Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[C:59](B(O)O)[CH:58]=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:30])[C:2]=2[C:59]2[CH:58]=[N:57][C:66]3[C:61]([CH:60]=2)=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cnc3ccccc3c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Yield: 95 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-quinolinylboronic acid instead of 3-pyridinylboronic acid and being purified by silica gel column chromatography (acetone/hexanes=1:3) to obtain the title compound (95%).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1.N1C=CC=CC=1C(=O)CC(C1C=CC=CN=1)=O.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.CN(C=O)C>[CH3:24][C:25]1[N:26]=[CH:27][N:28]([C:2]2[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)=[O:9])=[CH:4][CH:3]=2)[CH:29]=1
Reactant: Cc1c[nH]cn1
Reactant: O=C(NCc1ccc(Br)cc1)c1ccc(-c2ccccc2)cc1
Agent: [Cu]I
Agent: O=C(CC(=O)c1ccccn1)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(CNC(=O)c3ccc(-c4ccccc4)cc3)cc2)cn1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a reaction vessel was added N-(4-bromobenzyl)biphenyl-4-carboxamide 10-3 (50 mg, 0.14 mmol), 4-methyl-1H-imidazole 11-1 (17 mg, 0.2 mmol), CuI (9 mg, 0.05 mmol), 1,3-di(pyridin-2-yl)propane-1,3-dione (15 mg, 0.07 mmol), Cs2CO3 (89 mg, 0.27 mmol) and DMF (0.7 mL). The reaction was flushed with nitrogen and stirred at 110° C. overnight. After cooling to room temperature, the reaction was diluted into ethyl acetate. The salt was removed by filtration and filtrate was dried. The residue was purified by HPLC to give N-(4-(4-methyl-1H-imidazol-1-yl)benzyl)biphenyl-4-carboxamide 92. MS m/z 368.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.16 (t, 1H), 8.17 (s, 1H), 8.02 (d, 2H), 7.81 (d, 2H), 7.75 (d, 2H), 7.58 (d, 2H), 7.52-7.40 (m, 6H), 4.54 (d, 2H), 2.17 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].F[C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([O:21][CH3:22])[CH:20]=1>>[N+:23]([C:18]1[CH:17]=[CH:16][C:15]([O:13][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:10]([CH3:12])[CH3:11])=[CH:20][C:19]=1[O:21][CH3:22])([O-:25])=[O:24]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)c1cccc(C(C)C)c1O
Product: COc1cc(Oc2c(C(C)C)cccc2C(C)C)ccc1[N+](=O)[O-]
Yield: 77.4 %

Procedure:
2,6-Diisopropylphenol (11.6 g) was coupled with 5-fluoro-2-nitroanisole (17.5 g), using the same procedure as described in Example 30(a). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 16.6 g (87%) of 2-nitro-5-(2,6-diisopropyl-phenoxy)anisole was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:3]([OH:19])[C:4]([N:6]1[CH2:17][C@@H:16]([Cl:18])[CH2:15][C@H:7]1[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5].[CH2:27]([O:34][C:35]([NH:37][CH:38]([CH:42]([P:44]([O:48][CH3:49])([O:46][CH3:47])=[O:45])[CH3:43])[C:39](O)=[O:40])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]([NH:37][CH:38]([CH:42]([P:44]([O:46][CH3:47])([O:48][CH3:49])=[O:45])[CH3:43])[C:39]([NH:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:3]([OH:19])[C:4]([N:6]1[CH2:17][C@@H:16]([Cl:18])[CH2:15][C@H:7]1[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])=[O:40])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: COP(=O)(OC)C(C)C(NC(=O)OCc1ccccc1)C(=O)O
Product: COP(=O)(OC)C(C)C(NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1C[C@@H](Cl)C[C@H]1C(=O)NC(C)(C)C
Yield: 25.3 %

Procedure:
Following a procedure similar to that described in Example 66, but using 115 mg (0.3 mmol) of (4S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide [prepared as described in Preparation 21(b)] and 100 mg of 2-benzyloxycarbonylamino-3-dimethylphosphonobutyric acid, and then purifying the product by preparative thin layer chromatography, using a 8:1 by volume mixture of methylene chloride and methanol as the developing solvent, 52 mg of the title compound were obtained as a colorless powder from the upper fraction, melting at 93°-100° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31][C:32]1[N:37]=[C:36]([CH:38](O)[CH2:39][C:40]2[CH:48]=[C:47]([CH3:49])[C:46]3[C:42](=[CH:43][N:44]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:45]=3)[CH:41]=2)[CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.CCCCCC>[Br:31][C:32]1[N:37]=[C:36]([CH:38]([N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:39][C:40]2[CH:48]=[C:47]([CH3:49])[C:46]3[C:42](=[CH:43][N:44]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:45]=3)[CH:41]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cc(CC(O)c2cccc(Br)n2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc(CC(c2cccc(Br)n2)N2C(=O)c3ccccc3C2=O)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 118.3 %

