Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27]C)[CH:21]=4)[CH2:18][C:17](=[O:29])[NH:16][C:15]=3[CH3:30])=[O:13])[CH:9]=2)[NH:4][N:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O.O.[OH-].[Na+]>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:19]2[CH2:18][C:17](=[O:29])[NH:16][C:15]([CH3:30])=[C:14]2[C:12]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[Cl:1])=[O:13])=[CH:21][C:22]=1[OH:27]
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]nc(Cl)c3c2)ccc1Cl
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(Cl)c(O)c2)CC(=O)N1
Temperature: 35 °C
Reaction time: 90 h
Yield: 22.1 %

Procedure:
The product of Example 93, Step 5 (75 mg, 0.168 mmol, 1.0 equiv) was cooled to −78° C. in 1.75 mL CH2Cl2 and BCl3 (1.0 M in CH2Cl2, 2.5 mL, 2.526 mmol, 15.0 equiv) was added dropwise. The reaction was warmed to 35° C. and stirred for 90 hours. An additional portion of BCl3 (2.5 mL, 2.526 mmol, 15.0 equiv) in CH2Cl2 was added dropwise and the reaction was stirred for another 96 hours. The reaction mixture was diluted with EtOAc and water and basified to pH 14 with 6N NaOH. The phases were separated, and the aqueous phase was acidified to pH 4 with 6N HCl. The precipitate was filtered and washed with Et2O. The residue was purified by reverse-phase HPLC (10-90% CH3CN/H2O, 0.1% TFA over 18 minutes, retention time 10.55 min) to provide 16 mg (22%) of the title compound as a white solid. MS (ES+) m/e 432 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.C(N(C(C)C)CC)(C)C.Br[CH2:25][C:26](Cl)=[O:27].C(=O)([O-])[O-].[K+].[K+].[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:37])[CH3:36]>ClCCl>[CH3:36][CH:35]([N:38]1[CH2:43][CH2:42][N:41]([CH2:25][C:26]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=3)[CH2:6][CH2:7]2)=[O:27])[CH2:40][CH2:39]1)[CH3:37]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: CC(C)N1CCNCC1
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN1CCN(C(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.5 g, 2.57 mmols) and polymer-bound diisopropyl ethylamine (2.10 g, 7.73 mmol) in dichloromethane (50 mL) was added bromoacetyl chloride (0.49 g, 3.11 mmol) via a dropwise addition. After stirring for two hrs at room temperature, the solids were removed by vacuum filtration. The filtrate was concentrated under reduced pressure, maintained under high vacuum for several hours, redissolved in THF (20 mL) and to this crude mixture was added potassium carbonate (1.06 g, 7.68 mmols), catalytic Kl, and isopropyl piperazine (0.99 g, 7.68 mmols). After overnight stirring, the reaction was diluted with dichloromethane (50 mL), washed with water (25 mL), filtered through a cotton plug and concentrated by rotary evaporation to provide 1-{[4-(1-methylethyl)-1-piperazinyl]acetyl}-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.60 g, 64% yield). ESIMS (M+H)+=363.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:27][CH:28]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:29]1([C:26]2[S:27][CH:28]=[C:24]([CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:8]4[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[N:7]4)=[CH:36][CH:35]=3)[N:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-carboxylate (5.60 g), 4-(4-chloromethylphenoxy)methyl-2-phenylthiazole (7.96 g), potassium carbonate (6.98 g), and N,N-dimethylformamide (75 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (10.93 g, yield: 87%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 94˜95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:9]=[C:8]([F:10])[CH:7]=1)#[N:6]
Reactant: N#Cc1cc(N)cc(F)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1cc(F)cc(C#N)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 56 %

Procedure:
3-amino-5-fluorobenzonitrile (0.111 g, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.1 g, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.052 g, 55%) as a white solid. Mass Spectrum: M+H+ 465.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 4-(3-bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (48 mg, 37%)
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:23]=1[N:37]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=[CH:38]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:15]([C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:2]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([N:37]5[C:46](=[O:47])[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[N:39]=[CH:38]5)[C:22]=4[CH3:21])=[N:3][CH:4]=[C:5]([C:19]#[N:20])[C:6]=3[NH:7][C:8]=2[CH:9]=1)=[O:16]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1cnc2ccccc2c1=O
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(Cl)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Temperature: 110 °C
Yield: 39 %

