Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH2:7][C:8]([OH:10])=[O:9].[C:11](=[O:14])([O-])[O-].[K+].[K+].[C:17]1(C)[CH:22]=CC=[CH:19][CH:18]=1>>[O:14]1[CH2:11][CH2:19][CH2:18][CH2:17][CH:22]1[O:9][C:8](=[O:10])[CH2:7][Cl:6]
Reactant: O=C(O)CCl
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(CCl)OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 185 g (2.2 mol) 3,4-dihydro-2H-pyrene, 200 ml toluene and 0.2 ml concentrated sulfuric acid is added dropwise over a period of 15 min at a temperature of 15° C. with a solution of 142 g (1.5 mol) chloroacetic acid in 500 ml toluene. During the addition ice-cooling is provided. After finishing the addition of the chloroacetic acid solution the reaction mixture is stirred 2 hours at room temperature. 15 g anhydrous potassium carbonate are added for stabilizing purposes. The reaction mixture thus stabilized then is evaporated in a rotating evaporator at 45° C. applying the vacuum of a water-jet vacuum pump. Having thus stripped off the lower boiling volatile components a mixture of the tetrahydropyranyl ester and potassium carbonate in an amount of 283 g is obtained as a residue. Based on the chloroacetic acid the yield is 100%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)=[CH:5][CH:4]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O.CCOC(C)=O>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=2[N:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[CH:8][CH:7]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCN(C)CC4)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 5 %

Procedure:
To a stirred solution of 6-(4-(bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in dry DMF, 1-methylpiperazine (5 equiv.) was added at 0° C. and reaction mixture was stirred for overnight. After completion of reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by column chromatography/preparative HPLC to give the desired compound (5% yield). LCMS: 528.25 (M+1)+; HPLC: 98.21% (@ 254 nm) (Rt; 4.802); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.94 (bs, 1H), 8.36 (s, 1H), 8.19 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 7.46 (d, J=7.6 Hz, 2H), 5.89 (s, 1H), 5.33-5.30 (m, 1H), 4.41 (d, J=4 Hz, 2H), 3.52 (s, 3H), 2.30-2.45 (m, 7H), 2.21 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 1.54 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([O:15][C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[CH2:24][C@@H:25]([OH:27])[CH3:26])[CH:19]=[N:20][CH:21]=1)([CH3:14])[CH3:13]>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:27][C@H:25]([CH2:24]/[CH:23]=[CH:22]/[C:18]2[CH:19]=[N:20][CH:21]=[C:16]([O:15][CH:12]([CH3:14])[CH3:13])[CH:17]=2)[CH3:26])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)Oc1cncc(/C=C/C[C@H](C)O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cncc(OC(C)C)c2)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, p-toluenesufonyl chloride (11.45 g, 60.06 mmol) was added to a stirring solution of (2S)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol (7.00 g, 31.63 mmol) in dry triethylamine (30 mL) at 0° C. After stirring and warming to ambient temperature over 18 h, the mixture was concentrated on a rotary evaporator. The crude product was stirred with saturated NaHCO3 solution (100 mL) for 1 hour and extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford 10.00 g (84.2%) as a dark-brown oil, which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:23]5[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=5)[CH2:22][CH2:21][N:20]([CH3:30])[CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(C2CC2)cc2cn[nH]c12
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(C2CC2)cc2cn[nH]c12
Reaction time: 0.08 h

Procedure:
To a suspension of (±)-5-cyclopropyl-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole (13.5 mg, 0.036 mmol) and sodium cyanoborohydride (11.2 mg, 0.178 mmol) in acetonitrile (1 mL) at 0° C. was added formalin (0.027 mL). The reaction was treated with 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the ice bath was removed, stirring continued for another hour. The reaction was diluted with diethyl ether and washed with 1 M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. It was then purified by column chromatography (10% 2 M ammonia in MeOH/CH2Cl2) to give 10.5 mg (46.5%) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 9.63 (bs, 1H), 7.86 (s, 1H), 7.23-7.27 (m, 3H), 7.03-7.07 (m, 2H), 6.78 (s, 1H), 4.47 (q, J=5.0 Hz, 1H), 3.35 (d, J=10 Hz, 1H), 3.24 (d, J=5 Hz, 1H), 2.55-2.70 (m, 2H), 1.91-2.30 (m, 9H), 1.40 (d, J=10.0 Hz, 3H), 0.9-0.94 (m, 2H), 0.62-0.68 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 161.5 (d, J=978 Hz), 136.2, 135.9, 133.9, 128.8, 125.9, 124.3, 123.3, 115.8, 115.6, 115.4, 78.9, 51.9, 51.7, 46.1, 40.3, 32.4, 32.3, 22.4, 15.4, 8.7; Mass spec.: 408.09 (MH)+.
