Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5](S([O-])(=O)=O)=[N:6][CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].[CH2:15]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:23]([N:22]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([NH2:10])[CH:8]=[CH:7][N:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccnc(S(=O)(=O)[O-])c1[N+](=O)[O-]
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: Nc1ccnc(N(Cc2ccccc2)Cc2ccccc2)c1[N+](=O)[O-]

Procedure:
In step (2) of Reaction Scheme I a 3-nitro-4-aminopyridine-2-sulfonate of Formula XI is reacted with dibenzylamine to provide a 2-dibenzylamino-3-nitropyridin-4-amine of Formula XII. The reaction is carried out by combining a compound of Formula XI, dibenzylamine, and a tertiary amine such as triethylamine in an inert solvent such as benzene, toluene or xylene and heating the resulting mixture.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1)#[N:35].C(O)C(N)(CO)CO.CN(C=O)C>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:43]([NH:42][C:39]3[CH:40]=[CH:41][C:36]([C:34]#[N:35])=[CH:37][CH:38]=3)=[O:44])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)Nc3ccc(C#N)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 132.1 %

Procedure:
To a solution of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-phenoxy}acetate (37 mg, 0.084 mmol) in anhydrous DCM (2 ml) was added 4-cyanophenyl isocyanate (Aldrich, 45 mg, 0.31 mmol) and the reaction mixture was stirred at rt for 18 hrs. Then PS-trisamine resin (75 mg, Novabiochem, 3.5 mmol/g) and DMF (1 mL) were added and the resulting mixture was stirred at rt for 5 additional hrs. Removal of the resin by filtration followed by evaporation of the solvents gave 65 mg (97%) of the title compound as a pale yellow oil. HPLC, Rt: 5.7 min (purity: 74.1%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: CCOC(=O)C1(CC)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-ethyl-cyclopentane carboxylate (4.90 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.22 ml) was slowly added, then benzoyl chloride (4.68 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours; Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed in turn using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 8.86 g of yellow liquid. MS: m/e 290(M+″), 261, 216, 185, 168, 139, 105(base), 77.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2[C:15]3[N:16]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=3)[CH2:17][C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[Br:1][C:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:16]2[C:15]=1[C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[NH:19][C:18](=[O:20])[CH2:17]2
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cn2c(c(Br)c3ccccc32)-c2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.36 g N-bromosuccinimide in 50 ml dimethylformamide was added dropwise to a solution of 3.0 indolo[1,2-d][1,4]benzodiazepin-6(7H)-one in 50 ml dimethylformamide, during which the reaction mixture was cooled with cold water. The resulting solution was stirred at room temperature for two hours and then poured into 800 ml water. The precipitate was collected, washed with water and dried under vacuum (P2O5) to give 3.7 g solid, m.p. 247°-249° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8](Br)[C:7]1=O)=[O:5])[CH3:2].[C:14]([NH2:20])([NH2:19])=[N:15][C:16]([NH2:18])=[S:17]>>[CH2:1]([O:3][C:4]([CH:6]1[C:7]2[N:18]=[C:16]([NH:15][C:14]([NH2:20])=[NH:19])[S:17][C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC(Br)C1=O
Reactant: NC(=S)N=C(N)N
Product: CCOC(=O)C1CCCc2sc(NC(=N)N)nc21

Procedure:
Analogously to the preparation of Example C-01, 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester is reacted with 2-imino-4-thiobiuret to produce the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([CH:5]1[S:10][C:9]2[S:11][CH:12]=[CH:13][C:8]=2[C:7](=O)[CH2:6]1)=O.Cl>O1CCCC1>[CH3:15][N:2]([CH2:3][CH:5]1[S:10][C:9]2[S:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1)[CH3:1]
Reactant: CN(C)C(=O)C1CC(=O)c2ccsc2S1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CC1CCc2ccsc2S1
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a stirred, refluxing solution of N,N-dimethyl-4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-6-carboxamide (7.57 g, 0.0314 mol) under nitrogen in tetrahydrofuran (150 ml) was added dropwise over 10 minutes borane-dimethylsulfide complex (9.4 ml, 0.094 mol). Stirring at reflux was continued for 3 hours and 6N HCl (25 ml) was added dropwise and reflux was continued for 1/2 hour. Most of the tetrahydrofuran was removed in vacuo and the residue was diluted with 6N HCl (50 ml) and was heated for 1/2 hour at steam bath temperature under nitrogen. The mixture was cooled in ice and water (100 ml) was added to dissolve the solid, washed with ether (50 ml) and basified with 10N NaOH (75 ml). The product was extracted into ethyl acetate (200 ml) in four portions, washed with water and dried over Na2SO4. The solution was filtered and concentrated in vacuo to obtain an amber oil (5.7 g). Yield was 85%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[Cl:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([C@H:25]1[CH2:29][N:28]([C:30]([C:32]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33]2)=[O:31])[C@H:27]([C:42](O)=[O:43])[CH2:26]1)(=[O:24])=[O:23]>>[Cl:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([C@H:25]1[CH2:29][N:28]([C:30]([C:32]2([C:35]3[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=3)[CH2:34][CH2:33]2)=[O:31])[C@H:27]([C:42]([NH:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C:3](=[O:10])[C:4]([NH:6][CH:7]2[CH2:8][CH2:9]2)=[O:5])=[O:43])[CH2:26]1)(=[O:24])=[O:23]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide and (2S,4R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid in step 1. MS (m/e)=652.14 [M+H+].
Reaction SMILES: NC1C=CC=C2C=1N=C(C[N:13]1[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]1=[O:23])C(C1C=CC=CC=1Cl)=N2.CC(C)=O.Cl.N([O-])=O.[Na+].[I-].[K+]>>[C:14]1(=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[NH:13]1
Reactant: Nc1cccc2nc(-c3ccccc3Cl)c(CN3C(=O)c4ccccc4C3=O)nc12
Agent: Cl
Agent: O=N[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 0 °C