Procedure:
A stirred mixture of methyl 1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate (0.285 g, 0.998 mmol), 3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one (0.361 g, 0.998 mmol), Tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.050 mmol) and Sodium carbonate[2M] (0.499 mL, 0.998 mmol) in Dioxane (2 mL) was heated at 110° C. for 16 hours overnight. LC-MS showed complete conversion to the desired product mass plus residual starting material[boronic ester] and a byproduct. The reaction mixture was concentrated. The residue was taken up in 10 ml DMF, stirred and filtered. The filtrate was concentrated; the residue triturated with methanol and filtered. The solid residue was dried overnight. LC-MS showed the solid residue to be the desired product methyl-4-cyano-1-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-5H-pyrido[4,3-b]indole-7-carboxylate as a tan solid [0.192 g, 0.395 mmol, 39% yield]. The product had an HPLC Retention Time=3.521 min [mixture of rotamers][4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 486.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[S:15])[NH2:14])[CH:10]=[N:9]2)=[CH:5][CH:4]=1.Br[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].N1C=CC=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[S:15][CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]=3)[CH:10]=[N:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2cc(C(N)=S)cn2)cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(-c2cnn(Cc3ccc(OC)cc3)c2)n1
Yield: 57.7 %

Procedure:
According to Scheme 1 Step 5: A solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide (26.7 mmol, 6.60 g), ethyl 3-bromo-2-oxopropanoate (29.4 mmol, 4.62 mL) and pyridine (29.4 mmol, 2.37 mL) in acetone (53 mL) was stirred at room temperature for 2 hours and at 45° C. for 52 hours. After evaporation, the crude residue was partitioned between EtOAc and a saturated solution of Na2CO3. The aqueous phase was extracted with EtOAc and then with DCM. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel using DCM/EtOAc (100:0 to 70:30) to yield ethyl 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate (15.4 mmol, 5.28 g, 58%) as a dark oil.
Reaction SMILES: [NH2-].[Na+].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[CH:13]=[C:14]([CH3:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].CO>O1CCCC1>[CH2:3]([NH:10][C:15]1[CH:16]=[C:17]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C)cc1Br
Agent: [NH2-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C)c(NCc2ccccc2)c1
Temperature: 60 °C

Procedure:
20.3 g (0.520 mol) of sodium amide was added to 140 g (1.31 mol) of benzylamine under an argon atmosphere. After stirring under cooling with ice for 20 minutes, a solution of 34.84 g (0.129 mol) of 3-bromo-4-methoxytoluene dissolved in 220 ml of tetrahydrofuran was added dropwise over 90 minutes. The reaction mixture was heated to 60° C. and stirred for 60 minutes. Methanol was added under cooling with ice, followed by further addition of ice water. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized (chloroform-n-hexane) to obtain 26.96 g (yield, 68.4%) of colorless needles of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:11][C:12]([F:19])([F:18])[C@H:13]([OH:17])[CH2:14][O:15][CH3:16]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][C@H:13]([CH2:14][O:15][CH3:16])[C:12]([F:19])([F:18])[F:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: COC[C@@H](O)C(F)(F)F
Reactant: N#Cc1cnc(N)cc1F
Product: COC[C@@H](Oc1cc(N)ncc1C#N)C(F)(F)F

Procedure:
From intermediate 21 and (R)-1,1,1-trifluoro-3-methoxypropan-2-ol, reacted in an analogous manner to the preparation of intermediate 68. UPLC-MS 3: Rt=0.75 min; MS m/z [M+H]+ 262.1;
Reaction SMILES: O.S(=O)(=O)(O)O.[F:7][C:8]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][C:9]=1[NH2:10].[C:16]1([C:22](O)([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[F:7][C:8]1[CH:14]=[CH:13][C:12]([S:15][C:22]([CH3:24])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])=[CH:11][C:9]=1[NH2:10]
Reactant: Nc1cc(S)ccc1F
Reactant: CC(C)(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Sc1ccc(F)c(N)c1)c1ccccc1
Temperature: 0 °C
Yield: 45.9 %

