Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[C:16]([N:23]1[CH2:26][CH:25]([NH2:27])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].N12CCCN=C1CCCCC2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:19]([O:18][C:16]([N:23]1[CH2:26][CH:25]([NH:27][C:12]2[N:11]=[N:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:14][CH:13]=2)[CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(C(=O)NCCC3CC3)nn2)C1
Yield: 43 %

Procedure:
A mixture of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.350 g, 1.55 mmol), 1-BOC-3-aminoazetidine (0.400 g, 2.32 mmol), tetrabutylammonium bromide (0.120 g, 0.36 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.000 g, 6.00 mmol) in 1,4-dioxane (30 mL) was heated under reflux overnight. The solvent was evaporated. The residue was washed with 1 M citric acid (50 mL) and ethyl ether (50 mL) was added. Ultrasonication of the mixture followed by filtration afforded 3-[6-(2-cyclopropylethylcarbamoyl)pyridazin-3-ylamino]azetidine-1-carboxylic acid tert-butyl ester as a white solid in 43% yield (0.240 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)=[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:7]=[C:6]1[CH:39]=[CH2:40])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)=[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:7]=[C:6]1[CH2:39][CH3:40])[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1nc(-c2ccccc2)c(CN(Cc2cccc(OCC)c2)Cc2ccc3c(c2)OCCO3)n1CCCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCn1c(CC)nc(-c2ccccc2)c1CN(Cc1cccc(OCC)c1)Cc1ccc2c(c1)OCCO2

Procedure:
N-[(1-butyl-2-ethenyl-4-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine (5 mg) prepared in the previous example, is dissolved in 5 ml ethyl acetate and hydrogenated at room temperature under atmospheric pressure. 5% Pd/C (3 mg) is used as a catalyst. The reaction mixture is filtered through celite to provide the title compound (Compound 7). 1H NMR (CDCl3) δ 0.83(t, J=7.2 Hz, 3H), 1.10(m, 2H), 1.27(m, 2H), 1.31 (t, J=7.2 Hz, 3H), 1.40(t, J=7.2 Hz, 3H), 2.66(q, 7.2 Hz, 2H) 3.30(s, 2H), 3.36(s, 2H), 3.65(s, 2H), 3.98(m, 4H), 4.23(s, 4H), 6.76(m, 4H), 7.17(t, J=7.6 Hz, H), 7.26(m, 1H), 7.37(t, J=7.6 Hz, 2H), 7.58(d, J=7.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:23]#[N:24])([CH3:22])[CH3:21])[N:15]=2)[CH:3]=1.CO.[NH3:27]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:27])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:23]#[N:24])([CH3:22])[CH3:21])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C#N)n1
Solvent: CO
Product: CC(C)(C#N)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
In a 50 mL round bottom flask, ethyl 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (792 mg, 2.29 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). Sealed and stirred at room temperature for 18 h. The abundant solid formed during the reaction was separated by filtration, filter cake rinsed with fresh methanol and dried in high vacuum to give clean 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (581 mg, 80.1% yield) as an off-white solid. 1H NMR (DMSO-d6) δ: 12.14 (s, 1H), 9.22 (s, 1H), 8.89 (s, 1H), 8.23 (s, 1H), 7.87 (t, J=7.9 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 1.73 (s, 6H); LC-MS 316.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[CH3:6])[CH3:2].N1C=CC=CC=1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>C(Cl)Cl>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](=[O:16])/[C:5](/[CH3:6])=[CH:4]/[O:3][CH2:1][CH3:2]
Reactant: C/C=C/OCC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCO/C=C(\C)C(=O)C(Cl)(Cl)Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 18.6 %

Procedure:
A mixture of (E)-1-ethoxyprop-1-ene (6.41 mL, 57.9 mmol) and pyridine (4.68 mL, 57.9 mmol) was added to a soln. of 2,2,2-trichloroacetyl chloride (10.53 g, 57.9 mmol) in DCM (15 mL) at −10° C. at a rate of 6-10 drops/min. After the addition was completed, the mixture was stirred at r.t for 24 hrs. Filtered, and the filtrate was concentrated in reduced pressure (at first the temperature of the water bath was r.t, after most DCM was evaporated off, water bath was warmed to 50° C. to afford (E)-1,1,1-trichloro-4-ethoxy-3-methylbut-3-en-2-one (2.55 g, 10.79 mmol, 18.64% yield). 1H-NMR (500 MHz, CDCl3): δ: 7.96 (s, 1H), 4.21 (q, J=7.1 Hz, 2H), 1.94 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). This material was taken into Step G2 without further purification.
Reaction SMILES: [C:1]([S:4][CH3:5])(=[NH:3])[NH2:2].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.O>[C:6]([NH:3]/[C:1](/[S:4][CH3:5])=[N:2]/[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CSC(=N)N
Solvent: O
Solvent: C1CCOC1
Product: CS/C(=N\C(=O)c1ccccc1)NC(=O)c1ccccc1

