Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[C:23][Si](C)(C)C)=[N:20][C:19]([N:28]2[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:11]([O:10][C:9]([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[N:20][C:19]([N:28]2[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])[CH2:30][CH2:29]2)=[CH:18][N:17]=1)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1nc(N2CCN(S(=O)(=O)CC)CC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.8 %

Procedure:
Tert-butyl N-tert-butoxycarbonyl-5-(4-(ethylsulfonyl)piperazin-1-yl)-3-((trimethylsilyl)ethynyl)pyrazin-2-ylcarbamate (589 mg, 1.037 mmol) was dissolved in anhydrous MeOH (10 mL) and treated with K2CO3 (14.33 mg, 0.1037 mmol). The reaction was allowed to stir at ambient temperature for 45 minutes. The solvent was removed in vacuo and the residue redissolved in DCM and washed with water followed by brine. The solution was dried (MgSO4), filtered and concentrated and the residue was purified by column chromatography (ISCO Companion™, 24 g column, 0-100% EtOAc/Petrol) to afford the title compound as an orange solid (287 mg, 60% Yield). 1H NMR (400.0 MHz, DMSO) d 1.23 (t, J=7.4 Hz, 3H), 1.38 (s, 18H), 3.11 (q, 2H), 3.26-3.34 (m, 4H), 3.69-3.71 (m, 4H), 4.65 (s, 1H) and 8.27 (s, 1H) ppm; MS (ES+) 396.0
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:25]([C:29]1[CH:30]=[C:31]([CH:52]=[C:53]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:54]=1[OH:55])[C:32]([O:34][C:35]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][C:36]=1[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:33])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:39](=[O:40])[C:38]1[CH:42]=[C:43]([C:44]([CH3:45])([CH3:47])[CH3:46])[C:35]([O:34][C:32](=[O:33])[C:31]2[CH:52]=[C:53]([C:56]([CH3:57])([CH3:59])[CH3:58])[C:54]([OH:55])=[C:29]([C:25]([CH3:27])([CH3:28])[CH3:26])[CH:30]=2)=[C:36]([C:48]([CH3:51])([CH3:49])[CH3:50])[CH:37]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCNCCCCCCCC
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)Cl)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCN(CCCCCCCC)C(=O)c1cc(C(C)(C)C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4.83 grams of di-n-octylamine and 2.0 grams of triethylamine dissolved in 40 ml of toluene was added dropwise at 35° to 40° over a period of 10 minutes 10.0 grams of 4-(3,5-di-tert-butyl-4-hydroxybenzoyloxy)-3,5-di-tert-butyl-benzoyl chloride dissolved in 30 ml of toluene. The reaction mixture was stirred at 85° to 90°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered to remove the precipitated triethylamine hydrochloride. The filtrate was washed with water and dried over anhydrous sodium sulfate. After removal of the toluene by distillation, the product was isolated as white crystals (m.p. 145°-146°) by successive crystallization from acetonitrile and isopropanol.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.S(Cl)(Cl)=O.[CH3:30]O>>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH3:30])=[O:19])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 1, piretanide can be reacted with thionyl chloride and methanol to yield methyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.[C:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[C:27]#[CH:28])=[CH:21][CH:20]=1)#[C:17][CH3:18]>[Cu]I>[C:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[C:27]#[C:28][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1)#[C:17][CH3:18]
Reactant: OCc1ccc(I)cc1
Reactant: C#CC(=O)Nc1ccc(C#CC)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC#Cc1ccc(NC(=O)C#Cc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
40 mL of THF are degassed, combined with 2.62 g (8.03 mmol) of cesium carbonate and 4-iodobenzyl alcohol and again degassed. To this reaction mixture is added successively 138 mg (0.12 mmol) of tetrakistriphenylphosphine palladium, 53 mg (0.28 mmol) of copper (I) iodide, and 0.7 g (3.2 mmol) of propynoic acid-(4-prop-1-ynylphenyl)amide. The mixture is stirred for 24 hours at ambient temperature and the reaction mixture is then evaporated down. The purification of the residues is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol (60:1)). Yield: 0.5 g (57.8% of theory); C19H15NO2 (M=289.33); calc.: molecular ion peak (M+H)+: 290; found: molecular ion peak (M+H)+: 290; Rf value: 0.21 (silica gel, dichloromethane/ethanol (50:1)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1
Reactant: Oc1ccccc1
Reactant: CSc1nc(N)nc(Br)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CSc1nc(N)nc(Oc2ccccc2)c1C#N
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a stirred suspension of 500 mg (2.04 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 5 ml DME were added 192 mg (2.04 mmol) phenol and 0.31 ml (2.04 mmol) DBU and stirring continued for 16 hours at room temperature. 15 ml water was then added and the resulting crystals collected by filtration and triturated in hexane to afforded 400 mg (76%) 2-amino-4-methylsulfanyl-6-phenoxy-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 258 (M+, 100).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.CS(Cl)(=O)=O.O[C:13]1[CH:39]=[CH:38][C:16]2[N:17]=[C:18]([N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])[CH2:22][CH2:21]3)[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH2:4][CH2:5][O:6][C:13]2[CH:39]=[CH:38][C:16]3[N:17]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([O:26][CH2:27][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH3:29])[CH2:22][CH2:21]4)[O:19][C:15]=3[CH:14]=2)[CH2:3][CH2:2]1
Reactant: OCCC1CC1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3ccc(OCCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 2-cyclopropylethanol (550 mg) in THF (10 mL) were added triethylamine (0.80 mL) and methanesulfonyl chloride (0.50 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a suspension of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (250 mg) and potassium carbonate (1.8 g) in DMF (10 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (190 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]2[N:26]=[CH:25][CH:24]=[N:23]2)=[N:6][CH:7]=1.Cl.N[C@H]1CCC[C@@H]1NC(=O)C1C=CC=CC=1N1N=CC=N1.BrC1C=C([C:56]([F:59])([F:58])[F:57])C=CN=1>>[N:23]1[N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([NH:14][C@H:10]2[CH2:11][CH2:12][CH2:13][C@@H:9]2[NH:8][C:5]2[CH:4]=[C:3]([C:56]([F:59])([F:58])[F:57])[CH:2]=[CH:7][N:6]=2)=[O:27])[N:26]=[CH:25][CH:24]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(Br)cn1)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1ccnc(Br)c1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cc(C(F)(F)F)ccn1)c1ccccc1-n1nccn1
Temperature: 140 °C