Procedure:
To a mixture of water (10 mL) and concentrated sulfuric acid (10 mL) were added 2-fluoro-5-mercaptoaniline (1.85 g) and a solution of 2-phenyl-2-propanol (1.76 g) in tetrahydrofuran (10 mL) successively at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1−3/1) to give the title compound (1.55 g).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>>[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1
Reactant: COc1cccc(Cc2nnc(SC)[nH]c2=O)c1
Reactant: NCCSCc1nccs1
Product: COc1cccc(Cc2nnc(NCCSCc3nccs3)[nH]c2=O)c1
Yield: 47.6 %

Procedure:
3-Methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.18 g) and 2-(2-thiazolylmethylthio)ethylamine (0.87 g) were heated together on an oil bath (160°-70°) for 3/4 hour. The resulting oil, after chromatography and crystallisation from ethanol, gave the title compound as a colourless solid (0.83 g) m.p. 128°-29°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.C(OP([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(OCC)=O)C.[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](/[CH:11]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44 %

Procedure:
3-Quinolinecarbaldehyde (5.03 g) was added to a mixture of ethyl diethylphosphonoacetate (9.31 g) and NaH (60% oil dispersion,0.791 g) in THF under ice cooling. The mixture was stirred at room temperature for 14 hours. To the mixture were added water and ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate=10:1) followed by crystallization from CH2Cl2-cyclohexane to give the titled compound (3.20 g) as a colorless solid.
Reaction SMILES: C(O)(C)C.[O:5]([CH3:7])[Na].[CH3:8][C:9]1[C:14](C)=[CH:13][CH:12]=[C:11]([CH3:16])[C:10]=1[OH:17].C(OO)(C)(C)C>CO.O>[CH3:13][C:14]1[C:7](=[O:5])[CH:12]=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:8]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: CO[Na]
Agent: CC(C)(C)OO
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Temperature: 70 °C
Yield: 99.7 %

Procedure:
10 g of HCL gas were passed into 400 ml of isopropanol at room temperature, 4 g (0.028 mole) of Cu2O were added to the resulting solution, the mixture was heated at 70° C. and 75 liters/hour of air were passed in for 4 hours. Thereafter, 24 ml of a 30% strength solution of NaOCH3 in CH3OH were added at room temperature (a sample has a pH of 4.2 after water had been added), followed by the addition of 28 g (0.2 mole) of 2,3,6-trimethylphenol, the mixture was heated at 40° C. and 18 g (0.2 mole) of tert.-butyl hydroperoxide were then added in the course of 2 hours. At the same time, 75 liters/hour of air were passed into the reaction mixture. After a reaction time of 12 hours, the mixture was worked up as described in Example 1 to give 22.54 g of 99.7% pure 2,3,5-trimethyl-p-benzoquinone. The yield was thus 76% of theory.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>CO>[F:18][C:5]1[C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]([OH:1])=[N:3][C:4]=1[CH3:16]
Reactant: COC(=O)c1ccc2cc(C)nc(O)c2c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1ccc2c(F)c(C)nc(O)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.3 %

