Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl.Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][NH:39][CH2:38]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:38]1[C:37]2[C:41](=[CH:42][C:43]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]3)=[CH:35][CH:36]=2)[CH2:40][NH:39]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: Brc1ccc2c(c1)CNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CNC5)cc23)CC1
Yield: 7.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (150 mg, 0.325 mmol) in dioxane (0.75 mL) and water (0.25 mL), was added 5-bromo-2,3-dihydro-1H-isoindole hydrochloride (130 mg, 0.651 mmol), and cesium carbonate (636 mg, 1.952 mmol). The reaction mixture was kept under argon for 10 min before addition of tetrakis(tripehnylphosphine)palladium(0) (19 mg, 0.016 mmol). The resultant mixture was heated in a microwave for 20 min at 150° C. Mixture was then purified by HPLC to give 11 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][O:21][CH:22]([O:34][CH3:35])[C:23]1[C:28](F)=[C:27]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:25][C:24]=1[F:33]>C1COCC1>[CH3:35][O:34][CH:22]([O:21][CH3:20])[C:23]1[C:24]([F:33])=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: COC(OC)c1c(F)ccc([N+](=O)[O-])c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1c(F)ccc([N+](=O)[O-])c1Nc1ccc(I)cc1F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of 2-fluoro-4-iodo-aniline (2.24 g, 9.43 mmol) in anhydrous THF (30 ml) under an atmosphere of nitrogen was added 1M LHMDS in hexanes (18 ml, 1M, 18.0 mmol) keeping the internal temperature below −65° C. After complete addition the reaction mixture was stirred for 30 minutes at −70° C. A solution of 2-dimethoxymethyl-1,3-difluoro-4-nitro-benzene (2.0 g, 8.58 mmol) in anhydrous THF (20 ml) was added to the reaction mixture keeping the internal temperature below −68° C. After complete addition the reaction mixture was stirred for 30 minutes at −70° C. then allowed to warm to room temperature and stirred for 22 hours. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate (200 ml). The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo to a minimum volume and triturated with cyclohexane to yield the title compound (2.18 g, 56%). LCMS (Method B): RT=4.26 min, [M−H]−=449.
Reaction SMILES: [CH:1](OC)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][CH2:32][OH:33])=[C:25]([CH3:34])[CH:24]=2)=[CH:8][CH:7]=1>CCO>[OH:33][CH2:32][CH2:31][O:30][C:26]1[C:25]([CH3:34])=[CH:24][C:23]([C:13]2[N:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][CH:1]=[O:2])=[CH:7][CH:8]=3)[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:28][C:27]=1[CH3:29]
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cc(C)c1OCCO
Reactant: COC=O
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(NC=O)cc2)cc(C)c1OCCO
Yield: 33.5 %

Procedure:
Methyl formate (10 mL, 162 mmol) was added to a solution of 3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.200 g, 0.50 mmol) in EtOH (10 mL) and heated at reflux. More methyl formate (5 mL, 81 mmol) was added and the mixture was heated at reflux for 2 more days, before being concentrated in vacuo and purification by flash chromatography on silica gel eluting with 2% to 8% MeOH in CH2Cl2. Further purification was effected by reverse phase chromatography eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The desired fractions were collected, basified, extracted, and concentrated, to afford the title compound as a white solid (0.072 g, 33%). 1H-NMR (300 MHz, DMSO-d6, mixture of rotamers): δ 10.24 (s, 0.8H), 10.18 (m, 0.2H), 8.72-8.87 (m, 0.2H), 8.25 (d, J=1.7 Hz, 0.8H), 8.18 (dd, J=6.9, 1.1 Hz, 1H), 7.83-7.96 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.51-7.59 (m, 2.5H), 7.24 (d, J=8.7 Hz, 2H), 7.11-7.19 (m, 0.5H), 7.03 (s, 2H), 4.81 (t, J=5.4 Hz, 1H), 3.63-3.71 (m, 4H), 2.09 (s, 6H). MS (APCI) m/z: 430 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=[O:20])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[F:36])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[F:36][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=[O:20])=[CH:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3C)cc2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a suspension of 3-fluoro-4′-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid methyl ester (35 mg) in THF (0.2 ml) and MeOH (0.2 ml) was added a 1M aqueous LiOH solution (0.145 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. Since the reaction was not finished, 1 M aqueous LiOH solution (0.435 ml) was added portionwise while stirring for another 24 h at room temperature. The reaction mixture was acidified using 1 M HCl. The organic solvents were removed under vacuum. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (29 mg) as a colorless solid, MS (ESI−): m/z=468.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[OH:31][C:32]([CH3:39])([CH3:38])[C:33]#[C:34][C:35](O)=[O:36]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:35](=[O:36])[C:34]#[C:33][C:32]([OH:31])([CH3:39])[CH3:38])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(O)C#CC(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: CC(C)(O)C#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 25.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 4-hydroxy-4-methylpent-2-ynoic acid, to afford the title compound (8.0 mg, 25.1%). Data: UPLC (C) Rt: 1.53 min; m/z 510.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:27])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:35][C:34]([C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[C:39]#[N:40])=[CH:33][C:32](=O)[O:31]1>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:27][C:32](=[O:31])[CH2:33][C:34]([C:36]1[CH:43]=[CH:42][CH:41]=[C:38]([C:39]#[N:40])[CH:37]=1)=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 62.1 %