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-[(5-bromopyridin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 118) from N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 200 mg, 0.65 mmol) and 2-bromo-4-(trifluoromethyl)pyridine (CAS number 175205-81-9; 147 mg, 0.650 mmol) except this was heated to 140° C. for 17 hours to afford the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]2[CH:13]([O:21][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])[CH2:12][C:11]1=[CH:27][C:28](OCC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:44]>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]1[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]2[CH:13]([O:21][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])[CH2:12][C:11]1=[C:27]([OH:44])[CH3:28])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C=C1CC(OC(C)OCC)C2OC(C)(C)OC2C1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOC(C)OC1CC(=C(C)O)C(CO[Si](C)(C)C(C)(C)C)C2OC(C)(C)OC12
Reaction time: 3 h

Procedure:
Two grams of ethyl (2-(tert-butyldimethylsilyloxymethyl)-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy) cyclohexylidene)acetate were dissolved in 10 ml of dry toluene, and 4.7 ml of diisobutyl aluminum hydride (2N hexane solution, 9.4 mmol) was added at -78° C., followed by stirring the mixture for 3 hours. After stirring at 0° C. for 5 minutes, a 10% sulfuric acid aqueous solution was added gradually until the reaction mixture became white. The reaction mixture was extracted with diethyl ether. The extract was washed with a sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, and concentration was effected under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.47 g of (2-(tert-butyldimethylsilyloxymethyl)-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy)cyclohexylidene) ethanol having the following properties.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH2:13]([NH2:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:13]([NH:15][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 81447.5 %