Procedure:
To a stirred solution of methyl carbamimidothioate (0.901 g, 10 mmol) in 10 ml of THF were added TEA (6.97 ml, 50.0 mmol) and benzoyl chloride (3.48 ml, 30.0 mmol) at r.t. The reaction was stirred for over night. The reaction mixture was diluted with water (20 ml) and the resulting precipitates were collected by filtration. The filter cake was washed with water and heptane. It was dried by suction in air for 4 hours to yield (Z)-methyl N,N′-dibenzoylcarbamimidothioate. After the filtration, it was pure by LCMS. It was carried on to the next step. LCMS method A, (M+H)+299.1, ret T=1.66 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[N:6]=[C:5]([CH2:14][CH2:15][CH3:16])[C:4]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].CCOC(C)=O.C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:25]([O:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[N:6]=[C:5]([CH2:14][CH2:15][CH3:16])[C:4]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCc1nc2ccc(C)cc2c(CO)c1Cc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc2ccc(C)cc2c(CO[Si](C)(C)C(C)(C)C)c1Cc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
To 50 mg (0.13 mmole) of 54 in 0.5 mL of CH2Cl2 containing 25 λ Et3N (17.5 mg; 0.17 mmole) and 10 mg DMAP (0.08 mmole) was added dropwise with stirring under a nitrogen atmosphere while cooling to 0° C., 25 mg (0.17 mmole) of t-butyldimethylsilyl chloride in 0.5 mL of CH2Cl2. After stirring overnight, the reaction mixture was washed with water, dried (MgSO4) and the product isolated by preparative tlc on silica gel GF using 5% EtOAc/CH2Cl2, giving clean 55.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].O1CCCC1.[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:29]=[CH:30][CH:31]=1)#[CH:25]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[C:14]([O:13][C:12]([NH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:25]#[C:24][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:29]=[CH:30][CH:31]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Into the reaction flask was added tert-butyl (2-iodo-4-nitrophenyl)carbamate (2.71 g, 7.44 mmol), copper(I) iodide (0.057 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.21 g, 0.30 mmol), tetrahydrofuran (20 mL), and triethylamine (1.1 mL). It was stirred under N2 bubbling for 5 min. tert-Butyl (3-ethynylphenyl)carbamate (1.62 g, 7.44 mmol) was then added. The reaction mixture was stirred at 65° C. for 3 h. After concentration, the residue was diluted with EtOAc and water. The aqueous layer was extracted again with fresh EtOAc. The organic layers were combined and dried over Na2SO4. After filtration and concentration, the crude was purified by silica gel column chromatography to give the desired product (2.7 g, 80%). LCMS for C24H28N3O6 (M+H)+: m/z=454.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:36][CH3:37])=[C:20](/[CH:21]=[CH:22]\[CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[C:13]=3[O:12]2)=[N:2]1
Reactant: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1/C=C\C1CCNCC1)OC(=Cc1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A solution of tert-butyl 4-((Z)-2-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}vinyl)piperidine-1-carboxylate (0.0387 g, 0.0771 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The resulting residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol) to obtain (Z)-2-[(1H-indazol-3-yl-methylene]-6-methoxy-7-[(Z)-2-(piperidin-4-yl)vinyl]benzofuran-3(2H)-one (0.0108 g, 35%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>O1CCCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:32][CH2:31]3)[C:9]2=[O:13])=[CH:15][CH:16]=1
Reactant: O=C1NCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2=O)CC1
Temperature: 75 °C

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)pyrrolidin-2-one (Example 58B, 1.37 g, 5.00 mmol) in tetrahydrofuran (30 mL) was added potassium t-butoxide (1.0 M in tetrahydrofuran) (7.5 mL, 7.5 mmol) followed by the product from Example 63A (1.47 g, 5.00 mmol). The reaction mixture was heated at 75° C. for 18 hours. The reaction was concentrated, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with 3% methanol/dichloromethane to give the title compound. MS (DCI) m/z 486.3 (M+H)+.
Reaction SMILES: B.[C:2]([N:9]1[CH2:28][CH2:27][N:12]2[CH2:13][C@@H:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[C:20]([C@@H:11]2[CH2:10]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[ClH:29]>O1CCCC1>[ClH:29].[ClH:29].[CH2:2]([N:9]1[CH2:28][CH2:27][N:12]2[CH2:13][C@@H:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15]3[C:20]([C@@H:11]2[CH2:10]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(=O)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCN1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1

