Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:36])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][C:30]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][C:30]([CH:33]5[CH2:35][CH2:34]5)=[CH:31][CH:32]=4)[CH:22]=3)[CH2:18][C:17](=[O:36])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example M143) (332 mg, 0.638 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (163 mg, 64%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:12]12S[CH:13]1[CH:14]1S[C:15]1([OH:18])[CH:16]=[CH:17]2)([CH3:11])([CH3:10])[CH3:9].[S]>>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10].[CH3:10][C:8](=[CH2:9])[CH3:11].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C12C=CC3(O)SC3C1S2
Agent: [S]
Solvent: Oc1ccccc1
Product: C=C(C)C
Product: CC(C)(C)c1ccc(O)cc1

Procedure:
Para-tert. butyl phenol disulfide is produced by the reaction of para-tert. butyl phenol with sulfur monochloride. When the reaction is carried out using approximately 11:10 moles of phenol to monochloride, the para-tert. butyl phenol disulfide will have about 28% by weight of sulfur and a softening part of approximately 90°-105°C. The para-tert. butyl phenol is produced by the reaction of isobutylene and phenol according to the following scheme: ##SPC2##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1>[CH2:13]([O:12][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
10.0 g (0.0578 mole) of 2-amino-6-bromopyridine was dissolved in 40 ml dry pyridine and 6.4 ml (0.067 mole) of ethyl chloroformate was added dropwise while the solution was stirred and cooled in an ice-bath to maintain the reaction temperature at 15°-18° C. After 4 hours at room temperature, the reaction mixture was poured into 150 ml of ice water and kept at 0° C overnight. Impure 2-ethoxycarbonylamino-6-bromopyridine was obtained by filtration and subsequently recrystallized from 2:1 methanol-water solution, giving an 88% yield of white solid, m.p.=70.2°-71.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7](C#N)[C:8](=[CH:11][CH:12]=1)[C:9]#[N:10].S(=O)(=O)(O)[OH:20].[C:24](=[O:27])([O-])O.[Na+]>O>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:11][CH:12]=1)[C:9](=[O:20])[NH:10][C:24]2=[O:27]
Reactant: N#Cc1ccc(Oc2ccccc2N)cc1C#N
Reactant: O=C([O-])O
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Nc1ccccc1Oc1ccc2c(c1)C(=O)NC2=O

Procedure:
4-(2-Aminophenoxy)phthalonitrile (1.55 g, 6.6 mmol) was stirred with conc. sulphuric acid (9 ml) at room temperature for 15 hours. The mixture was purred into crushed ice and the pH was adjusted to 10 with diluted sodium hydrogencarbonate in water. The mixture was left for the weekend at room temperature. The resulting precipitate was filtered off and washed twice with water (2×50 ml). The crystals were dried to give yellow crystals of 5-(2-aminophenoxy)isoindole-1,3dione) (yield: 1.41 g (84%)). Mp: 211.6-211.9° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=S)[NH:11][NH2:12].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Cc1cccc(C)c1NC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(C)cccc2C)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A mixture of 9.8 g (0.05 mole) of 4-(2,6-dimethylphenyl)-3-thiosemicarbazide and 8.48 g (0.05 mole) of ethyl 2-chloroacetoacetate (97%) in 75 mL of absolute ethanol was stirred under nitrogen atmosphere for one hour at room temperature. The reaction was slightly exothermic and the mixture changed from a white slurry to a yellow slurry as most of the solid dissolved. The mixture was treated with 40 mL of 2N ethanolic hydrogen chloride and allowed to stir at room temperature for 16 hr. The reaction mixture was heated at reflux for two hours; during this time it took on a dark orange color which cleared later as all the material dissolved (a small amount of insoluble material was also present). The reaction mixture was filtered and the solvent removed under reduced pressure leaving a yellow-orange solid. The solid was triturated with acetone which dissolved most the orange color. Filtration gave 12.6 g of pale yellow crystals, mp 131°-137° C. Recrystallization of the yellow solid from acetone gave two crops of soft, fluffy, white product. Both crops were combined and analyzed, yield 8.5 g (62%), mp 142°-144° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH2:24][C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>CO>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]2[NH:36][CH:35]=[CH:34][N:33]=2)[CH2:24][C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC(=O)OC(C)(C)C)cc1)Cc1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCN)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 115.3 %