Procedure:
2-((8-amino-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)isoindoline-1,3-dione (1.1337 g, 2.733 mmol) was dissolved in acetone (39.04 mL, 2.733 mmol) and cooled to 0° C. While being stirred, the solution was treated first with 2 M hydrochloric acid (7.652 mL, 15.30 mmol) and then dropwise with 1 M aq. sodium nitrite (5.466 mL, 5.466 mmol) while maintaining the temperature of the mixture at 0° C. After the additions were complete, the mixture was stirred for 15 min and then treated with 5 M aq. potassium iodide (5.411 mL, 27.06 mmol) maintaining the temperature below 5° C. The mixture was then allowed to warm to 15° C. over 3.5 h. The acetone was removed under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic solution was washed with 10% aqueous sodium bisulfite (100 mL×1) and saturated aqueous sodium bicarbonate (100 mL×1), brine (100 mL×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give a dark violet syrupy solid. The dark violet syrupy solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 15 min and then 50% isocratic of EtOAc in hexane for 25 min as eluent to give 24(3-(2-chlorophenyl)-8-iodoquinoxalin-2-yl)methyl)-isoindoline-1,3-dione as a solid: LC-MS (ESI) m/z 526.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([NH:10]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)=[CH:3][N:2]=1.[ClH:18]>O1CCOCC1>[ClH:18].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2([NH2:10])[CH2:9][CH2:8]2)=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccnnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccnnc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of tert-butyl 1-(pyridazin-4-yl)cyclopropylcarbamate (0.100 g, 0.425 mmol, 1.0 eq) in a solution of 4.0 M HCl in 1,4-dioxane (4.0 ml) was stirred at r.t. for 5 hr. The reaction mixture was concentrated under vacuum and dried HCl salt was taken to next step.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([O:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:11](=[O:12])[CH2:10][Cl:9])=[CH:4][CH:3]=1)=[O:12]
Reactant: Oc1ccc(O)cc1
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Oc1ccc(OC(=O)CCl)cc1
Yield: 46 %