Procedure:
A solution of phthalimide (294 mg, 2 mmol) and triphenylphosphine (525 mg, 2 mmol) in anhydrous methylene chloride (10 mL) was added via syringe to (±)-1-(6-bromopyridin-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethanol (460 mg, 1 mmol). To the resulting suspension was then added diisopropylazidodicarboxylate (0.3 mL, 1.5 mmol) under nitrogen at room temperature via syringe. The resulting mixture was stirred at room temperature overnight (17 h). The mixture was diluted with hexane and purified by flash column chromatography to give a light yellow oil (700 mg, 100%). MS (ESI) [M+H]+=592. HPLC tR=2.05 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=1.[CH3:11][CH2:12][Mg+].[Br-]>C1COCC1.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2([NH2:10])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC[Mg+]
Reactant: COc1cccc(C#N)n1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C2(N)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a solution of 6-methoxy-pyridine-2-carbonitrile (1.50 g, 11.2 mmol) in THF (75 mL) at room temperature was added Ti(OiPr)4 (7.21 mL, 24.6 mmol). EtMgBr (14.9 mL, 44.7 mmol) was added dropwise. and the clear brown solution became heterogeneous. The reaction mixture was stirred for 1 h at room temperature. The reaction was diluted with water (10 mL), extracted with EtOAc (3×25 mL) and dried with MgSO4. After filtration, the solvent was removed in vacuo. The residue was purified by reverse phase HPLC to afford 380 mg (22%) of 1-(6-methoxy-pyridin-2-yl)-cyclopropylamine, m/z 166.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:26]1([CH3:29])[CH2:28][CH2:27]1.Cl>CC(C)=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:7]([CH2:29][CH:26]2[CH2:28][CH2:27]2)[C:6]1=[O:17]
Reactant: COC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: CC1(Br)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC2CC2)c1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
300 mg (1.13 mmol) of the compound from Example 232A together with 1.10 g (3.38 mmol) of caesium carbonate are placed in 12 ml acetone and treated with 456 mg (3.38 mmol) of bromo-methylcyclopropane. This is stirred for 2 hrs at 50° C. The reaction mixture is then diluted with 10 ml each of ethyl acetate and water and acidified with 1 N hydrochloric acid. The phases are separated and the aqueous phase is once again extracted with 10 ml ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. Further purification is effected by preparative HPLC [Method 10]. 60 mg (17% of theory) of the target compound are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([NH2:11])[N:3]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc(N)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.5 %

Procedure:
2,6-Diaminopurine (5.00 g, 33.3 mmol) and potassium carbonate (6.91 g, 50.0 mmol) were suspended in DMF (250 ml). Benzyl bromide (8.55 g, 50 mmol) was added thereto and the mixture was stirred at room temperature for 5 hours. After condensing the reaction mixture in vacuo, to the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (5% methanol/chloroform) to give the subject compound (1.56 g, yield 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])=[CH2:9])=[CH:4][CH:3]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>C(O)C(F)(F)F.CC1C(C)=CC2N([C@H]3O[C@H](CO)[C@@H](OP(O[C@@H](CNC(CC[C@]4(C)[C@@H](CC(N)=O)[C@H]5[N-]C4=C(C)C4=NC(C(C)(C)[C@@H]4CCC(N)=O)=CC4=NC([C@](CC(N)=O)(C)[C@@H]4CCC(N)=O)=C(C)C4=N[C@]5(C)[C@](CC(N)=O)(C)[C@@H]4CCC(N)=O)=O)C)([O-])=O)[C@H]3O)C=NC=2C=1.O.[Co+2]>[CH2:17]([O:16][C:14]([CH:13]1[CH2:9][C:8]1([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[F:10])=[O:15])[CH3:18]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(F)c1ccc(Cl)cc1
Agent: [Co+2]
Agent: C/C1=C2/[N-][C@H]([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(=O)([O-])O[C@H]2[C@@H](O)[C@@H](n3cnc4cc(C)c(C)cc43)O[C@@H]2CO)[C@]2(C)N=C(/C(C)=C3\N=C(/C=C4\N=C1[C@@H](CCC(N)=O)C4(C)C)[C@@H](CCC(N)=O)[C@]3(C)CC(N)=O)[C@@H](CCC(N)=O)[C@]2(C)CC(N)=O
Agent: CC1=C2[N-][C@H]([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(=O)([O-])O[C@H]2[C@@H](O)[C@@H](n3cnc4cc(C)c(C)cc43)O[C@@H]2CO)[C@]2(C)N=C(C(C)=C3N=C(C=C4N=C1[C@@H](CCC(N)=O)C4(C)C)[C@@H](CCC(N)=O)[C@]3(C)CC(N)=O)[C@@H](CCC(N)=O)[C@]2(C)CC(N)=O
Solvent: O
Solvent: OCC(F)(F)F
Product: CCOC(=O)C1CC1(F)c1ccc(Cl)cc1
Yield: 68.5 %

