Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.[CH3:52][N:53]([CH3:60])[CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:52][N:53]([CH3:60])[CH:54]1[CH2:59][CH2:58][N:57]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=5)=[O:49])[CH2:38][CH2:39]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:56][CH2:55]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70.3 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added N,N-dimethyl-N-(piperidin-4-yl)amine dihydrochloride (79.4 mg), triethylamine (0.157 ml) and water (0.10 ml), followed by stirring at room temperature for 10 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1, then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (30.6 mg, 70.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[C:14]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(/C=C/C(=O)O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1cccc(OC)c1

Procedure:
A mixture of (E)-3-(3-methoxyphenyl)acrylic acid (3.56 g, 20 mmol). K2CO3 (3.1 g, 22 mmol), and iodomethane (4.0 g, 28 mmol) in acetone (20 mL) was heated to 70° C. for 16 hours. The mixture was concentrated and partitioned between water and ethyl acetate to afford the crude title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][O:1][C:30](=[O:31])[NH:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)=[CH:9][CH:8]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Product: COc1ccc(NC(=O)OCCc2ccc(CC(OC(C)C)C(=O)O)cc2)cc1

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][OH:11])[N:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][OH:11])[N:5]=1
Reactant: O=[N+]([O-])c1ccn(CCO)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccn(CCO)n1
Reaction time: 1 h
Yield: 107.9 %

Procedure:
A solution 2-(3-nitro-pyrazol-1-yl)-ethanol (3.46 g, 22.02 mmol) in ethanol (40 mL) was placed in a Parr shaker bottle and treated with 10% palladium on carbon (350 mg). The bottle was then put on the Parr shaker and charged with hydrogen to 50 psi and let shake for 1 h. After this time, the reaction mixture was filtered through celite and the celite washed with ethanol. The filtrate was then concentrated in vacuo and azeotroped with acetonitrile and then chloroform to afford 2-(3-amino-pyrazol-1-yl)-ethanol (3.02 g, >quant.) as a light yellow viscous oil: 1H NMR (300 MHz, DMSO-d6 δ ppm 7.26 (d, J=1.83 Hz, 1H), 5.34 (d, J=2.20 Hz, 1H), 4.76 (t, J=5.31 Hz, 1H), 4.50 (s, 2H), 3.78-3.88 (m, 2H), 3.62 (q, J=5.74 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].C(N(CC)CC)C.[F:37][C:38]([F:44])([F:43])[S:39](Cl)(=[O:41])=[O:40]>ClCCl>[F:37][C:38]([F:44])([F:43])[S:39]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29])(=[O:41])=[O:40]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Yield: 62.1 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (300 mg, 0.765 mmol) was dissolved in dichloromethane (12 mL), and the solution was treated with triethylamine (0.533 mL, 3.83 mmol) and trifluoromethanesulfonyl chloride (0.138 mL, 1.30 mmol) under ice-cooling, followed by purification by flash column chromatography (chloroform/methanol=100/0 to 98/2) to obtain 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (249 mg, yield 62%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:9])([CH2:7][CH3:8])[CH2:5][OH:6].Cl[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:3][C:4]([CH3:9])([CH2:7][CH3:8])[CH2:5][O:6][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=1
Reactant: CCC(C)(C)CO
Reactant: ClCc1cccc(Oc2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(C)(C)COCc1cccc(Oc2ccccc2)n1
Reaction time: 12 h
Yield: 23 %