Procedure:
A mixture of hydroquinone (50 grams, 454.09 mmol) and chloroacetyl chloride (150 mL) was refluxed for 48 hours. Excess chloroacetyl chloride was distilled off, and the residue taken into ice water, filtered, dried, and recrystallised from ethyl acetate:hexane (1:6) to get pure product (55 grams, 46%) as a white fluffy powder. M.p: 127-128° C. 1H NMR (CDCl3) δ 4.20 (s, 25H, CH2), 7.24 (s, 2H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11]COC)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl>C1COCC1.O>[OH:11][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[N:10][CH:9]=1
Reactant: COCOc1cnc(OC)cc1C=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(O)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 0.05 mol) in THF (100 mL) was added 3 N HCl (150 mL). The reaction was stirred at 50° C. for 30 min, cooled to rt, and diluted with water (100 mL). The mixture was neutralized to pH 7-8 and extracted with EtOAc (200 mL) three times. The organic layer was dried over Na2SO4 and concentrated to give 5-hydroxy-2-methoxyisonicotinaldehyde (4.2 g, 55%) as a yellow solid. 1H NMR (400 MHz; DMSO) δ=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH2:14]1[CH:18]2[CH2:19][CH:20]([NH2:21])[CH:16]([CH2:17]2)[CH2:15]1>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C@H:16]12[CH2:17][C@H:18]([CH2:14][CH2:15]1)[CH2:19][C@H:20]2[NH:21][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4]
Reactant: NC1CC2CCC1C2
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CN[C@@H]1C[C@H]2CC[C@@H]1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.152 mmol ) in acetonitrile (1 mL) at room temperature was added exo-2-aminonorborane (0.036 mL, 0.305 mmol) and a catalytic amount of tetrabutylammonium iodide. The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (CI) m/z 271 (M+1)+; 1H NMR (300 MHz, MeOH-d4): δ ppm 4.7-4.8 (m, 2H), 3.61-3.8 (m, 2H), 3.2-3.3 (m, 1H), 3.02-3.11 (1H, s), 2.62-2.72 (m, 1H), 2.37-2.44 (m, 3H), 2.2-2.3 (br s, 2H), 1.0-1.7 (m, 8H).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:23][O:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(C)(C)c1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one (83.8 mg, 0.30 mmol) in methanol (1 ml) is added toluene-4-sulfonic acid monohydrate (5.2 mg, 0.030 mmol). The reaction mixture is stirred for 5 days at ambient temperature. The reaction mixture, a white suspension, is evaporated and the residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 3-[4-(1-methoxy-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one as white crystals; HPLC/MS 2.66 min (B), [M+H] 294;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:24]([NH:23][CH2:21][CH3:22])=[O:25])=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
2,7-Diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]-pyrimidine was reacted with ethyl isocyanate according to the general procedure of Example 2. The crude product was purified by radial chromatography eluting with a gradient of 70% ethyl acetate/30% chloroform to 100% chloroform to give the title compound, 1-[2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-yl]-3-ethylurea, mp 185-187° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:16]1[CH:21]=CC(S(Cl)(=O)=O)=[CH:18][CH:17]=1.NC1C(C)=CC=CC=1>ClCCl.C([O-])([O-])=O.[K+].[K+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:14]2[CH:18]=[CH:17][CH:16]=[CH:21][C:13]=2[CH3:12])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1N
Product: Cc1ccccc1NS(=O)(=O)c1ccc(Br)cc1

Procedure:
The title compound is analogously synthesized as described for 1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) from 1.28 g of 4-bromo-benzenesulfonyl chloride, 643 mg of commercially available o-toluidine in 20 ml of dichloromethane and 10 ml of K2CO3 solution. Purification by chromatography on flash silica gel (eluent: neat dichloromethane) affords 830 mg of the title compound as colorless, amorphous solid of m.p. 114° C. GC-MS: 327.0 (MH+). TLC: Rf=0.58 (neat dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O.Cl.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(NN)C=CC=CC=1.S(=O)(=O)(O)O>C1C=CC=CC=1.O.C(O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH3:13])[C:6]2[NH:22][C:16]3[C:21]([C:7]=2[CH2:8][CH2:9][CH2:10][CH2:11]1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: COC(=O)CC1(C)CCCCCC1=O
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: COC(=O)CC1(C)CCCCc2c1[nH]c1ccccc21
Temperature: 150 °C