Procedure:
Vitamin B12a (1.00 g; 0.723 mmol) was dissolved in dry trifluoroethanol (70 ml) and 1-chloro-4-(1-fluoro-vinyl)-benzene (6.50 g; 41.5 mmol) and ethyl diazoacetate (6.30 g; 50 mmol; 90% purity) was added. The solution was stirred, under reflux, under nitrogen atmosphere for 18 h. After cooling the solvent was evaporated and the residue purified by flash chromatography using 9:1 hexane/ethyl acetate. 6.9 g of 2-(4-chlorophenyl)-2-fluoro-cyclopropane carboxylic acid ethyl ester was obtained in the form of an oil (81% of theory) as a 7:3 mixture of cis/trans isomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][Cl:24])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:38])[C:13]=2[N:12]=[C:11]1[CH2:23][Cl:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Example 5 Part B, a solution of tert-butyl[2-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (27.45 g, 76.1 mmol) in chloroform (500 mL) was treated with 3-chloroperoxybenzoic acid (25.6 g of 77% max, 114 mmol) and the resulting 5-oxide was aminated using ammonium hydroxide (150 mL) and para-toluenesulfonyl chloride (17.4 g, 91.3 mmol) to provide 41.83 g of crude tert-butyl[2-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a brown solid. A portion (˜32 g) of the crude material was dissolved in dichloromethane and then washed with 1 N hydrochloric acid (×3). The organic layer was allowed to stand for several days and a precipitate formed. This material was isolated by filtration to provide 7.0 g of tert-butyl[2-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as an off white solid.
Reaction SMILES: COCCOC.CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]([O:35][C:36]1[CH:63]=[C:62](I)[CH:61]=[CH:60][C:37]=1[C:38]([NH:40][C:41]1[CH:53]=[C:52]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:51]=[CH:50][C:42]=1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>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(OCC)(=O)C.O>[CH2:28]([O:35][C:36]1[CH:63]=[C:62]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:61]=[CH:60][C:37]=1[C:38]([NH:40][C:41]1[CH:53]=[C:52]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:51]=[CH:50][C:42]=1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:39])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(I)cc1OCc1ccccc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccncc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
Ethylene glycol dimethyl ether (12 mL), water (3.6 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.49 g), sodium carbonate (0.50 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg) were added to tert-butyl 2-(2-(benzyloxy)-4-iodobenzamido)-4-phenylbenzoate (1.2 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and bis(triphenylphosphine)palladium(II) dichloride (28 mg) was added thereto, followed by heating to reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and bis(triphenylphosphine)palladium(II) dichloride (28 mg) was added thereto, followed by heating to reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 80-60% hexane/ethyl acetate] to obtain 0.55 g of tert-butyl 2-(2-(benzyloxy)-4-(pyridin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: C(OC([C:6]1([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:19])=[C:11]([O:17][CH3:18])[C:12]=2[Cl:16])[C:7]1=[O:20])=O)C.Cl>CC(O)=O>[CH2:21]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:19])=[C:11]([O:17][CH3:18])[C:12]=2[Cl:16])[C:7]1=[O:20])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC1(C(=O)OCC)CCc2c(cc(F)c(OC)c2Cl)C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCCCC1CCc2c(cc(F)c(OC)c2Cl)C1=O
Temperature: 80 °C
Reaction time: 1.25 h