Procedure:
The compound (902.3 mg) obtained in Example 102-3 was dissolved in methanol (4.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (4.0 ml), followed by stirring at room temperature for 8.5 hours. After the reaction, the solvent was dissolved off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution (7 ml) and subjected to extraction with chloroform. Then, the extract was dried with magnesium sulfate and the solvent was dissolved off. The residue was then purified through a solid-phase extraction column (ODS type), thereby obtaining the subject compound (844.3 mg) as a brown viscous solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=O)=[C:7]([CH3:18])[C:6]=1[CH3:19].[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21].[CH2:26]1COC[CH2:27]1>[Cl-].[Na+].O>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:26][CH:27]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([CH3:18])[C:6]=1[CH3:19]
Reactant: CCOC(C)=O
Reactant: COc1cc(C)c(C=CC=CC=O)c(C)c1C
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C=CC=CC=CC=Cc1c(C)cc(OC)c(C)c1C

Procedure:
To a suspension of sodium hydride (1.4 g, 50% dispersion in mineral oil) in 30 mL of THF stirred in an ice bath under nitrogen was added dropwise a solution of triethyl phosphonocrotonate (7.8 g, 0.03 mol) in 30 mL of THF. The resulting mixture was stirred at 0° C. for additional 1/2 hr and a solution of 5-(4-methoxy-2,3,6-trimethylphenyl)penta-2,4-dienal (4.8 g, 0.02 mol) in 15 mL of THF was added rapidly. The mixture was stirred at room temperature for 18 hrs. Brine (50 mL) was added to the mixture, followed by 200 mL of ethyl acetate. The layers were separated. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give 6.1 g of the crude product as a yellow oil. This material was used in the reaction described in Example 2 without further purification.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1([C:9]#N)[CH2:7][C:6](=[CH2:8])[CH2:5]1.[OH2:11]>CCO>[CH3:3][C:4]1([C:9]([OH:11])=[O:1])[CH2:7][C:6](=[CH2:8])[CH2:5]1
Reactant: [OH-]
Reactant: O
Reactant: C=C1CC(C)(C#N)C1
Agent: [K+]
Solvent: CCO
Product: C=C1CC(C)(C(=O)O)C1
Temperature: 25 °C

Procedure:
To a solution of KOH (12.0 g, 213 mmol) in water (10 mL) and EtOH (10 mL) was added 1-methyl-3-methylidenecyclobutanecarbonitrile (53.3 mmol, crude) and the resulting solution was heated to reflux for 2.5 hrs. The mixture was cooled to rt and the solvent was removed under vacuum. The residue was diluted with water (30 mL) and washed with EtOAc (30 mL). The aqueous layer was acidified with concentrated HCl to pH˜1 in ice bath, and then extracted with EtOAc (two×30 mL). The combined organics were dried over MgSO4 and concentrated to give the title compound acid as pale brown liquid. 1H NMR (400 MHz, chloroform-d) δ ppm 4.90 (quin, J=2.41 Hz, 2H), 3.16-3.34 (m, 2H), 2.54 (qd, J=2.10, 16.57 Hz, 2H), 1.49 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl[C:13]1[C:21](C(F)(F)F)=[CH:20][CH:19]=[CH:18][C:14]=1C(O)=O.N1C=CC=CC=1[N:32]1[C:40]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N:34]=[CH:33]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:37]1[CH2:38][CH2:39][C:40]2[N:32]([C:13]3[CH:14]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:33]=[N:34][C:35]=2[CH2:36]1)=[O:6]
Reactant: c1ccc(-n2cnc3cnccc32)nc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(c1cccc(Cl)c1Cl)N1CCc2c(ncn2-c2ccccc2)C1

Procedure:
Example 3 was made in a manner analogous with Example 1 substituting 2,3-dichlorobenzoic acid for 2-chloro-3-trifluoromethyl benzoic acid in Step C and substituting Intermediate 2 for Intermediate 3 in Step A.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[N:26][C:27]#[N:28])OC4C=CC=CC=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:33][C:18](=[N:26][C:27]#[N:28])[N:15]1[CH2:14][CH2:13][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:17][CH2:16]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: N#CN=C(Oc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: CC(C)(C)N
Solvent: c1ccncc1
Product: CC(C)(C)NC(=NC#N)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-[4-(cyanimino(phenoxy)methyl)piperazin-1-yl]quinoline (53 mg, 0.14 mmol) and tert-butylamine (2.0 mL, 19 mmol) are heated in pyridine (10 mL) for 6 h at reflux. The solvent is removed, and the residue purified by column chromatography with CH2Cl2-MeOH giving the title product as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:4].[N:32]#[C:33]Br.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[F:1][C:2]([F:30])([F:31])[C:3]([N:5]([CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:33]#[N:32])=[CH:22][CH:21]=1)[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:4]
Reactant: CCOC(=O)c1ccc(N(CCOc2cccc3ccccc23)C(=O)C(F)(F)F)cc1
Reactant: N#CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N(CCOc2ccc(C#N)c3ccccc23)C(=O)C(F)(F)F)cc1
Reaction time: 5 h