Procedure:
To a stirred solution of 1.0 M borane in tetrahydrofuran (100 ml) maintained under nitrogen at ambient temperature was added cis-1,3,4,6,7,11b-hexahydro-2-hexanoyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (8.3 g, 0.019 m) and the mixture heated to reflux for 3 hours, then cooled in an ice bath and carefully treated with 10% HCl (100 ml). This mixture was heated to reflux for 1 hour, then cooled, and the tetrahydrofuran removed on an aspirator. The residue was treated with 20% NaOH (300 ml) and extracted with chloroform (3×75 ml). The extracts were dried over MgSO4 and evaporated to an oily residue, 12.3 g. This was dissolved in methanol (100 ml) and isopropanol (50 ml) and acidified with HCl gas. A white solid crystallized which was collected by filtration, recrystallized from methanol/water, and vacuum dried at 110° for 24 hours to give 7.1 g cis-1,3,4,6,7,11b-hexahydro-2-hexyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 221°-222°.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(N(CC)C(C)C)(C)C.FC(F)(F)C(O[C:24]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34])=O>C(Cl)Cl>[O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:24]1[C:25]([F:34])=[C:26]([F:33])[C:27]([F:32])=[C:28]([F:31])[C:29]=1[F:30])=[O:7]
Reactant: CC(=O)CCCC(=O)O
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CCCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 1 h
Yield: 79.3 %

Procedure:
5-Oxohexanoic acid (2.6 g; 20 mmol) was dissolved in CH2Cl2 (50 mL). N,N-Diisopropylethylamine (10.4 mL, 60 mmol) was added followed by pentafluorophenyl trifluoroacetate (3.61 mL; 21 mmol). The reaction mixture was kept at room temperature for 1 hour and evaporated. The residue was resuspended in EtOAc:Hexanes (1:1) and loaded on a silica gel column (5×20 cm) equilibrated and developed with the same mixture. Fractions containing the product (14) (Rf ˜0.7) were pooled and concentrated to give 4.7 g (79%) of yellowish oil after drying in vacuum. 1H NMR (CDCl3) δ 2.05 (m, 2H), 2.18 (s, 3H), 2.61 (t, 2H), 2.74 (t, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH:17]=[O:18])([CH3:16])[CH2:8][CH2:7]2)([O-:3])=[O:2].CC(=CC)C.Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH3:16])([C:17]([OH:26])=[O:18])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: [O-][Cl+][O-]
Reactant: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C=O)CC2
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
2.3 g of 6-nitro-2-formyl-2,5,7,8-tetramethylchroman was dissolved in 150 ml of t-butanol and 23 g of 2-methyl-2-butene was added at room temperature. An aqueous solution prepared by dissolving 5.8 g of sodium chlorite and 7.6 g of sodium dihydrogen phosphate dehydrate in 60 ml of water was added dropwise at room temperature, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction solution was poured into water and then extracted with ether. The organic layer was partitioned with an aqueous 5% sodium hydrogen carbonate solution and the ether layer was discarded. The pH of the aqueous layer was adjusted to 4 with 10% hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the resulting crystal was washed with hexane to obtain 1.6 g of the objective product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:28]([C:31]1[C:32]([CH:37]=O)=[N:33][CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:37][C:32]2[C:31]([CH:28]([CH3:30])[CH3:29])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCNCc3ncc(C)cc3C)c2)cc1
Reactant: CC(C)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(CCN(Cc3ncc(C)cc3C)Cc3ncccc3C(C)C)c2)cc1