Reaction SMILES: CO.[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:23]([OH:25])=[O:24])[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:27][O:24][C:23](=[O:25])[C@H:14]([CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:13][C:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(N[C@@H](CSc1ccccc1)C(=O)O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 1974 %

Procedure:
In a nitrogen atmosphere, 150 ml of methanol was added to 30.01 g of N-benzyloxycarbonyl-S-phenyl-L-cysteine and 864 mg of p-toluenesulfonic acid monohydrate, and the reaction was allowed to proceed under reflux. After 6 reaction hours, the mixture was cooled to about 50° C., and the pH was adjusted to 5.5 by adding 8 ml of a 5% (by weight) aqueous solution of sodium hydrogen carbonate. Then, the methanol was replaced with toluene at about 50° C., to give 103.87 g of a toluene-substituted reaction mixture containing 30.97 g (concentration: 29.8% by weight; yield: 99%; optical purity: 99.7%) of N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester (Example 4). Then, 15 ml of pure water was added to this toluene-substituted reaction mixture at room temperature, and the mixture was stirred for 15 minutes and then allowed to stand, whereupon the aqueous phase formed a large number of droplets, which remained dispersed or settled in the organic phase but did not unite with one another. This procedure thus failed to form two layers, namely the upper and lower layers, separable from each other, hence to enable phase separation (Reference Example 2).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([Cl:8])(Cl)=[O:6].[F:9][CH:10]([F:25])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([CH:22]([CH3:24])[CH3:23])C(O)=O)=[CH:14][CH:13]=1>>[F:9][CH:10]([F:25])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([CH:22]([CH3:23])[CH3:24])[C:5]([Cl:8])=[O:6])=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Solvent: O=S(Cl)Cl
Product: CC(C)[C@H](C(=O)Cl)c1ccc(OC(F)F)cc1
Reaction time: 3 h

Procedure:
Add 1-3 moles of thionyl chloride or phosgene into (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid, and allow the mixture to react at 10° C. to reflux temperature of the solvent for 0.1-100 hours, preferably for 1-5 hours. After the reaction is completed, distill off the unreacted thionyl chloride or phosgene to give the (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyryl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[C:17]([C:20]#[N:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH:27]1[CH2:29][CH2:28]1)=[O:25].Cl.Cl[CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:9][C:6]1[CH:5]=[CH:4][C:3]([NH:23][C:24]([NH:26][CH:27]2[CH2:28][CH2:29]2)=[O:25])=[C:2]([CH3:1])[C:7]=1[CH3:8])#[N:21]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Reactant: ClCCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OCCCN4CCCC4)c(C#N)cc23)c1C
Temperature: 60 °C
Yield: 38.1 %

Procedure:
After adding the N-[2,3-dimethyl-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-cyclopropylurea (100 mg) synthesized in Example 721, 1-(3-chloropropyl)pyrrolidine hydrochloride (95 mg) and potassium carbonate (150 mg) to dimethylformamide (2 ml), the mixture was heated at 60° C. for 7 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (49 mg) as light yellow crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:19][C@H:11]2[CH2:12][N:13]([C:15](=[O:18])[NH:16][CH3:17])[CH2:14][C@@:10]2([C:20]([N:22]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[CH:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:19][C@H:11]2[CH2:12][N:13]([C:15]([NH:16][CH3:17])=[O:18])[CH2:14][C@@:10]2([C:20]([N:22]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[CH:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9]1
Reactant: CNC(=O)N1C[C@@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1C[C@@H]2C[C@@H](N)C[C@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A solution of the product from Step A (0.08 g, 0.156 mmol) in TFA (1.5 mL) and DCM (1.5 mL) was stirred at rt for 1.5 h. The volatile organic compounds were removed by evaporation, and the residue was diluted with DCM and evaporated again to give the product as a TFA salt. LC/MS: C19H24F3N5O2: m/z 412.5 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CC(C1C=CC(C2C=CC(OC)=CC=2)=CC=1)C(OCC)=O>>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(OC(C)=O)cc2)cc1
Agent: CCOC(=O)C(C)c1ccc(-c2ccc(OC)cc2)cc1
Product: CC(=O)Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