Procedure:
A mixture of the compound of formula 3, 1-methyl-2-oxocycloheptaneacetic acid methyl ester (16 g, 0.08 mole), described in Example 10, phenylhydrazine hydrochloride (12 g, 0.08 mole), phenylhydrazine (8 g, 0.07 mole) and anhydrous ethanol (100 ml) is heated at reflux for 20 hr. After cooling, water is added and the reaction mixture is extracted with benzene (2X). Evaporation to dryness of the organic layer affords a residue. The residue is heated with a 20% sulfuric acid solution (230 ml) at reflux (oil bath at 150° C.) for 1 hr. The reaction mixture is poured on ice and extracted with benzene and ether. Evaporation to dryness affords a residue which is subjected to chromatography on silica gel (500 g) using benzene as eluant. The title compound, νmaxCHCl3 1736 cm-1 is eluted first, followed by 2,2a,3,4,5,6-hexahydro-2a-methyl-1H-10b-azabenzo[a]cyclopent[d]azulen-1-one (6, R1 = CH3, R2 and R3 = H, m = 4 and n = 1), nmr (CDCl3) δ 1.42 (s, 3H), 2.90 (s, 2H), 7.0-7.7 (m, 3H), 7.9-8.2 (m, 1H), followed by 2,4,4a,5,6,7,8,9-octahydro-4a-methyl-2-phenyl-3H-cyclohepta[c]pyridazin-3-one (14, R1 = CH3, R2 and R3 = H and m = 4), nmr (CDCl3) δ 1.18 (s, 3H), 2.18 (d, J = 16.5, 2H), 7.1-7.7 (m, 5H).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([CH2:12][NH2:13])[CH:10]=[CH:11][C:2]1=2.[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=2)[CH:20]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24]([NH:13][CH2:12][C:9]3[CH:10]=[CH:11][C:2]4[O:1][CH2:7][CH2:6][CH2:5][O:4][C:3]=4[CH:8]=3)=[O:25])[N:23]=2)[CH:20]=1
Reactant: NCc1ccc2c(c1)OCCCO2
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1ccc2c(c1)OCCCO2)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18]Br)[CH3:16].CN(C=O)C>CCOCC.CCCCCC.O>[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: CCCCC(CC)CBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CCCCC(CC)COc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a 1-L round-bottomed flask were added 4-bromophenol (60.0 g, 0.35 mol), potassium carbonate (52.7 g, 0.38 mol), 2-ethylhexyl bromide (73.7 g, 0.38 mol) and DMF 200 mL. The reaction mixture was stirred at 90° C. under nitrogen overnight. The reaction was poured into water and extracted with ether three times and the combined organic phase was washed with water three times and dried over MgSO4. After solvent was removed, the crude product was obtained as light brown liquid. Pure product was obtained by column chromatography on silica gel using ether/hexane (10/90) as an eluent to give 71.2 g of light yellow liquid at 72% yield. 1H NMR (CDCl3)δ (ppm): 0.88-0.93 (m, 6 H, CH3), 1.27-1.46 (m, 8 H), 1.65-1.74 (m, 1 H), 3.78 (d, J=5.7 Hz, 2 H, OCH2), 6.76 (d, J=8.9 Hz, 2 H), 7.33 (d, J=8.9 Hz, 2 H). 13C NMR (CDCl3): 11.08, 14.08, 23.03, 23.80, 29.05, 30.46, 39.29, 70.72, 112.42, 116.29, 132.11, 158.47. FD-MS: m/z 285 (M+).
Reaction SMILES: C([O:8][C:9](=[O:52])[CH:10]([O:27][C:28](=[O:51])[C@H:29]([CH:48]([CH3:50])[CH3:49])[NH:30][C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:31]([NH:30][C@H:29]([C:28]([O:27][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:9]([OH:52])=[O:8])=[O:51])[CH:48]([CH3:49])[CH3:50])([O:33][CH2:34][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:32]
Reactant: CCCCCCCCCCCCCCCCC(OC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCC(OC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)O

Procedure:
A solution of benzyl-2-(N-FMOC-L-valyloxy)stearate (4.4 g, 6.2 mmole) in 50 ml ethyl acetate was hydrogenated with 10% palladium on charcoal (0.5 g) with normal pressure for two hours. The catalyst was filtered and washed with ethyl acetate and 1,4-dioxane. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography. Yield: 3.4 g
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=C[C:38]([CH2:41][C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])=[CH:37][CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:36]2[CH:35]=[CH:40][C:41]([C:42](=[O:43])[NH:44][CH:45]3[CH2:46][CH2:47]3)=[CH:38][CH:37]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Br)cc1)NC1CC1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NC1CC1)c1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 2-(4-bromo-phenyl)-N-cyclopropyl-acetamide (41.6 mg, 0.16 mmol), and Pd[P(Ph)3]4 (12.7 mg, 6.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 7.1 mg. MS: 498.2 (M+H+); H1-NMR (DMSO-d6): δ (ppm) 0.37-0.44 (m, 2H), 0.58-0.66 (m, 2H), 1.80-2.04 (m, 3H), 2.14-2.36 (m, 1H), 2.55-2.68 (m, 1H), 3.36-3.57 (m, 2H), 4.32-4.43 (m, 1H), 4.91-5.14 (m, 2H), 7.00-7.65 (m, 12H), 7.87-7.95 (m, 1H), 8.12-8.18 (m, 1H), 10.08-10.14 (s, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:12]1[N:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:13]=1[C:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18]1)=[O:15]>C1COCC1.O>[Cl:31][C:29]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([C:23]([F:24])([F:25])[F:26])[CH2:21][CH2:22]2)=[O:15])=[C:12]([O:4][CH2:3][CH2:2][F:1])[N:30]=1
Reactant: OCCF
Reactant: O=C(NC1CCC(C(F)(F)F)CC1)c1ccc(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1OCCF
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Fluoroethanol (380 μL, 6.45 mmol) is added to potassium tert-butoxide (730 mg, 6.16 mmol) in THF (60 mL) and stirred for 5 min at rt. After the addition of 2,6-dichloro-N-(4-trifluoromethyl-cyclohexyl)-nicotinamide (2.00 g, 5.86 mmol) the reaction mixture is stirred for 1 h hour at rt, then diluted with water and concentrated. The residue is stirred in ice water, the precipitate is filtered off and dried.