]4[O:28][C:29]([CH3:32])([CH3:31])[O:30][C:26]=4[CH:25]=[C:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=34)=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.[Li]CC[CH2:53][CH3:54].[CH2:55]([O:57][C:58](Cl)=[O:59])[CH3:56]>C1COCC1>[CH2:55]([O:57][C:58]([C:41]1[C:35]2[O:36][C:37]([CH3:40])([CH3:39])[O:38][C:34]=2[C:33]([CH:16]([C:17]2[C:18]3[O:22][C:21]([CH3:23])([CH3:24])[O:20][C:19]=3[C:25]([C:11]([O:12][CH2:53][CH3:54])=[O:10])=[C:26]3[O:30][C:29]([CH3:31])([CH3:32])[O:28][C:27]=23)[C:7]2[C:5]3[O:6][C:2]([CH3:49])([CH3:1])[O:3][C:4]=3[C:15]([C:2]([O:3][CH2:4][CH3:5])=[O:6])=[C:9]3[O:10][C:11]([CH3:13])([CH3:14])[O:12][C:8]=23)=[C:43]2[C:42]=1[O:46][C:45]([CH3:48])([CH3:47])[O:44]2)=[O:59])[CH3:56]
Reactant: CC1(C)Oc2cc3c(c(C(c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Reactant: CCOC(=O)Cl
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c(c(C(c3c4c(c(C(=O)OCC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)OCC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Temperature: -60 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Tris(2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methane (1.35 g, 2.0 mmol (Example 17)) was dissolved in dry THF (400 mL) under N2, and the temp was lowered to -40° C. and n-BuLi (4.86 mL, 12.2 mmol) was added and the temperature was allowed to rise gradually to 0° C. The mixture was cooled to -60° C., and a solution of ethylchloroformate (4.0, 36.7 mmol) in THF (50 mL) was added. The reaction mixture was left overnight and worked up as described under Example 20 above. The chromatography gave (0.41 g, 24%) of tris(8-ethoxycarbonyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methane.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[N:12][C:13](=[O:15])[CH:14]=1.[H][H].S(O[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([C:38]1[CH:39]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([N+:57]([O-:59])=[O:58])[CH:52]=2)[C:40]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[C:41]([CH3:45])[NH:42][C:43]=1[CH3:44])=[O:37])(C1C=CC(C)=CC=1)(=O)=O>CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][N:12]=[C:13]([O:15][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([C:38]2[CH:39]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([N+:57]([O-:59])=[O:58])[CH:52]=3)[C:40]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[C:41]([CH3:45])[NH:42][C:43]=2[CH3:44])=[O:37])[CH:14]=1
Reactant: O=C1C=C(c2ccccc2Cl)N=N1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOS(=O)(=O)c2ccc(C)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccccc3Cl)[nH]n2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
0.24 g (10 mmole) of sodium hydride was suspended in 10 ml of dimethylsulfoxide, to which was added gradually 1.95 g (10 mmole) of 3-o-chlorophenyl-5-pyrazolone with stirring at room temperature. After evolution of hydrogen had ceased, to this solution was added 10 ml of a solution of 6.01 g (10 mmole) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester in dimethylsulfoxide, and stirring with heating at 80° C. was continued for an hour. The resultant reaction mixture was poured into 150 ml of ice water, and the separated product was extracted with 50 ml of chloroform. This chloroform solution was washed with 50 ml of water 4 times, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily residue. This residue was purified by chromatography on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 100:1) as an eluent, and further by chromatography on a silica gel column eluting with a toluene-ethyl acetate mixed solution, and the eluate fractions containing the purified intended compound were concentrated to dryness under reduced pressure to obtain 2.55 g (yield 40.9%) of the 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-ethoxycarbonylpyridine-5-carboxylic acid 6-(5-o-chlorophenyl-3-pyrazolyloxy)hexyl ester as a pale yellow powder.