Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 17] (0.105 g) in DCM (10 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.152 g), HOBT (0.107 g) and triethylamine (0.222 ml) and the mixture was stirred at room temperature for 30 min. Morpholine (0.07 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 5:1, and ethyl acetate) to give the title compound (0.1 g) as a white solid.
Reaction SMILES: C(O)(C)(C)C.[C:6]1([C:14]([CH2:16][C:17]2[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[CH:19][CH:18]=2)=[O:15])[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].CO[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[O:36]>CCCCCC>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:14]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[CH:12][CH:13]=2)=[O:15])=[CH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:24][CH:23]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Reactant: COC=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCCCCC
Product: COC(=O)CC=C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To 430 ml of tert-butanol were added 128 g of deoxyanisoine, 67.3 g of potassium tert-butoxide and 116 g of methyl 3-methoxyacrylate, and the mixture was stirred at 70° C. for 3 hours. To the resulting mixture was added n-hexane, and the mixture was allowed to stand at room temperature. A formed precipitate was filtered and dissolved by adding 1,000 ml of ethyl acetate and 300 ml of 3N-sulfuric acid. An organic layer was separated, washed with 3N-sulfuric acid and saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give 153 g (yield 90%) of methyl 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenoate as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[CH2:20]1[NH:25][CH2:24][CH2:23][N:22]2[CH2:26][C@H:27]([CH2:30][OH:31])[CH2:28][CH2:29][C@@H:21]12>CS(C)=O>[NH2:14][C:13]1[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:19]=[C:9]2[N:10]=[C:11]([N:25]2[CH2:24][CH2:23][N:22]3[CH2:26][CH:27]([CH2:30][OH:31])[CH2:28][CH2:29][CH:21]3[CH2:20]2)[N:12]=1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Solvent: CS(C)=O
Product: Nc1nc(N2CCN3CC(CO)CCC3C2)nc2nc(-c3ccco3)nn12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (1 eq.; for reference, see J. Chem. Soc. Perkin Trans. 1, 801 (1995)) and cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1-2 eq; see U.S. Pat. No. 5,122,525) were dissolved in DMSO. The mixture was stirred at around 80° C. for 2 hours. The solution was then cooled to room temperature, filtered and purified by preparative HPLC using aqueous CH3CN solution (buffered with 0.1% TFA) to give the desired compound as a white solid. Alternatively, for scale up synthesis, the DMSO solvent was removed and the crude product was chromatographed on silica gel column using 5-10% MeOH/CH2Cl2 as eluant to afford the desired product. 1H NMR (400 Hz, CD3OD) δ 7.70 (d, J=2.0 Hz, 1H), 7.12 (d, J=3.5 Hz, 1H), 6.62 (dd, J=3.5, 2.0 Hz, 1H), 4.75 (d, J=12.0 Hz, 1H), 4.65 (d, J=12.5 Hz, 1H), 3.82 (dd, J=10.5, 7.5 Hz, 1H), 3.74 (dd, J=10.5, 7.5 Hz, 1H), 3.11 (dt, J=13.0, 3.0 Hz, 1H), 2.93 (d, J=11.5 Hz, 1H), 2.78 (d, J=11.5 Hz, 1H), 2.68 (dd, J=13.0, 10.5 Hz, 1H), 2.22 (dd, J=11.5, 3.0 Hz, 1H), 2.14 (dt, J=12.0, 3.0 Hz, 1H), 1.93 (m, 1H), 1.85 (brd, J=12.0 Hz, 2H), 1.60 (m, 1H), 1.43 (m, 2H). MS m/z: 371 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9](=O)[CH3:10].[Cl:12][CH2:13][C:14]#[N:15]>O1CCOCC1.Cl>[Cl:12][CH2:13][C:14]1[N:15]=[C:9]([CH3:10])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[N:1]=1
Reactant: N#CCCl
Reactant: CC(=O)c1c(C)cccc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc2nc(CCl)nc(C)c12

Procedure:
Prepared by reacting 1-(2-amino-6-methyl-phenyl)-ethanone with chloroacetonitrile in dioxane while piping in hydrogen chloride at 30-38° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)cc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2,4-dichlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 233.0–234.0° C. 1H NMR (acetone-d6/300 MHz) 7.90 (s, 1H), 7.73 (s, 1H), 7.69 (d, 1H, J=2.6 Hz), 7.47 (dd, 1H, J=8.7 Hz, 2.6 Hz), 7.28 (d, 1H, J=8.7 Hz), 6.57 (s, 1H), 5.81 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz). FABLRMS m/z 437 (M−H). ESHRMS m/z 436.9379 (M−H, Calc'd 436.9362). Anal. Calc'd for C17H9Cl3F3O4: C, 46.45; H, 1.83; Cl, 24.19. Found: C, 46.38; H, 1.59; Cl, 24.46.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH:15]=[CH2:16])[CH3:12].C(O)(=O)C>C(#N)C>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][CH2:16][SH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[CH3:12]
Reactant: Cc1nc2ccccc2s1
Reactant: C=CC(OCC)OCC
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(CC[SH]1C(C)=Nc2ccccc21)OCC

Procedure:
1-(3,3-Diethoxypropyl)-2-methyl-benzothiazole was prepared by reaction of 2-methylbenzothiazole (125 mg, 0.84 mmol) with acrolein diethyl acetal (1.64 g, 12.6 mmol) and acetic acid (100 μl) in acetonitrile (4 ml) by a method analogous to that described in Section 1.2. The product was purified by HPLC on a Rainin Dynamax C18, 8 μm using a 0–100% gradient elution of water/acetonitrile (containing 0.1% TFA) over 60 minutes at 20 ml/min. The product was obtained as a colourless oil (220 mg, 95%); m/z (FAB−): 280.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12][C:13]#[CH:14].[CH2:17]([C:19]1[C:20]([C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH:25]=[O:26])[NH:22][C:23]=1I)[CH3:18]>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].[Cu]I.O1CCOCC1>[CH2:17]([C:19]1[C:20]([C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH:25]=[O:26])[NH:22][C:23]=1[C:14]#[C:13][CH2:12][Si:11]([CH3:16])([CH3:15])[CH3:10])[CH3:18]
Reactant: C#CC[Si](C)(C)C
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OC
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(C#CC[Si](C)(C)C)[nH]c(C=O)c1C(=O)OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate was obtained following the procedures described in Example 3. Pd(Pt-Bu3)4 (18.4 mg, 0.040 mmol), Pd2(dba)3 (16.5 mg, 0.020 mmol), and CuI (4.6 mg, 0.020 mmol) were combined in a dry flask under N2 prior to evacuating the flask and refilling with argon. After the flask was charged with dioxane (4.0 mL), i-Pr2NEt (0.0675 mL, 0.48 mmol), trimethyl(prop-2-ynyl)silane (90.0 mg, 0.80 mmol), and methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate (123.0 mg, 0.40 mmol) were added sequentially. The reaction was stirred overnight at 80° C. After the reaction was cooled to ambient temperature, it was filtered through a plug of silica gel and concentrated in vacuo. The resultant residue was dissolved in acetonitrile and purified by reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 10.04 (s, 1H); 3.90 (s, 3H); 2.78 (q, J=7.5 Hz, 2H); 1.77 (s, 2H); 1.16 (t, J=7.5 Hz, 3H); 0.17 (s, 9H). HRMS (ES) exact mass calculated C15H22NO3Si (M+H): 292.1364. Found 292.1364
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[C:8]([Br:11])[C:7]([Br:12])=[C:6]([Br:13])[C:5]=1[Br:14].C1([O-])C=CC=CC=1.[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>COCCO>[Br:3][C:4]1[C:9]([O:10][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[CH2:23][Cl:22])=[C:8]([Br:11])[C:7]([Br:12])=[C:6]([Br:13])[C:5]=1[Br:14]
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Reactant: O=C(Cl)c1ccccc1CCl
Agent: [Na+]
Agent: [O-]c1ccccc1
Agent: [OH-]
Solvent: COCCO
Product: O=C(Oc1c(Br)c(Br)c(Br)c(Br)c1Br)c1ccccc1CCl
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
In a 500-ml three-necked flask, 4 g (= 0.1 mole) of sodium hydroxide was dissolved at 60° C in 270 ml of methyl glycol, and 48.9 g of pentabromophenol was stirred in for the preparation of a phenolate solution, as in Example 8c. At 30° to 34° C, 18.9 g (- 0.1 mole) of o-chloromethylbenzoyl chloride was added drop by drop, with stirring, over a period of about 40 minutes, whereupon a white, crystalline preciptate settled out, which after 1 hour was suction filtered. After the product had been stirred up in water, suction filtered, washed and dried, 58 g (= 90.5%) of o-chloromethylbenzoic acid pentabromophenyl ester was obtained, which melted at 201°-205° C.