Procedure:
Using General Procedure B: Reaction of (3,5-dimethyl-pyridin-2-ylmethyl)-{2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine and 3-isopropyl-pyridine-2-carbaldehyde in CH2Cl2 (5 mL) with NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-{2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine. 1H NMR (CDCl3) δ 0.91 (d, 6H, J=6.51 Hz), 2.04 (s, 3H), 2.24 (s, 1H), 2.26 (s, 3H), 2.41 (s, 3H), 2.71 (m, 2H), 2.82 (m, 2H), 3.75 (d, 4H, J=4.50 Hz), 6.63 (s, 1H), 7.14 (q, 1H, J=4.25 Hz), 7.22 (s, 1H), 7.30 (d, 2H, 7.86 Hz), 7.49 (d, 1H, J=7.0 Hz), 7.70 (d, 2H, J=8.40 Hz), 7.80 (s, 1H), 8.19 (s, 1H), 8.32 (d, 1H, J=4.19 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)nn(-c3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.3 mmol) in CH2Cl2 (5 mL) was treated with phenylboronic acid (0.6 mmol), pyridine (0.6 mmol), and copper(II) acetate (4.5 mmol). The mixture was stirred at RT for 16 h. After concentration and purification (SiO2, EtOAc/hexanes), 3-(4-chloro-phenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained. This intermediate was then diluted with CH2Cl2 (10 mL), and TFA (1 mL) was added. The mixture was stirred at RT for 4 h. The mixture was concentrated and the residue was purified (SiO2, 2 M NH3 in MeOH/CH2Cl2) to provide the title compound (40 mg). MS (ESI): exact mass calculated for C19H18ClN3, 323.12; found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.46-7.40 (m, 4H), 7.36-7.32 (m, 5H), 3.09-3.07 (br m, 4H), 3.00-2.98 (br m, 2H), 3.92-2.90 (br m, 2H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17]C)=[O:15])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]1[C:25]([O:27][CH2:28]C)=[O:26]>CO>[CH3:1][O:2][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH3:17])=[O:15])[C:10]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:9]1[C:25]([O:27][CH3:28])=[O:26]
Reactant: C[O-]
Reactant: CCOC(=O)c1c(-c2ccccc2)c(C(=O)OCC)n(CCCCl)c1C
Agent: [Na+]
Solvent: CO
Product: COCCCn1c(C)c(C(=O)OC)c(-c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Yield: 32.8 %

Procedure:
Sodium methoxide (190 mg, 3.50 mmol) was added to a solution of diethyl 1-(3-chloropropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (1.1 g, 2.91 mmol) in methanol (10 mL) and stirred at reflux for 28 h. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in water and the aqueous layer was extracted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford dimethyl 1-(3-methoxypropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (330 mg, 33%) as a yellow oil. The aqueous layer was acidified with 2N hydrochloric acid to pH 2 and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated to afford 4-methoxycarbonyl-1-(3-methoxypropyl)-5-methyl-3-phenyl-pyrrole-2-carboxylic acid (170 mg, 18%) as a pink oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([Cl:18])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
200.0 mg (0.92 mmol) of trans-4-trifluoromethylcinnamic acid were treated with 200 μl of thionyl chloride. After addition of 2 drops of DMF, the reaction solution obtained was stirred at 75° C. for 3 h. It was then concentrated to dryness, and the residue was taken up in toluene 2× and concentrated to dryness again. Drying in a high vacuum yielded 237.0 mg of the title compound as a slightly yellow, amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]=1[C:9]([O:11]CC)=O.C([O-])=O.[NH4+].[CH:18]([NH2:20])=O>O>[CH3:7][C:4]1([CH3:8])[C:3]2[C:9](=[O:11])[NH:20][CH:18]=[N:1][C:2]=2[CH2:6][CH2:5]1
Reactant: NC=O
Reactant: CCOC(=O)C1=C(N)CCC1(C)C
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CC1(C)CCc2nc[nH]c(=O)c21
Temperature: 150 °C

Procedure:
A mixture of ethyl 2,2-dimethyl-5-oxocyclopentanecarboxylate (3.426 g) and ammonium acetate (14.33 g) in EtOH (100 mL) was heated at 85° C. (bath) for 1 hour. The contents were concentrated. The residue was partitioned between water and DCM. The organic phase was separated. The aqueous solution was extracted with DCM. The combined DCM solutions were washed with water and dried (Na2SO4). Upon filtration and concentration, solid ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate (2.933 g) was yielded. The ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate was mixed with ammonium formate (5.054 g) and formamide (7 mL) and heated at 150° C. for 16 hours. The mixture was diluted with water and extracted with 5:1 DCM-IPA. The combined extracts were dried (Na2SO4) and concentrated to give 5,5-dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one as a viscous oil (1.185 g). 5,5-Dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (1.063 g) was dissolved in acetonitrile (20 mL) with POCl3 (1.78 mL). The mixture was heated at 80° C. for 10 hours. The mixture was cooled to 0° C. 50% KOH (15.3 mL) was added dropwise. t-Butyl piperazine-1-carboxylate (3.615 g) was added. The mixture was heated at 80° C. for 24 hours. The contents were concentrated. Water was added. The mixture was extracted with DCM (2×) and dried (Na2SO4). The crude material was purified with flash chromatography to give tert-butyl 4-(5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.021 g). 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.57 (s, 1H), 3.56-3.54 (m, 4H), 3.37-3.34 (m, 4H), 2.90 (t, J=7.3 Hz, 2H), 1.89 (t, J=7.3 Hz), 3H)1.48 (s, 9H), 1.40 (s, 6H). MS: 333.2 (M+1).