Procedure:
To a solution of 5.4 g. of ethyl 4-[N-trifluoroacetyl-2-(1-naphthyloxy)ethylamino]benzoate and 1.5 g. of cyanogen bromide in 200 ml. of methylene chloride at -5° C. is added 5.7 g. of anhydrous aluminum chloride. The solution is allowed to stand at room temperature for 5 hours and then poured into 200 ml. of ice and water. After addition of 20 ml. of concentrated hydrochloric acid, the organic layer is seperated, washed with water, dried and evaporated to dryness. Recrystallization from 75% aqueous acetonitrile gives material, m.p. 150°-151° C.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]1.O>C(O)C>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH2:19][CH2:20][O:21][CH:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[NH:25][C:26]([CH3:28])([CH3:29])[CH2:27]2)=[CH:8][CH:7]=1
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Reactant: CC1(C)CC(OCCBr)CC(C)(C)N1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(OCCOc2ccc(-c3nc4ccccc4o3)cc2)CC(C)(C)N1

Procedure:
Equal molar quantities of p-hydroxybenzaldehyde and o-aminophenol in excess nitrobenzene was refluxed for five hours. The nitrobenzene was removed and the residue was washed with hot xylene. 2-(4-Hydroxyphenyl)benzoxazole was obtained by crystallization from ethanol in 64% yield (m.p. 253°). A mixture of the sodium salt of 2-(4-hydroxyphenyl)benzoxazole (0.01 mole) and 4-(2-bromoethoxy)-2,2,6,6-tetramethylpiperidine (0.01 mole) in 250 ml of ethanol was refluxed for 20 hours. The reaction mixture was cooled, 200 ml. of water was added and the product, I, was filtered out.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]([OH:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]([O:13][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
To a solution of 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol (500 mg) in dichloromethane (20 mL) at 0° C. was added triethylamine (0.28 mL) and then methanesulphonyl chloride (0.14 mL) and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into dichloromethane (2×20 mL). The combined organic layers were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester as a yellow solid.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>CCO.[Pd]>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 99.9 %

Procedure:
A solution of tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (335 mg, 0.93 mmol) and 10% Pd/C (35.0 mg) in EtOH (20.0 mL) was hydrogenated at room temperature overnight using the hydrogen balloon method. The reaction mixture was filtered through celite and washed with ethanol (3×10 mL). The combined extracts were concentrated in vacuo to afford tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinecarboxylate (335 mg, 100%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[C:8](=[O:20])[NH:7][C:6]2=1.B(Br)(Br)Br>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[C:8](=[O:20])[NH:7][C:6]2=1
Reactant: COc1ccc2oc3c4ccccc4c(=O)[nH]c3c2c1
Agent: BrB(Br)Br
Solvent: O
Product: O=c1[nH]c2c3cc(O)ccc3oc2c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-Methoxy-6H-11-oxa-6-aza-benzo[α]fluoren-5-one (22a) (5.0 g) was cooled using an ice bath, and boron tribromide (1 M in methylene chloride, 95 mL, 95 mmol, 5 eq.) added in a steady stream under nitrogen. The reaction was heated at reflux under inert atmosphere for two hours, then cooled to room temperature and poured into water (150 mL). The resulting suspension was allowed to stir for 1 h, filtered, and the solids were washed with water (2×200 mL). The solids were then diluted with 5 N sodium hydroxide (600 mL) using heating. The resulting solution was cooled to 0° C. using an ice bath and the solution was acidified to pH 1 using conc. HCl. The resulting precipitate was vacuum filtered, and the solids washed sequentially with water (3×300 mL) and diethyl ether (300 mL) then dried overnight using a vacuum oven at 500C to provide Compound 23a as a gray solid. Yield=4.74 g (100%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[ClH:20].[CH3:21][CH2:22]O>>[ClH:20].[NH2:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([O:12][CH2:21][CH3:22])=[O:11]
Reactant: CCO
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: C=CCCCCC[C@H](N)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of (2S)-2-[(t-butoxycarbonyl)amino]non-8-enoic acid (ACME Bioscience Inc) (1.00 g, 3.69 mmol) in EtOH (10 ml) was saturated with HCl gas. The mixture was stirred at RT for 2 hours, then concentrated to give the title product (0.85 g). LRMS (ESI) m/z 200.4 [(M+H)+; calcd for C11H22NO2: 200.2].
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)C=CC=CC=1.[CH3:25][O:26][C:27](=[O:51])[CH2:28][CH2:29][NH:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][CH:40]2[CH2:45][CH2:44][CH:43]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:42][CH2:41]2)=[CH:34][CH:33]=1.FC(F)(F)C([O-])=O.C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1>[CH3:25][O:26][C:27](=[O:51])[CH2:28][CH2:29][NH:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([CH:40]2[CH2:41][CH2:42][CH:43]([C:46]([CH3:47])([CH3:48])[CH3:49])[CH2:44][CH2:45]2)[C:8]([NH:9][C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:21])[F:22])[CH:11]=2)=[O:24])=[CH:34][CH:33]=1
Reactant: COC(=O)CCNC(=O)c1ccc(CNC2CCC(C(C)(C)C)CC2)cc1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCC(C(C)(C)C)CC2)cc1
Yield: 67 %