Reaction SMILES: C1(C[O:8][C:9](=[O:51])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48](=[O:50])[NH2:49])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1.[H][H].CN(C=O)C>[Pd].C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48](=[O:50])[NH2:49])[CH:24]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:51])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(N)=O)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(N)=O)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A mixture of 2.2 g of N-[(3-carbamoyl)-5-(octadecyloxy)phenyl]-N-[2(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 3 hours. DMF (150 ml) was added and the mixture was heated todissolve the precipitated product. The hot mixture was filtered to remove the catalyst and the filtrate was concentrated at reduced pressure to a solid. Recrystallization from THF gave 1.1 g (69% yield, mp 213°-216°) of N-(carboxymethyl)-N-[(3-carbamoyl)-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:7]1[C:6]2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: Fc1cccc(CBr)c1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3cccc(F)c3)c12
Yield: 90 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3-fluorobenzyl bromide as starting materials, the title compound was obtained in a yield of 90% as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH:44]([NH2:46])[CH3:45]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:46][CH:44]([C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)[CH3:45])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(N)c1cccs1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4cccs4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 92 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-thiophen-2-yl-ethylamine: yield 92%.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([C:15]1[CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=1)#[N:14].Cl>CN(C=O)C>[NH:1]1[C:13]([C:15]2[CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=2)=[N:14][N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C#N)cc(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
Sodium azide (880 mg) and triethylamine hydrochloride (1.9 g) were added to a DMF (40 mL) solution of methyl 5-cyanobiphenyl-3-carboxylate (1.09 g), and stirred at 100° C. for 9 hours. With cooling with ice, diluted hydrochloric acid was added to it, the formed precipitate was taken out through filtration, washed with water, and dried to obtain the title compound as a white powder.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH2:11][N:12]2C(=O)C3=CC=CC=C3C2=O)[CH:10]=1.Cl>C(O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH:10]=1)[CH2:11][NH2:12]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cc(F)ccc1[N+](=O)[O-]
Temperature: 40 °C

Procedure:
85% Hydrazine hydrate (1.67 ml) was added to a suspension of N-(5-fluoro-2-nitrophenyl)methyl-phthalimide (7.1 g) in ethanol (90 ml). The reaction mixture was heated to reflux for 3 hours, then cooled to 40° C. Hydrochloric acid was added and stirring was continued at that temperature for a further hour; then the solvent was removed under vacuum. The residue was taken up in water and the solid which separated was discarded. The mother liquors were treated with 10% sodium hydroxide and extracted with diethyl ether. After evaporation of the solvent 3.5 g of title compound were obtained as a reddish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[CH3:42][N:43]([CH3:53])[C:44]1[CH:49]=[CH:48][C:47]([N:50]=[C:51]=[O:52])=[CH:46][CH:45]=1.ClCCl>O>[CH3:42][N:43]([CH3:53])[C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]4)[N:17]=[C:16]4[C:12]=2[N:13]=[CH:14][N:15]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]3)=[O:52])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: O
Solvent: ClCCl
Product: CN(C)c1ccc(NC(=O)Nc2ccc3c(c2)CCN3c2nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c2ncn3C(=O)OC(C)(C)C)cc1
Reaction time: 20 h

Procedure:
80 mg of product obtained in stage 4 of example 41 are mixed with 32.2 mg of 4-dimethylaminophenyl isocyanate and 5 ml of dichloromethane. Stirring is carried out for 20 hours at ambient temperature, 0.5 ml of water is added, and the mixture is evaporated to dryness. Purification is carried out on an Xterra LCMSprep column, eluting with acetonitrile/ammonium hydrogen carbonate buffer, pH 9. 55 mg of expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10]Br.[C-:12]#[N:13].[Na+]>CO.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:12]#[N:13]
Reactant: Clc1cc(Cl)c(Cl)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCc1cc(Cl)cc(Cl)c1Cl
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 70 %

Procedure:
A solution of 19.2 grams (0.070 mole) of 2,3,5-trichlorophenylmethyl bromide in 50 mL of methanol was stirred, and a solution of 4.1 grams (0.084 mole) of sodium cyanide in 10 mL of water was added dropwise during a 10 minute period. The addition caused an exothermic reaction which raised the reaction mixture temperature to about 35° C. Upon completion of addition, the reaction mixture was warmed to reflux, where it was stirred for 4.5 hours. The reaction mixture was allowed to cool to ambient temperature, where it was stirred for about 60 hours. After this time the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with two portions of water, two 25 mL portions of aqueous 10% hydrochloric acid, and then with three portions of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 10.8 grams of 2,3,5-trichlorophenylacetonitrile. The infrared spectrum was consistent with the proposed structure.