Procedure:
4.4 Grams of a 45% aqueous sodium hydroxide solution, 100 mg of tetrabutylammonium bromide and 5 ml of toluene were mixed, and to the resulting mixture, a solution of 0.7 g of 2,2-dimethylbutanol and 1.72 g of 2-chloromethyl-6-phenoxypyridine in 10 ml of toluene was added at room temperature under a nitrogen atmosphere. After 12 hours, the reaction solution was poured into hydrochloric acid-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was treated by preparative thin layer chromatography (developing solvent, hexane:ethyl acetate=5:1) to obtain 0.45 g of desired 6-phenoxy-2-pyridylmethyl 2,2-dimethylbutyl ether [present compound (17)] as an oily product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([F:60])=[CH:57][CH:58]=2)[C:53]([CH2:61][C:62]([CH3:65])([OH:64])[CH3:63])=[CH:52]1>CN(C=O)C.CCOC(C)=O>[F:60][C:56]1[CH:55]=[C:54]2[C:59](=[CH:58][CH:57]=1)[N:51]([NH:50][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:10])[CH:52]=[C:53]2[CH2:61][C:62]([OH:64])([CH3:63])[CH3:65]
Reactant: CC(C)(O)Cc1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(CC(C)(C)O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (748 mg, 3.48 mmol) in DMF (30 mL) is treated with HATU (1.3 g, 3.48 mmol) and DIPEA (1.2 mL, 6.96 mmol), and the mixture is stirred at rt for 30 min. 1-(1-Amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol (2.9 mmol) is added and the mixture is stirred at 80° C. for 12 h. The mixture is diluted with EtOAc, washed with saturated aqueous NH4Cl and saturated aqueous Na2CO3, dried (Na2SO4), filtered and concentrated in vacuo to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid [5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide (990 mg, 81%). MS: 420 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.13 (s, 6H), 2.75 (s, 2H), 2.85 (s, 3H), 6.84 (m, 1H), 7.24 (m, 1H), 7.37 (m, 1H), 7.53 (m, 1H), 7.95 (s, 1H), 7.98 (m, 1H), 8.44 (m, 1H), 8.76 (m, 1H), 9.15 (s, 1H).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].[CH3:11][S:12][CH2:13]Cl>CO>[CH3:11][S:12][CH2:13][S:10][C:9]1[CH:8]=[CH:7][O:6][C:5]=1[CH3:4]
Reactant: Cc1occc1S
Reactant: CSCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSCSc1ccoc1C

Procedure:
Into a 25 ml round bottom flask equipped with magnetic stirrer, thermometer, water bath, and reflux condenser is added a solution containing 0.27 g of sodium methoxide (0.005 moles) in 3 ml. absolute methanol. While maintaining the solution at 25° - 30° C, 0.57 g (0.005 moles) of 2-methyl-3-furan thiol in 2 ml of absolute methanol is added thereto. At 25° C, 0.483 g (0.005 moles) of chloromethyl methyl sulfide having the formula:
Reaction SMILES: [CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH2:15][Cl:20])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCON=C(C(=O)CCl)C(=O)OCC

Procedure:
Ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer, 57.5 g.), acetic acid (58.5 ml.) and sulfuryl chloride (20.9 ml.) were treated in a similar manner to that of Example F-(2) to give ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.1 g.), oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2Cl.[OH-].[NH4+:15].N>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[NH2:15]
Reactant: [NH4+]
Reactant: Clc1nc(Cl)c2cccc(Br)c2n1
Agent: N
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Cl)nc2c(Br)cccc12
Reaction time: 1 h
Yield: 68 %