Procedure:
Prepared from [2-amino-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G36) (196 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (126 mg, 0.55 mmol) according to the general procedure K. Obtained as an off-white solid (175 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1)[C:7](OCC)=[O:8])[CH3:2].Cl.[CH3:22][NH:23][O:24][CH3:25].C([Mg]Cl)(C)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([S:15]([F:16])([F:20])([F:17])([F:18])[F:19])[CH:14]=1)[C:7]([N:23]([O:24][CH3:25])[CH3:22])=[O:8])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)cc(S(F)(F)(F)(F)F)c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
Ethyl 3-ethoxy-5-(pentafluorosulfanyl)benzoate (4.8 g) was dissolved in THF (150 ml) and admixed with N,O-dimethylhydroxylamine hydrochloride (2.20 g). The mixture was cooled to approx. −15° C. under argon, and isopropylmagnesium chloride (22.5 ml, 2 M in THF) was added dropwise within 10 min. After stirring at −15° C. for 20 min, the cooling bath was removed and the mixture was stirred at RT for another 1 h. Then saturated ammonium chloride solution was added and the mixture was extracted three times with EA. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MtB ether gradient of 20-100% within 60 min). 2.80 g of the title compound were obtained.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])(=O)C.[Na+]>ClCCCl>[CH:9]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][C:17]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:10]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A mixture of N-methylformanilide (2.25 ml) and phosphoryl chloride (1.70 ml) was stirred at ambient temperature for 15 minutes. 1,2-dichloroethane (30 ml) was then added, followed by ethyl indole-2-carboxylate (3 g) and the reaction was heated at reflux for 90 minutes. The reaction mixture was then poured into a mixture of ice/water (200 ml) and sodium acetate (10 g) and extracted with ethyl acetate (2×200 ml). Combined organic phases were evaporated and the crude residue purified by column chromatography using dichloromethane as eluent to give the product as a white solid (2.27 g, 66%); NMR d (CD3SOCD3) 1.40 (t, 3H), 4.42 (q, 2H), 7.25 (m, 1H), 7.40 (m, 1H), 7.55 (m, 1H), 8.20 (m, 1H), 12.77 (s, 1H); M/z (+) 218.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([CH:18]([NH2:21])[CH2:19][CH3:20])[CH3:17]>>[CH2:16]([CH:18]([NH:21][C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:19][CH3:20])[CH3:17]
Reactant: Cc1cnc2c(Cl)nc3ccccc3n12
Reactant: CCC(N)CC
Product: CCC(CC)Nc1nc2ccccc2n2c(C)cnc12

