Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:12][NH:13][OH:14].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N+:13]([CH3:12])[O-:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[N+]([O-])=Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
A mixture of 4-cyanobenzaldehyde (3.3 g, 25.2 mmol), N-methylhydroxyamine hydrogen chloride and sodium bicarbonate (4.23 g, 50.4 mmol) in dry methylene chloride (80 ml) was stirred at rt for 5 hrs. The solid portion was filtered off and the filtrate was concentrated to give the product as white solid (98% yield). 1H NMR (300 MHz, CDCl3) δ3.94(s, 3H), 7.46(s, 1H), 7.72(d, J=8 Hz, 2H), 8.32(d, J=8 Hz, 2H). MS (NH3-CI) Calc. for (M+1)+: 161. Found: 161.
Reaction SMILES: [CH2:1]([N:5]([CH2:49][CH2:50][C:51](O)=[O:52])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:54][CH:55]([CH2:58][OH:59])[CH2:56][OH:57]>>[CH2:1]([N:5]([CH2:49][CH2:50][C:51]([NH:54][CH:55]([CH2:58][OH:59])[CH2:56][OH:57])=[O:52])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NC(CO)CO
Reactant: CCCCN(CCC(=O)O)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Product: CCCCN(CCC(=O)NC(CO)CO)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 23.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 124, 3-(N-butyl-4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)propanoic acid (Intermediate 158B, 20 mg, 0.026 mmol) and 2-amino-1,3-propanediol (Aldrich, 8 mg, 0.088 mmol) were converted to the title compound (5 mg, 21%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.72 (br s, 1H), 8.15-7.94 (m, 6.5H), 7.76-7.62 (m, 3.5H), 7.25-7.03 (m, 3.5H), 6.94-6.81 (m, 0.5H), 4.75-4.00 (m, 2H), 3.97-3.70 (m, 2H), 3.65-3.43 (m, 7H), 2.94-2.64 (m, 3H), 2.58-2.12 (m, 5H), 1.58-1.14 (m, 4H), 1.13-0.85 (m, 3H), 0.76 (t, J=7.3 Hz, 1H), 0.68 (t, J=7.5 Hz, 1H); MS(ESI+) m/z 829.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:15][CH2:14]3)=[C:11]([C:16]([O:18]CC)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]3[CH2:14][CH2:15]3)=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnn(-c2ccc(Br)cc2)c1C1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylate (Intermediate #31) (423 mg, 1.29 mmol) was dissolved in methanol (20 mL) and treated with 2M aqueous sodium hydroxide solution (3.23 mL, 6.46 mmol). The mixture was stirred at ambient temperature for 24 h and then the methanol was removed by evaporation under reduced pressure. The residue was dissolved in water (50 mL), acidified to pH4 with 2M HCl and extracted with EtOAc (3×25 mL). The combined extracts were washed with water and brine, dried (MgSO4) and evaporated to leave 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylic acid a white solid. (343 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.Cl[CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:22][C:23]2[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2.8 g), ethyl 5-chloromethyl-2-furancarboxylate (1.8 g), potassium carbonate (2.1 g) and toluene (60 ml) was heated while stirring at 70° C. for 4 hours. The mixture thus obtained was concentrated under reduced pressure. To the resultant residue, water was added. After extraction was performed with dichloromethane, an organic phase was dried over anhydrous sodium sulfate and evaporated. The resultant residue was purified by column chromatography to obtain a target substance (0.9 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([NH:15][C:16](=[O:29])[CH:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:4]=1)#[N:2].I[CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH:33][CH2:32][CH2:31][O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[NH:15][C:16](=[O:29])[CH:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: CC(C(=O)Nc1cc(C#N)ccc1CCCC(=O)O)c1cccc2ccccc12
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)Nc1cc(C#N)ccc1CCCC(=O)OCCO)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of the compound prepared in Example 2(6) (150 mg) and 2-iodoethanol (100 mg) in DMF (2 ml), potassium carbonate (65 mg) was added under an atmosphere of argon. The mixture was stirred for overnight at room temperature. Water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over and concentrated to give the crude crystal. The crude crystal was recrystallized with ethyl acetate/hexane to give the title compound (95 mg) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[C:3]([CH3:10])[CH:4]=1
Reactant: COc1ccc(Br)c(C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)c(C)c1

Procedure:
The title compound was prepared by reacting 4-bromo-3-methylanisole (10 g, 0.050 mol) with n-butyl lithium (24 mL of 2.5 M solution in hexane, 0.055 mol) followed by triisopropyl borate (57.7 mL, 47.02 g, 0.25 mol) according to method F to yield 5.7 g (69%) of a white solid: MS (ESI) m/z 313 (2M−H2O—H)−.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:5]=1[CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)([CH3:3])[CH3:2].O.NN>CO>[CH:25]([C:18]1[CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[CH2:6][NH2:7])([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(C(C)C)c(CN2C(=O)c3ccccc3C2=O)c(C(C)C)c1
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)c1cc(C(C)C)c(CN)c(C(C)C)c1
Reaction time: 8 h