Procedure:
A suspension of 2,4-difluoro-1-nitrobenzene (0.50 g, 0.003 mmol), ethylamine hydrochloride (0.49 g, 0.006 mmol), K2CO3 (1.66 g, 0.012 mmol) in acetonitrile (30 mL) was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated and dissolved in small amount of CHCl3. Purification by column chromatography on silica using pentane/diethyl ether 95:5 as eluent gave 0.45 g of a yellow solid. 1H NMR (CDCl3) δ 8.23-8.18 (m, 1H), 8.08 (br s, 1H), 6.49-6.45 (m, 1H), 6.38-6.32 (m, 1H), 3.34-3.27 (m, 2H), 1.38 (tr, J=7.22 Hz, 3H); 13C NMR (CDCl3) δ 167.55 (d, JCF=255.6 Hz), 147.4 (d, JCF=12.9 Hz), 129.91 (d, JCF=12.9 Hz), 128.71 (br s), 103.73 (d, JCF=24.8 Hz), 99.14 (d, JCF=27.6 Hz), 37.88, 14.05; MS (posESI) m/z=found 184.0653. calc 184.0648. Anal. (C12H18N4O2) C, H, N.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9](=[O:36])[CH2:10][CH2:11][C@@H:12]([NH:20]C(NC2C=CC(C3C=CC=CC=3)=CC=2)=S)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:37]([NH:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:45][CH:44]=1)=S)#[N:38]>>[N:1]1([CH2:6][CH2:7][NH:8][C:9](=[O:36])[CH2:10][CH2:11][C@@H:12]([NH:20][C:40]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:45][CH:44]=2)=[N:39][C:37]#[N:38])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(CC[C@H](Cc1ccccc1)NC(=S)Nc1ccc(-c2ccccc2)cc1)NCCN1CCCC1
Reactant: N#CNC(=S)Nc1ccc(Oc2ccccc2)cc1
Product: N#CN=C(Nc1ccc(Oc2ccccc2)cc1)N[C@H](CCC(=O)NCCN1CCCC1)Cc1ccccc1

Procedure:
Prepared as in Example 1, step D, from [(R)-1-benzyl-3-(2-pyrrolidin-1-yl-ethylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (Example 31, step A) and 1-cyano-3-(4-phenoxy-phenyl)-thiourea (Example 55, step B). MS (electrospray): mass calculated for C31H36N6O2, 524.29; m/z found, 525.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.37–7.10 (m, 10H), 7.02 (d, J=7.9 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.58 (br s, 1H), 4.21–4.08 (m, 1H), 3.39–3.30 (m, 2H), 2.85 (d, J=6.4 Hz, 2H), 2.58 (t, J=6.0 Hz, 2H), 2.53–2.49 (m, 4H), 2.41–2.30 (m, 1H), 2.25–2.18 (m, 1H), 1.84–1.73 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[C:23]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:22]=[CH:21][C:20]=2[CH3:33])=[O:18])=[C:13]([Cl:34])[CH:12]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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:34][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[CH3:9])[CH:16]=[CH:15][C:14]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:21][C:20]=1[CH3:33])=[O:18]
Reactant: Cc1cc(F)ccc1Br
Reactant: Cc1ccc(C(=O)N2CCOCC2)cc1C(=O)c1ccc(N)cc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(C(=O)N3CCOCC3)ccc2C)c(Cl)c1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
2-Bromo-5-fluorotoluene (47 μL, 0.37 mmol) was dissolved in 3 mL dry 1,4-dioxane in a vial under an argon atmosphere. Compound 404 (110 mg, 0.31 mmol) was added and dissolved in the solvent. Rac-BINAP (7.3 mg, 0.012 mmol), Pd2(dba)3 (7.0 mg, 0.008 mmol) and Cs2CO3 (141 mg, 0.43 mmol) were added, and the reaction mixture was stirred under an argon atmosphere at 100° C. for 72 h. The reaction mixture was filtered and then purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v:v=0:100 to 50:50) as the eluent to afford the title compound as brown oil. 13C NMR (CDCl3) δ 195.4, 169.7, 160.6, 150.3, 139.8, 139.7, 136.6, 135.4, 134.0, 133.7, 132.4, 131.5, 129.2, 127.9, 127.4, 127.0, 117.8, 115.0, 113.8, 111.7, 66.8, 48.3, 42.8, 20.2, 18.1.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[NH:4][CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(Br)c2c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc2[nH]cc(-c3ccccc3)c2c1
Reaction time: 8 h
Yield: 9 %