Procedure:
The above carbamic acid phenyl ester (1.0 g, 2.9 mmol) was mixed with 3-{4-[(4-tert-butyl-cyclohexylamino)methyl]benzoylamino}propionic acid methyl ester, trifluoroacetate (1.07 g, 2.9 mmol), prepared as described above and triethylamine (1.2 mL, 8.6 mmol) in dichloromethane (55 mL) and the resulting mixture was refluxed for 4 hours. The cooled reaction mixture was diluted with toluene (50 mL) and washed with water (3×50 mL) and a mixture of water and saturated aqueous sodium chloride (1:1, 3×100 mL), dried (MgSO4) and concentrated in vacuo to afford 1.2 g (67%) of 3-{4-[3-(3,5-bis-trifluoromethylphenyl)-1-(4-tert-butyl-cyclohexyl)ureidomethyl]benzoylamino}propionic acid methyl ester as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:19]=[C:18]2[C:5](=[N:6][CH2:7][N:8]2[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:4](Cl)([NH2:20])[N:3]=1.[CH:22]1(N)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: NC1(Cl)N=C(Cl)N=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NC1CCCCC1
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 229.1 %

Procedure:
A mixture of 2,6-dichloroadenosine (1.0 g) and cyclohexylamine (0.926 g) in ethanol (30 ml) was heated at reflux for 6 hours then cooled to room temperature. The mixture was concentrated under vacuo. The residue was purified on the silica gel column using MeOH—CH2Cl2 (1:6 to 1:5). The combined fractions were concentrated and dried under vacuum to provide 2-chloro-N6-cyclohexyladenosine as a white solid (2.600 g). 1H NMR (DMSO-D6): δ 1.12-1.21 (m, 2H), 1.33-1.43 (m, 3H), 1.63-1.86 (m, 6H), 3.57-3.62 (m, 1H), 3.66-3.69 (m, 1H), 3.97 (d, J=3 Hz, 1H), 4.16 (d, J=3.3 Hz, 1H), 4.54 (d, J=5.4 Hz, 1H), 5.08-5.11 (m, 1H), 5.24 (d, J=4.8 Hz, 1H), 5.51 (d, J=5.7 Hz, 1H), 5.85 (d, J=5.7 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.41 (s, 1H).
Reaction SMILES: C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:5](C)=O.[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCCl.C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[CH3:5])[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CCCCN2)CC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCCCC1CN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h

Procedure:
1.91 ml of 37% aqueous formaldehyde and a few beads of 4 Å molecular sieve, followed by 5 g of NaBH(OAc)3, are added to a solution of 3.34 g of the compound prepared in step 6.2, in 40 ml of DCE, and the medium is stirred at AT for 48 h. The medium is diluted in DCM, and filtered through cotton wool. The organic phase is washed twice with a saturated NaHCO3 solution, and then with a saturated NaCl solution. After drying over MgSO4 and evaporation of the solvents, 3.28 g of the expected product are recovered.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>CS(C)=O.C(O)(C)C>[N+:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
A suspension of 1.735 g (10 mmol) of 2-amino-6-chloro-3-nitropyridine, 1.66 ml (20 mmol) of pyrrolidine and 1.66 ml (10 mmol) of diisopropylethylamine in a mixture of 1 ml of dimethyl sulfoxide and 5 ml of isopropanol is heated at 60° C., with stirring, in a sealed tube, for 20 hours. The mixture is cooled to ambient temperature and then diluted with 10 ml of isopropanol. The solid is collected by filtration and is then washed with 2×5 ml of isopropanol. The solid is taken up with 20 ml of water. The suspension is stirred for 30 minutes. The solid is filtered off and then washed with 2×5 ml of water and 2×5 ml of ether, and dried under vacuum in the presence of phosphorus pentoxide so as to obtain 1.91 g (9.17 mmol) of product in the form of a vivid yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]1[C:12]2[CH:13]=[CH:14]C=CC=2N=C1>>[O:8]1[CH2:12][CH:13]1[CH2:14][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: c1ccc2ocnc2c1
Product: c1cncc(OCC2CO2)c1

Procedure:
Compound 73 was prepared in the manner of compound 6 substituting 3-hydroxy-pyridine for compound 8 in part C-5 of Example 1.