Procedure:
By reaction of 4-chloro-1-methylimidazo[1,2-a]quinoxaline (example 2) with 1-ethylpropylamine, according to a procedure that is similar to that followed in example 3 there is obtained 4-(1-ethylpropylamino)-1-methylimidazo[1,2-a] quinoxaline. m.p. (DSC)=75.9° C. (onset); IR (KBr): 3231, 2965, 1546 cm-1 ; 1H-NMR (CDCl3): δ8.0 (1H,dd), 7.7 (1H,dd), 7.4÷7.1 (3H,m), 5.9 (1H,d), 4.2 (1H,m), 2.85 (3H,s), 1.65 (4H,m), 0.95 (6H,t); UV (EtOH): λmax =221, 241, 268, 298, 313 nm. Elementary analysis for C14H20N4 (m.w. 268.36): calcd. C 71.61, H 7.51, N 20.83%; found C 71.12, H 7.53, N 20.79%.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].CN(C=O)C>[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC=CC=1>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH2:7][OH:8]
Reactant: OCc1ncsc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1scnc1CO
Temperature: 90 °C

Procedure:
(5-Bromothiazol-4-yl)-methanol (6.15 g), 8.9 ml of triethylamine, 61 mg of copper(I) iodide, 5.4 ml of trimethylsilylacetylene, and 223 mg of bis(triphenylphosphine) palladium(II) dichloride were added in that order to 25 ml of DMF, the mixture was stirred, and the air in the system was replaced by argon. The reaction mixture was stirred with heating at 90° C. for 90 min and was then allowed to stand for cooling. Toluene (74 ml) and 25 ml of water were added to the reaction mixture, and the aqueous layer was separated. Water (25 ml) was added to the organic layer, and the mixture was adjusted to pH 2 by the addition of 5 N hydrochloric acid, followed by separation of the aqueous layer. The organic layer was washed with 25 ml of 5% sodium bicarbonate water and 25 ml of 10% brine in that order and was then treated with 1.4 g of activated carbon and anhydrous magnesium sulfate. The solvent was removed by distillation, and the solid was separated to give 5.35 g of [5-[2-(trimethylsilyl)ethynyl]thiazol-4-yl]-methanol.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:10])(=[S:9])[CH3:8].[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19][C@H:18]1[CH2:27][CH2:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)=[O:16])[CH:12]=[CH2:13]>CN(C)C=O>[C:7]([S:9][C@@H:20]1[CH2:21][N:17]([C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[C@H:18]([CH2:27][CH2:28][C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[CH2:19]1)(=[O:10])[CH3:8]
Reactant: CC(O)=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCc1nccn1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCc1nccn1C
Temperature: 0 °C

Procedure:
To a solution of potassium t-butoxide (2.32 g) in N,N-dimethylformamide (25 ml) was added dropwise thioacetic acid (1.48 ml) with stirring at -10°~-5° C. and the mixture was stirred at -5°~0° C. for 10 minutes. To a solution of (2R,4R)-1-allyloxycarbonyl-2-[2-(1-methylimidazol-2-yl)ethyl]-4-methanesulfonyloxypyrrolidine (5.69 g) in N,N-dimethylformamide (55 ml) was added the mixture obtained above with stirring at ambient temperature. The mixture was stirred at 80°-90° C. for 3 hours. The reaction mixture was poured into ice-water (100 ml) and extracted three times with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo, the resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-[2-(1-methylimidazol-2-yl)ethyl]pyrrolidine (3.20 g).
Reaction SMILES: C(=N[C@H](C)C(C1C=CC=CC=1OC)(C1C=CC=CC=1OC)O)C1C(=CC=CC=1)O.[CH3:30][C:31](=[CH:33][CH:34]=[C:35]([CH3:37])[CH3:36])[CH3:32].C1(NN)C=CC=CC=1.[N+](=[CH:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[N-]>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:53][CH2:52][O:51][C:49]([CH:48]1[C:35]([CH3:37])([CH3:36])[CH:34]1[CH:33]=[C:31]([CH3:32])[CH3:30])=[O:50]
Reactant: CC(C)=CC=C(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: COc1ccccc1C(O)(c1ccccc1OC)[C@@H](C)N=Cc1ccccc1O
Solvent: O
Solvent: NNc1ccccc1
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
22.6 mg (0.05 mmol) of copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate-mono hydrate and 21.5 mg of (R)-N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)propanol, and 6.0 g (55 mmol) of 2,5dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk's tube wherein the atmosphere is substituted with nitrogen, followed by the addition of 5.4 mg of phenylhydrazine, and 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise at 80° C. over 2 hours. After the completion of the dropwise addition of ethyl diazoacetate, the mixture was further stirred at 25° C. for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.76 g and the yield was 90.0% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 58/42. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51° C./30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100° C. for 1 hour. The resulting chrysanthemic acid was reacted with I-menthol and the formed diastereomer was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 63% e.e., whereas, the optical purity of the (+)-cis isomer was 63% e.e.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:22][CH3:23])=[O:20])=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:24][C@H:21]([CH2:22][CH3:23])[C:19]([NH:18][C:15]1[CH:14]=[N:13][C:12]([O:11][C:6]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[N:17][CH:16]=1)=[O:20]
Reactant: CCOc1cc(Oc2ncc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn2)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(Oc2ncc(NC(=O)[C@H](N)CC)cn2)ccc1C
Temperature: 0 °C
Yield: 105.9 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-1-{[(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)amino]carbonyl}propyl)carbamate (Intermediate 93, 80 mg) in dichloromethane (1 mL) cooled to 0° C., TFA (573 μl, 7.43 mmol) was added dropwise. The mixture reaction was stirred at 0° C. for 1.5. The solvent and the TFA were evaporated. The mixture was diluted with dichloromethane and an aqueous saturated solution of NaHCO3. The organic layer was separated, dried over sodium sulphate, filtered end evaporated to afford the title compound (65 mg) which was directly used in the next step.
Reaction SMILES: Br[CH2:2][CH:3]([CH2:13]Br)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[OH-].[Na+].C(OCC)(=O)C>ClCCl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:2]=[C:3]1[CH2:13][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]1=[O:5]
Reactant: O=C(Nc1ccccc1)C(CBr)CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C=C1CN(c2ccccc2)C1=O
Reaction time: 7 h
Yield: 104.3 %