Procedure:
A mixture of methyl 1-hydroxy-3-methylisoquinoline-7-carboxylate (120 mg), Selectfluor (registered trademark) (215 mg), acetonitrile (2 mL), and methanol (2 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water. Then, the precipitate was collected by filtration to obtain methyl 4-fluoro-1-hydroxy-3-methylisoquinoline-7-carboxylate (55 mg).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[CH2:8]([Li])[CH2:9]CC.C(OCC)(=O)C.[CH:19]([N:22](C(C)C)[C:23]([C:25]1C=C[C:32]2[C:27](=C[CH:29]=[C:30]([C:35]([C:37]3[N:38]=[CH:39][N:40](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:41]=3)=[O:36])[CH:31]=2)[CH:26]=1)=[O:24])(C)C>C1COCC1.O>[OH:36][C:35]1([C:30]2[CH:31]=[C:32]3[C:1](=[CH:3][CH:29]=2)[CH:2]=[C:25]([C:23]([NH:22][CH3:19])=[O:24])[CH:26]=[CH:27]3)[C:37]2[N:38]([CH:39]=[N:40][CH:41]=2)[CH2:9][CH2:8]1
Reactant: CC(C)NC(C)C
Reactant: [Li]CCCC
Reactant: CC(C)N(C(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
Dry THF (600 ml) containing diisopropylamine (21.3 ml) was cooled to −70° C. and n-butyl lithium (1.6 M; 95.0 ml) was added dropwise. The mixture was stirred for 10 min and ethyl acetate (14.9 ml) was added dropwise. The mixture was stirred at the same temperature for 30 min. A solution of N,N-diisopropyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (60.0 g) in dry THF (150 ml) was added dropwise at −70° C. The mixture was stirred at the same temperature for 30 min and the reaction mixture was gradually warmed to −30° C. Water was added to stop the reaction. The organic layer was separated and the aqueous layer was extracted with a THF-toluene (1:1) mixture. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated to give the title compound quantitatively as a pale yellow oil.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:14][O:15][C:16](=[O:21])[C@H:17]([CH3:20])[CH2:18][OH:19].O>CN(C)C=O>[CH3:14][O:15][C:16](=[O:21])[C@H:17]([CH3:20])[CH2:18][O:19][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](C)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
Imidazole (6.44 g, 42.8 mmol) and tert-butyldimethylsilyl chloride (6.05 g, 88.8 mmol) were added to a solution of (R)-3-hydroxy-2-methylpropionic acid methyl ester (5.0 g, 42.33 mmol) in dimethylformamide (50 mL), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with hexane twice. The extract was then dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 9.3 g (95%) of the title compound as a colorless oil.
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([CH:25]([N:27]([CH3:40])[C:28]3[N:32]([CH3:33])[C:31]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[N:30][N:29]=3)[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1.CI>O>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([C:25]([N:27]([CH3:40])[C:28]3[N:32]([CH3:33])[C:31]([C:34]4[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=4)=[N:30][N:29]=3)([CH3:2])[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: [Li]CCCC
Reactant: CC(c1noc(-c2cccc(Cl)c2)n1)N(C)c1nnc(-c2ccncc2)n1C
Solvent: CI
Solvent: O
Solvent: CC(C)NC(C)C
Product: CN(c1nnc(-c2ccncc2)n1C)C(C)(C)c1noc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
n-BuLi (132 ml 2.5 M in hex., 0.33 mmol) was added to diisopropyl amine (55 ml, 0.39 mmol). After stirring for 20 minutes at 0° C. the mixture was cooled to −78° C. and N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine (110 mg, 0.28 mmol) was added. After 15 min. methyl iodide (20 μl, 0.33 mmol) was added and the temperature was raised to r.t. After stirring for 2 h five drops of water were added. After solvent removal in vacuo, the crude was taken up in DCM, washed with water and brine, dried and concentrated. The desired product was obtained by prep. HPLC in 20 mg yield. 1H NMR: 1.7 (s, 6 H) 2.8 (s, 3 H) 3.8 (s, 3 H) 7.5 (t, 1 H) 7.6 (d, 1 H) 7.7 (s, 2 H) 8.0 (d, 1 H) 8.1 (s, 1 H) 8.8 (s, 2 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:24]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
2-Fluorophenylacetic acid (2.96 g, 19.24 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (2.1 ml, 24.05 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-bromoanisole (3.0 g, 16.03 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (3.21 g, 24.05 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (4.0 g, 81% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 11.97(s,1H), 8.01(d, J=1.7Hz, 1H), 7.58(dd, J=8.8,2.3.1Hz, 1H), 7.35(m,1H), 7.23(d, J=7.3 Hz, 1H), 7.17(m, 2H), 6.92(d, J=8.9 Hz, 1H),4.33(s, 2H).