Procedure:
To a slurry of 8-bromo-2,4-dichloroquinazoline (407b; 0.50 g, 1.80 mmol) in 2 mL THF at 0° C. was added ammonium hydroxide, 28% ammonia in water (3.25 mL, 23.39 mmol). The reaction was sealed and the ice/water bath was removed. The heterogeneous reaction was stirred rapidly. In the morning starting material was still evident. 2 mL THF and 1 mL 28% ammonia in water were added and the reaction became homogeneous. After 1 h, reaction was checked and judged complete. The reaction was partitioned between water and DCM. The layers were separated and the aqueous layer was filtered through Celite and the filtrate was extracted 2×DCM and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-chloroquinazolin-4-amine (0.318 g, 1.23 mmol, 68% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (2H, br. s.), 8.24 (1H, d, J=8.4 Hz), 8.14 (1H, d, J=7.6 Hz), 7.42 (1H, t, J=7.9 Hz). m/z (ESI, +ve ion) 257.9/259.9 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[O:17])[N:10]=[C:9]3[C:3]([NH2:27])([CH2:4][O:5]2)[CH2:2]1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:36][C:35]([NH:27][C:3]12[CH2:4][O:5][CH:6]([CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:17])[N:10]=[C:9]31)[CH2:1][CH2:2]2)=[O:37]
Reactant: NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-(epoxymethano)pyrimido[1,2-a]azepine-2-carboxamide (30 mg, 0.080 mmol) in CH2Cl2 (2 mL) was added Et3N (0.056 mL, 0.401 mmol) followed by acetyl chloride (0.05 mL, 0.401 mmol) and the resulting mixture stirred at room temperature for 16 h. The reaction mixture was concentrated and the resulting residue dissolved in methanol (2 mL) and treated with 2M dimethylamine in methanol (0.5 mL). The resulting reaction mixture was stirred at 60° C. for 2 h, cooled and purified by preparative HPLC to afford the title compound as a white solid (9 mg, 27% yield). 1H NMR (500 MHz, CDCl3) δ: 11.92 (s, 1H), 7.39 (brs, 1H), 7.29-7.33 (m, 2H), 7.05-7.09 (m, 2H), 6.13 (s, 1H), 4.59-4.65 (m, 2H), 4.48-4.55 (m, 3H), 4.30 (d, 1H, J=11.9 Hz), 4.10 (d, 1H, J=16.17 Hz), 2.52-2.58 (m, 1H), 2.30-2.36 (m, 1H), 1.82 (s, 3H), 1.75-1.82 (m, 1H), 1.50-1.55 (m, 1H). LCMS (M+H)=417.25. HPLC purity>95%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccccn1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2ccccn2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
The product from Example G ((S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)-propionic acid tert-butyl ester) (4.00 g, 8.64 mmol), 2-pyridylcarbinol (0.92 mL, 9.50 mmol) and triphenylphosphine (2.24 g, 8.64 mmol) were dissolved in 50 mL of dry THF. The solution was cooled in an ice bath under an argon atmosphere and diethyl azidocarboxylate (1.36 mL, 8.64 mmol) was added dropwise over 20 minutes. The ice bath was removed and the solution allowed to stir overnight at room temperature. The solution was concentrated under reduced pressure and partitioned between ethyl acetate and water (100 mL each) and separated. The organic layer was washed with 10% aqueous HCl (2×50 mL), 10% sodium bicarbonate (2×50 mL), brine (2×50 mL), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a foam (4.80 g). The foam was purified by chromatography (silica gel, 1:1.5 ethyl acetate/hexane) to give the product as a white foam (3.90 g, 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=1
Reactant: COc1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-bromo-1-methoxy-4-(trifluoromethyl)benzene (825 mg, 3.23 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 3.23 mmol), potassium carbonate (1.34 g, 9.697 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complex with dichloromethane (1:1) (158 mg, 0.193 mmol) in N,N-dimethylformamide (19 mL) was purged with argon. After 30 minutes, the reaction mixture was heated at 90° C. and stirred for 22 hours before cooling to room temperature and filtering through Celite™, washing with ethyl acetate. The filtrate was concentrated in vacuo to ˜quarter and partitioned between water (100 mL) and ethyl acetate (75 mL). The aqueous layer was extracted with ethyl acetate (2×75 mL). Combined organic layers were washed with water, aqueous lithium chloride solution, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by automated flash chromatography (24 g silica gel) eluting with hexanes:ethyl acetate (gradient 1:0 to 3:1, by volume) to afford the title compound as a clear oil, 1.1 g.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:36])=[C:8]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[S:22]([N:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH3:35])COC)(=[O:24])=[O:23])=[O:16])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=[O:3])[CH3:2]>C(O)(=O)C.O.S(=O)(=O)(O)O>[C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:36])=[C:8]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[S:22](=[O:24])(=[O:23])[NH:25][C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH3:35])=[O:16])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=[O:3])[CH3:2]
Reactant: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Nc1c(C)cc(C)c(COC(C)=O)c1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCc1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2C)c1C
Temperature: 80 °C
Yield: 27.9 %