Procedure:
2-butyl-5-chloro-7-fluoro-6-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (263 mg, 0.74 mmol) was dissolved in AcOH (6 mL) then treated with 6N HCl (6 mL). This solution was heated with stirring at 80° C. for 75 minutes, then at 100° C. for 2 hours. After cooling to room temperature the mixture was partitioned between EtOAc/5% NaHCO3. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated under vacuum. Two successive purifications of the crude product by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7.5 cm) silica gel columns, eluting with EtOAc/hexane yielded 2-butyl-5-chloro-7-fluoro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one and recovered starting material.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])=[S:16].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CS(C)=O.[OH-].[Na+]>O>[NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15](=[N:17][C:18]([O:20][CH3:21])=[O:19])[S:16][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)NC(=S)NC1C(=N)C=CC=C1Cc1ccco1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)N=C(NC1C(=N)C=CC=C1Cc1ccco1)SCc1ccccc1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To 100.0 g (0.33 mole) of imino(2-furylmethyl)-2-(3-carbomethoxythioureido) benzene and 50.0 g. (0.395 mole) of benzyl chloride in 275 ml. of dimethyl sulfoxide is slowly added 15.0 g (0.375 mole) of sodium hydroxide in 260 g. of water. The resulting mixture is stirred for 1/2 hour and the yellow precipitate is separated by filtration and recrystallized from 800 ml of methylene chloride-hexane (1:1) to give 91.1 g (70.1%) of 1-imino-(2-furylmethyl)-2-(3-carbomethoxy-S-benzylisothioureido)benzene m.p. 112°-114° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[F:23][C:24]1([F:35])[O:28][C:27]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[CH:32][C:26]=2[O:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:35][C:24]1([F:23])[O:28][C:27]2[CH:29]=[CH:30][C:31]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)=[CH:32][C:26]=2[O:25]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)OC(F)(F)O5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To 10 mL of a chloroform solution containing 226 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 150 mg of 2,2-difluorobenzo[1,3]dioxol-5-carbaldehyde, 43 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 257 mg of sodium triacetoxyborohydride was added, and stirred for 2.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=10:1] to give 188 mg of 1-(2-(4-((2,2-difluorobenzo[1,3]dioxol-5-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]([OH:15])[CH:9]=1)[CH3:5].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]([O:15][CH2:1][CH3:2])[CH:9]=1)[CH3:5]
Reactant: CCI
Reactant: CCOC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(I)c(OCC)c1
Temperature: 65 °C

Procedure:
Reflux 3-hydroxy-4-iodo-benzoic acid (38 g, 144 mmol) and saturated solution of HCl in ethanol (600 mL) overnight. Evaporate the solvent yielding 42 g, 99% of 3-hydroxy -4-iodo-benzoic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.1 Hz, 3H), 4.36 (q, J=7.1 Hz, 2H), 7.33 (dd, J=8.3 and 2.0 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H). Add ethyl iodide (33.8 g, 216 mmol) to a solution of 3-hydroxy -4-iodo-benzoic acid ethyl ester (42 g, 144 mmol) and K2CO3 (39.9 g, 288 mmol) in acetonitrile (400 mL) under magnetic stirring. Heat the reaction mixture at 65° C. for 2 hours, allow the mixture to cool and maintain at RT overnight. Evaporate the solvent and add ethyl acetate to the crude. Filter the solid through Celite® and evaporate the solvent. Yield 42 g, 96%. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.1 Hz, 3H), 1.50 (t, J=7.0 Hz, 3H), 4.16 (q, J=7.0 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 7.36 (dd, J=8.1 and 1.8 Hz, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH:17](C)C)[C:8](=[O:20])[C:7]=12)=[O:2].C(N1C2C(=CC=CC=2)N2C=NC(C(OCC)=O)=C2C1=O)C(C)C>>[CH2:16]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]2[CH:5]=[N:4][C:3]([CH:1]=[O:2])=[C:7]2[C:8]1=[O:20])[CH3:17]
Reactant: CC(C)Cn1c(=O)c2c(C=O)ncn2c2ccccc21
Agent: CCOC(=O)c1ncn2c1c(=O)n(CC(C)C)c1ccccc12
Product: CCn1c(=O)c2c(C=O)ncn2c2ccccc21

Procedure:
In the same manner was prepared 4,5-dihydro-3-formyl-5-isobutyl-4-oxo-imidazo[1,5-a]quinoxaline, m.p. 239°-240° C. from reduction of ethyl 4,5-dihydro-5-isobutyl-4-oxoimidazo[1,5-a]quinoxaline-3-carboxylate. (Compound 20).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].C([O-])(=O)C.[K+]>O.C1(C)C=CC=CC=1>[C:20]([O:5][CH:4]=[CH:3][C:2]([CH3:12])([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])(=[O:22])[CH3:21]
Reactant: CC(C)=CCCC(C)(C)CC=O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OC=CC(C)(C)CCC=C(C)C
Temperature: 25 °C

Procedure:
The general method for the preparation of the starting enol esters is illustrated by the following example: 0.063M of 3,3,7-trimethyl-oct-6-ene-1-al were added under stirring to a mixture consisting of 0.06M of triethylamine, 0.126M of acetic anhydride and 1.1 g of potassium acetate pre-heated to 80°. The reactive mixture was refluxed for approximately 7 h. After cooling to room temperature, toluene and water were added and the two phases separated. 3,3,7-Trimethyl-1,6-octadienyl acetate was then obtained as a toluene solution and finally isolated by evaporation at reduced pressure.