Procedure:
A solution of 3-bromo-5-nitroindole from above (625 mg, 2.1 mmol), phenylboronic acid (381 mg, 3.13 mmol), triphenylphosphine (109.3 mg, 0.417 mmol) in dimethoxyethane (4.16 mL) was degassed. To this mixture 2N sodium carbonate (6.25 mL) was added, and reaction mixture was degassed again. To the reaction was added palladium (II) acetate (23.4 mg, 0.104 mmol), and the reaction was refluxed under dry nitrogen with stirring for 8 hours. The reaction mixture was then diluted with 1 M HCl (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL), and brine (100 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography over silica gel (EtOAc/hexanes, 10/90) to afford 3-phenyl-5-nitroindole as an orange powder (45 mg, 9% yield).
Reaction SMILES: [OH:1][C:2]1C(Cl)=CC(Cl)=C[C:3]=1C(N[C@H](C(O)=O)CC1C=CC=CC=1)=O.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:27]([C:28]([OH:30])=[O:29])[C:26]=1[OH:35].C(OC(=O)C)(=O)C>>[C:2]([O:35][C:26]1[C:25]([Cl:24])=[CH:33][C:32]([Cl:34])=[CH:31][C:27]=1[C:28]([OH:30])=[O:29])(=[O:1])[CH3:3]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc(Cl)cc(Cl)c1O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)O

Procedure:
In one non-limiting example of a synthesis method for N-(2-hydroxy-3,5-dichlorobenzoyl)-L-phenylalanine, synthesis begins with reaction of 3,5-dichlorosalicylic acid with acetic anhydride to obtain 2-acetoxy-3,5-dichlorobenzoic acid which in turn is converted into the acid chloride by the action of oxalyl chloride. The 2-acetoxy-3,5-dichlorobenzoic acid chloride is then reacted in situ with phenylalanine ethyl ester hydrochloride, in the presence of triethylamine, to yield ethyl ester of N-(2-acetoxy-3,5-dichlorobenzoyl)-L-phenylalanine. The last step of the synthesis method introduces novel and highly specific hydrolysis of both ester functions of N-(2-acetoxy-3,5-dichloro benzoyl)-L-phenylalanine ethyl ester to obtain the OTA template, N-(2-hydroxy-3,5-dichlorobenzoyl)-L-phenylalanine (I) with 98% yield. This synthesis reaction is summarized in FIG. 2.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10](S(C)(=O)=O)[N:9]=2)=[CH:4][CH:3]=1.[OH-:20].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(COc2ccc(Cl)cc2)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1nc(COc2ccc(Cl)cc2)cc[nH]1
Temperature: 25 °C
Yield: 54 %

Procedure:
4-((4-Chlorophenoxy)methyl)-2-(methylsulfonyl)pyrimidine Part B (0.8 g, 2.68 mmol) was stirred in 1N NaOH (5 mL, 5.36 mmol) and THF (13 mL) at 80° C. for 30 min. The solution was cooled to RT, acidified to pH 3 using 10% aqueous HCl. The precipitated product after isolation by filtration, was washed with CH2Cl2 to afford the desired product 4-((4-chlorophenoxy)methyl)pyrimidin-2(1H)-one 6C (0.344 g, 1.45 mmol, 54% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (1H, d, J=5.27 Hz), 7.28-7.36 (2H, m), 6.94-7.02 (2H, m), 6.10 (1H, d, J=5.27 Hz), 4.78 (2H, s).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:1]1)(=[O:28])=[O:27]
Reactant: CCOC(=O)COc1cccc2c1CCNC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cccc2c1CCN(S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of ethyl 2-((1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetate (300 mg, 1.28 mmol) and Et3N (387 mg, 3.83 mmol) in DCM (25 mL) cooled in an ice-water bath was added MsCl (176.6 mg, 1.54 mmol) drop wise. The mixture was stirred at 25° C. for 16 h and then quenched with aq.NH4Cl. The mixture was extracted with ethyl acetate and the combined organic layers were concentrated under vacuum to give the crude product (312 mg, 78%) which was used to the next step without purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([S:27]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:29])=[O:28])[CH3:26]
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 3-(4-piperidinyl)-5-(2-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 17) (0.117 mmol) was reacted with ethane sulfonyl chloride (0.02 mL, 0.234 mmol) in the presence of triethylamine (0.04 mL, 0.468 mmol) in methylene chloride (10 mL) to give the title compound (4.9 mg, 10% for the last two steps)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH:25]1[CH:29]([CH3:30])[CH2:28][NH:27][CH2:26]1)[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH:29]([CH3:30])[CH:25]([CH2:24][NH:23][CH2:21][CH3:22])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CNCC1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-ethylaminomethyl-4-methylpyrrolidine (0.38 g) and DBU (0.27 g) was refluxed for an hour and allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and ether successively and recrystallized from chloroform-methanol-concentrated aqueous ammonia to give the title compound (0.47 g) as pale yellow powder, mp 224°-226° C.