Procedure:
16.05 g (50 mmol) 3-Bromo-2-bromomethyl-N-phenylpropionamide were dissolved in 250 ml dichloromethane and added to a solution of 30 g sodium hydroxide in 30 ml water. 1.6 g Benzyltriethylammonium chloride were added and the mixture was vigorously stirred for 7 hours. The suspension was then poured on 200 ml ethyl acetate, and the organic phases were separated, washed twice with 150 ml water and dried over magnesium sulfate. Evaporation of the solvent yielded 8.3 g of an oil which was purified by chromatography on silica gel (eluent: dichloromethane). Yield: 8.0 g (100%) M.p. 57°-58° C. Microanalysis: C10H9NO calc. C 75.45 H 5.70 N 8.80 found C 75.06 H 5.76 N 8.71
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([F:41])[CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:36]=[C:35]([F:34])[CH:40]=[C:39]([F:41])[CH:38]=4)(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cc(F)cc(F)c3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3,5-difluorobenzene-1-sulfonyl chloride (38.26 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 25 mg (35%); 1H NMR (CDCl3, 300 MHz): δ 9.553 (s, 1H), 8.002-8.032 (d, 1H, J=9 Hz), 7.752-7.798 (m, 4H), 7.664-7.701 (dd, 1H, J=8.7, 2.1 Hz), 7.466-7.495 (d, 2H, J=8.7 Hz), 7.175 (m, 1H), 7.002-7.009 (d, 1H, J=2.1 Hz), 1.831 (s, 6H); MS: m/z 583 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][SiH3:22])[CH:16]=1)[C:8]2=[O:13])([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][SiH3:22])[CH:16]=1)[C:8]2=[O:13]
Reactant: O=C1c2cccc([N+](=O)[O-])c2CN1Cc1cccc(C[SiH3])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1CN(Cc1cccc(C[SiH3])c1)C2=O
Reaction time: 20 h

Procedure:
A solution of 4-nitro-2-[3-(silylmethyl)benzyl]-1-isoindolinone (5.2 g, 12.5 mmol) in tetrahydrofuran (60 ml) is, in the presence of palladium (10% on carbon, 375 mg), stirred under an atmosphere of hydrogen for 20 h and filtered, and the filtrate is concentrated under reduced pressure. The desired product is purified by flash chromatography (cyclohexane/ethyl acetate mixtures). Yield: 3.8 g, 79% of theory.