The title compound is prepared using the method of part B of Example 16 substituting 4-acetoxy-4'-methoxy-1,1'-biphenyl for α-methyl-4'-(methoxy)[1,1'-biphenyl]-4-acetic acid, ethyl ester. Normal workup affords a white solid, m.p. 204°-207° C.; MS (EI m/z): 212 (M)+, 197 (b.p.,M--CH3)+.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].[CH2:11]([C:14]#[N:15])[CH2:12]Br.Cl.O.O1CCOC[CH2:19]1>>[OH:4][C:3]1[CH:10]=[CH:9][C:7]([O:8][CH2:19][CH2:12][CH2:11][C:14]#[N:15])=[CH:6][CH:5]=1
Reactant: Oc1ccc(O)cc1
Reactant: C1COCCO1
Reactant: N#CCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCCCOc1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.7 g of NaOH in 80 ml of H2O:dioxane 1:1, 2.2 g (20 mmol) of hydroquinone are added. The solution is stirred for 15 min. Then, 3.5 g (24 mmol) of 3-bromopropanitrile is dropwise added. After complete addition, the mixture is heated up to reflux and stirred for 24 hours. 45 mL of a 1N HCl solution is added to the above mixture. The solution is extracted with ethylacetate and concentrated under reduced pressure to give 2.8 g of 4-(4-hydroxyphenoxy)butanenitrile which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=O)=O)=[CH:4][CH:3]=1.Cl.[NH2:13][C:14]1[N:18]([NH2:19])[C:17]([CH3:20])=[N:16][N:15]=1.[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:10]=[N:19][N:18]3[C:17]([CH3:20])=[N:16][N:15]=[C:14]3[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1nnc(N)n1N
Reactant: O=CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc2nc(-c3ccc(Cl)cc3)cnn12

Procedure:
A solution of 7.8 g. of p-chlorophenylglyoxal, 6.3 g. of 3,4-diamino-5-methyl-4H-1,2,4-triazole hydrochloride and 1.7 g. of sodium hydroxide in 90 ml. of 67% acetic acid is heated on a steam bath for 1/2 hour. Water is added and heating is continued until yellow crystals separate. These crystals are collected by filtration and washed with hot ethanol, giving the desired product as a yellow solid, m.p. 240° C. (dec.).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.OCCS(C1C=C(C=CC=1)[NH2:35])(=O)=O.[N+:39]([C:42]1[CH:43]=[C:44]([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=1)([O-])=O>>[S:49]([CH2:48][C:44]1[CH:43]=[C:42]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:47]=[CH:46][CH:45]=1)(=[O:51])(=[O:50])[NH2:35]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Product: NS(=O)(=O)Cc1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-(2-hydroxy-ethanesulfonyl)-aniline [CAS-Nr. 344750-15-8; prepared from commercially available 3-nitro-phenylmethane-sulfonyl chloride] according to general procedure II. Yellow solid. MS (ISP) 524.0 [(M−H)−]; mp 280° C.
Reaction SMILES: [I:1]I.C([Sn](CCCC)(CCCC)[C:8]1[CH:9]=[C:10](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][F:23])CCC.C(Cl)Cl>C1COCC1>[I:1][C:8]1[CH:9]=[C:10](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][F:23]
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(/C=C/c2ccc(N(C)C)cc2)cnc1OCCOCCOCCF
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)c1ccc(/C=C/c2cnc(OCCOCCOCCF)c(I)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of iodine (I2, 0.063 g, 0.24 mmol) in THF (2 mL) was added dropwise to an ice bath cooled solution of 12a (0.114 g, 0.172 mmol) in THF (3 mL). After the addition, the reaction was stirred at 0° C. for 1 h. Following standard workup with CH2Cl2, the crude product was purified by FC (EtOAc/Hexanes, 25/75) to give a light yellow solid 13a (0.037 g, 48%). 1H NMR δ8.22 (d, 1H, J=2.1 Hz), 8.10 (d, 1H, J=2.1 Hz), 7.38 (d, 2H, J=8.8 Hz), 6.92 (d, 1H, J=16.3 Hz), 6.72 (d, 1H, J=16.3 Hz), 6.71 (d, 2H, J=8.8 Hz), 4.72-4.67 (m, 1H), 4.54-4.44 (m, 3H), 3.93-3.69 (m, 8H), 3.00 (s, 6H). 13C NMR δ 160.4, 150.5, 144.6, 144.55, 129.8, 129.5, 127.8, 125.3, 118.8, 112.6, 85.1, 81.7, 80.6, 71.3, 71.1, 70.8, 70.5, 69.6, 67.1, 40.6. HRMS calcd for C21H26FIN2O3 (M+), 500.0972. found, 500.0959.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[N:7]/[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][O:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH:26]=O.[O-:28][CH2:29][CH3:30].[Na+].C(O)C>C(OCC)(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[CH:26]([C:22]3[N:21]([CH3:20])[CH:25]=[CH:24][N:23]=3)[C:29](=[O:28])[C:30]3[C:13]([C:12]([O:11][CH2:10][CH3:9])=[O:17])=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7]2)=[CH:18][CH:19]=1
Reactant: Cn1ccnc1C=O
Reactant: O=C1OCc2c(/N=C/c3ccc(Cl)cc3)cccc21