Procedure:
To a solution of N2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarboxamide (0.78 g, 1.46 mmol) in acetic acid (7 mL) and water (3 mL) was added 2N sulfuric acid (3 drops). The reaction was heated at 80° C. for 4 hours, then allowed to cool to room temperature. The mixture was poured into ice water (50 mL), extracted with ethyl acetate (3×50 mL), washed with saturated sodium chloride (50 mL), dried (MgSO4), then concentrated. The residue was purified by reverse-phase HPLC (20-80% acetonitrile in water) which gave N2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide (0.2 g, 28%) as an off-white powder, mp 75-77° C. 1H NMR (400 MHZ, DMSO-d6δ7.84 (d, J=5.12 Hz, 1H), 7.34 (d, J=5.12 Hz, 1H), 7.00 (s, 1H), 5.12 (s, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.65 (s, 3H) IR (KBr) 3458, 1738, 1646, 1356, 1181 cm−1. And N2-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide (45 mg, 6.9%), ratio 4:1 respectively, as a white powder, mp 100-115° C. 1H NMR (400 MHZ, DMSO-d6δ7.84 (3, J=5.12 Hz, 1H), 7.34 (d, J=5.16 Hz, 1H), 6.92 (s, 1H), 4.48 (s, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H), 1.65 (s, 3H) IR (KBr) 3439, 1651, 1341, 1181 cm−1.
Reaction SMILES: P([O-])([O-])([O-])=O.CCC(CO[C:13]([C:26]([N:28](CC[NH+](C)C)C)=O)(C1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC.[Cl-]>>[NH:28]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:26]1
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Product: c1ccc2[nH]ccc2c1

Procedure:
50 mg of wet cells were added to 1 ml of a reaction solution for measurement of the tryoptophanase activity (0.1M phosphate buffer pH 8.0, 10 mM tryptophan, 0.1% Triton X-100), and reacted at 37° C. for 30 minutes. Indole formed was reacted with p-dimethylbenzaldehyde and spectrophotometically quantitated. Some strains exhibit high activity and from these cells a plasmid was extracted by the alkaline SDS method. [T. Maniatis, E. F. Fritsch and J. Sambrook: "Molecular Cloning" (1982) pages 90 to 91] and digested with BamHI and HindIII. Fragment length of the digest was determined by using an agarose gel. It was found that a DNA fragment of about 3.2 kb was inserted into the HindIII and BamHI sites of pBR322 (this plasmid will be referred to as pBR322tna).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:21]2[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=[CH:19][C:20]=2[O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: CC1(C)OB(c2cnc(Cl)cc2F)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)c(-c2cnc(Cl)cc2F)c1
Temperature: 70 °C
Yield: 57.3 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (170 mg, 0.66 mmol), 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (326 mg, 0.98 mmol), Pd2(dba)3 (30 mg, 5%), and tricyclohexylphosphine (280 mg, 10%) was suspended in 1,4-dioxane (4 mL) and aqueous 1M K3PO4 (2 mL). The mixture was heated to 70° C. using microwave irradiation (normal) for 45 min. The crude reaction mixture was filtered through a short plug of celite and the celite plug was washed with EtOAc (˜50 mL). The filtrate was washed with water (2×30 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (12 g ISCO, gradient 05-75% EtOAc in hexanes) to afford the free base of the desired product, 2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine as a yellow solid (144 mg, 57%). LCMS (M+H)+=381.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCCCCCCl)cc1

Procedure:
A stirred solution of 4-cyanophenol (80.9 g, 0.679 mol) in 1260 mL of acetonitile is treated with potassium carbonate (93.9 g, 0.679 tool) and 1-bromo-5-chloropentane (126 g, 0.679 mmol). The reaction is refluxed overnight and potassium carbonate is filtered off. The filtrate is concentrated in vacuo to generate oil which is partitioned between ether and water. The organic layer is washed with water, dried with magnesium sulfate, and concentrated in vacuo to afford 5-(4-cyanophenoxy)pentyl chloride as a white solid.