Reaction SMILES: N[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.N1C=CC(=O)NC1=O.[N:18]([O-])=[O:19].[Na+]>C(O)(=O)C.O>[N:18]([C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][CH:2]=1)=[O:19]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Agent: O=c1cc[nH]c(=O)[nH]1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1c[nH]c(=O)[nH]c1=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1-Propyl, 3-cyclopropyl, 6-aminouracil (; (12.8 g, 61.2 mmol) was dissolved in acetic acid (25 ml) in 200 ml of water and the mixture was cooled to 10° C. To the uracil solution, NaNO2 (7.6 g, 110.1 mmol) in 50 ml of water was added dropwise at 10° C. The mixture was stirred at 10° C. for 30 min and then at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in the mixture of absolute ethanol and CH2Cl2 (1:1) and boiled for 20 min. The hot mixture was filtered through a layer of Celite 545 to remove the insoluble inorganic salts. The mother liquid was evaporated under reduced pressured to remove the solvent to give 1-propyl, 3-cyclopropyl, 6-amino, 5-nitrosouracil (4) (11.4 g, 78%).
Reaction SMILES: [O:1]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]=O)=[CH:15][C:14]=1[O:23][CH3:24])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[I-:25].[CH3:26][N+:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH3:37])=[CH:29][CH:28]=1.C([O-])(=O)C.[NH4+]>C(O)C>[I-:25].[C@@H:2]1([O:1][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]=[CH:37][C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N+:27]([CH3:26])=[CH:28][CH:29]=3)=[CH:15][C:14]=2[O:23][CH3:24])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: Cc1cc[n+](C)c2ccccc12
Reactant: COc1cc(C=O)cc(OC)c1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(C=Cc2cc[n+](C)c3ccccc23)cc(OC)c1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 60 °C
Reaction time: 5 h
Yield: 70.5 %

Procedure:
A suspension of 4-formyl-2,6-dimethoxyphenyl β-D-galactopyranoside (2c)(0.20 g, 0.58 mmol), 1,4-dimethylquinolinium iodide (0.17 g, 0.58 mmol) in ethanol (20 ml) containing ammonium acetate (0.15 g 1.9 mmol) was stirred at about 60° C. for 5 h. The dark orange precipitate which formed during the reaction was then filtered off and washed with ethanol followed by acetone to give (24c)(0.25 g, 70%) an orange solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@@H:59]5[CH2:64][CH2:63][CH2:62][CH2:61][C@@H:60]5[OH:65])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCC[C@@H]2O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-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 cis-(±)-2-aminocyclohexanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.93 (m, 18H) 3.31 (s, 3H) 3.73-3.91 (m, 2H) 3.95 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.47 (m, 1H) 4.70 (br. s., 1H) 7.47 (d, J=8.0 Hz, 1H) 7.53 (s, 1H) 7.79 (d, J=7.83 Hz, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.34 Hz, 1H). [M+H] calculated for C28H36F2N6O4, 559. found 559.