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(Cl)cc1)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture of (E)-4-(4-chlorobenzylideneamino)isobenzofuran-1(3H)-one (500 mg, 1.85 mmol) and N-methyl-2-imidazolecarbaldehyde (222 mg, 2.1 mmol) in ethyl propionate (20 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (174 mg, 7.4 mmol) in ethanol (10 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the title compound (150 mg, yield 20%). LC-MS (ESI) m/z: 410 (M+1)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:11]=1[NH2:18].[C-:19]#[N:20].[K+]>[Cl-].[Zn+2].[Cl-].O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:11]=1[NH:18][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]#[N:20]
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Reactant: [C-]#N
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [Zn+2]
Solvent: O
Product: N#CC(Nc1cc(Cl)c(Cl)cc1Cl)c1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 53 parts of benzaldehyde in 820 parts of water are added successively 78.6 parts of 2,4,5-trichlorobenzenamine, 81.8 parts of zinc chloride and 32.6 parts of potassium cyanide and the whole is stirred for 18 hours at 50° C. The reaction mixture is cooled to room temperature. The precipitated product is filtered off, triturated in 1000 parts of water, filtered off again and dissolved in 750 parts of trichloromethane. The solution is washed twice with water, dried, filtered and evaporated. The solid residue is triturated in petroleum ether, filtered off again and dried, yielding 83.1 parts of α-[(2,4,5-trichlorophenyl)amino]benzeneacetonitrile; mp. 123.7° C.
Reaction SMILES: N[C@H](C(O)=[O:11])CC1C=CC=CC=1.C1C(N)=NC(=O)N([C@@H]2O[C@H](COP(OCCCCCCCCCCCCCCCC(O)=O)(O)=O)[C@@H](O)[C@@H]2O)C=1.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H]([O:96][C@H:97]2[O:102][C@H:101]([CH2:103][OH:104])[C@@H:100]([OH:105])[C@H:99](N)[C@H:98]2[OH:107])[C@@H]1N>>[O:104]=[CH:103][C@@H:101]([C@H:100]([C@@H:99]([C@@H:98]([CH2:97][OH:96])[OH:107])[OH:11])[OH:105])[OH:102]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)OCCCCCCCCCCCCCCCC(=O)O)[C@@H](O)[C@@H]2O)c(=O)n1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Two strains (designated as WWQ51.1 and WSQ1) were constructed from the E. coli phenylalanine overproducing strain E. coli NST74 by transformation with pCA16 and pKSM-pdc1 and selection for ampicillin and kanamycin resistance, as described in Example 4. Since preliminary experiments showed similar patterns for both constructs, we chose strain WWQ51.1 for further studies.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13]CC1C2SC3C(=CC=CC=3)C(=O)C=2C(NCCN(CC)CC)=CC=1.O.[OH-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,4-dichlorobenzenesulfonyl chloride (1.84 g, 7.5 mmol) in 35 mL of dry pyridine was added 2.5 g (7 mmol) of 4-(aminomethyl) -1-[[2-(diethylamino)ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) under nitrogen and the reaction mixture was stirred at room temperature for 15 min. and then was allowed to stand for approximately 72 hours. The reaction mixture was poured into 75 mL of water containing 0.75 g of NaOH, and extracted into chloroform. The organic layer was washed with water (2×) and brine, and dried over sodium sulfate. Chloroform was removed in vacuo, the residue was recrystallized from ethanol to afford 1.24 g of N-[[1-[[2-(diethylamino) ]ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-3,4-dichlorobenzenesulfonamide, m.p. 95° C. (dec.). The free base was dissolved in methanol and treated with methanesulfonic acid in methanol to afford the methanesulfonate.1/2hydrate, m.p. 55° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=1.CC1(C)C2C(=CC=C(C)C=2)NC(C2C=C(N)C=CC=2)C1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:36]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)(=[O:38])=[O:37])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Agent: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccnc3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.47 mmol) in pyridine (0.74 mg, 0.94 mmol) and dichloromethane (3 mL) at 0° C. was added dropwise a solution of pyridine-3-sulfonyl chloride (100 mg, 0.56 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight. Thin layer chromatography and LC-MS indicated that 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine was consumed completely. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford pyridine-3-sulfonic acid [3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (170 mg, 78.7%) as a white solid. MS (ESI+APCI) M+1=442.3.