Procedure:
A mixture of N-(2,4,6-triisopropylbenzyl)phthalimide (4.62 g, 13.7 mmol), hydrazine hydrate (0.5 mL), and methanol (150 mL) was heated on the steambath for 3 hours, at which time 0.3 mL more hydrazine hydrate was added. The reaction mixture was allowed to stand overnight at room temperature. Methanol (150 mL) was added and heated on the steambath. The methanol was removed on the rotary evaporator without heating. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (1×200 mL and 1×100 mL), the extracts were combined, dried (magnesium sulfate), filtered, and concentrated. The residue was filtered through silica using ethyl acetate as eluant. The product was obtained as an oil, 1.93 g, (65%).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc(O)cc1)C1CCCC1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1

Procedure:
In analogy to the procedure of Example III, the title compound is prepared from 21.5 g (0.113 mol) of the compound from Example VII, 25 g (0.116 mol) of 2-chloromethylquinoline hydrochloride and 35.15 g (0.254 mol) of potassium carbonate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([OH:14])=O)[CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:26]1([S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([O:41][CH3:42])=[O:40])=[CH:34][C:33]=2[C@H:43]2[C@H:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:45][NH:44]2)(=[O:31])=[O:30])[CH2:28][CH2:27]1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][C@H:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([N:44]2[CH2:45][CH2:46][C@@H:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[C@@H:43]2[C:33]2[CH:34]=[C:35]([NH:38][C:39]([O:41][CH3:42])=[O:40])[CH:36]=[CH:37][C:32]=2[S:29]([CH:26]2[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[O:14])[CH:9]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)[C@@H]1CCN[C@H]1c1cc(NC(=O)OC)ccc1S(=O)(=O)C1CC1
Reactant: COc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Agent: Cl
Product: CCOC(=O)[C@@H]1CCN(C(=O)[C@H](Nc2cc(C(N)=O)ccc2F)c2ccc(F)c(OC)c2)[C@H]1c1cc(NC(=O)OC)ccc1S(=O)(=O)C1CC1

Procedure:
Example 81 was prepared according to the general coupling condition using 27A and 76P. 1H NMR (400 MHz, Methanol-d4) δ ppm 0.92-1.09 (m, 2H) 1.08-1.19 (m, 1H) 1.19-1.28 (m, 3H) 1.33-1.48 (m, 1H) 2.18-2.51 (m, 2H) 2.89 (dd, J=5.31, 2.27 Hz, 1H) 3.03-3.19 (m, 1H) 3.64-3.76 (m, 6H) 3.79-3.96 (m, 1H) 4.00-4.27 (m, 3H) 5.44 (s, 1H) 6.18 (d, J=2.02 Hz, 1H) 6.93-7.22 (m, 7 H) 7.27 (dd, J=8.21, 2.15 Hz, 1H) 7.66-7.75 (m, 1H) 9.48 (s, 1H), LC-MS 715 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][C:16]([CH3:18])=O.N1CCCC1>CO>[CH3:15][C:16]1([CH3:18])[CH2:13][C:12](=[O:14])[C:3]2[C:2](=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccc(C(F)(F)F)cc2O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75.5 %

Procedure:
The crude 1-[2-hydroxy-4-(trifluoromethyl)phenyl]ethanone (9.90 g, 48.5 mmol) from above was dissolved in methanol (100 mL) and acetone (3.56 mL, 48.5 mmol), and pyrrolidine (8.02 mL, 97.0 mmol) were added. The reaction was stirred at ambient temperature for 14 h; LCMS showed reaction completion. The reaction mixture was concentrated and diluted with EtOAc (300 mL), then washed with water (100 mL), 2N HCl (2×100 mL), water (50 mL), 2N NaOH (2×100 mL), water (50 mL), and brine (20 mL). The organic portion was dried (Na2SO4), filtered, concentrated, and the residue purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to give the title compound (8.93 g, 36.6 mmol, 75%) as a white solid. MS (ESI) m/z 245 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[S:17][CH3:18].[C:19](=[O:21])=[O:20].Cl>CCOCC>[CH3:18][S:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[C:19]([OH:21])=[O:20]
Reactant: CSc1cc(C(F)(F)F)ccc1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (2.5M solution in hexane; 25 ml) was added under an inert atmosphere to a stirred solution of 4-bromo-3-methylsulphenylbenzotrifluoride (16.4 g) in ether whilst maintaining the temperature below -70° C. The mixture was stirred at 70° C. for 2 hours and then poured onto solid carbon dioxide pellets. The mixture was stirred for 10 minutes and aqueous hydrochloric acid was added. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated and the residue was triturated with cyclohexane and filtered to give 2-methylsulphenyl-4-trifluoromethylbenzoic acid (12.4 g) as a white solid, NMR (CDCl3 +DMSO-d6): 2.45 (s,3H), 7.2(d, 1H), 7.3(s, 1H), 8.0 (d, 1H), 10.7-11.1 (bs, 1H).
Reaction SMILES: [CH3:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.C1C(C(OO)=[O:18])=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]2[O:18][CH:9]2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(OO)c1ccccc1
Reactant: CC=CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC=CCC1=CC=CC2OC12
Reaction time: 8 h
Yield: 19 %

Procedure:
To 5.3 g of m-methylallylbenzene was added 85 ml of chloroform solution containing perbenzoic acid and the mixture was allowed to stand at room temperature overnight. The resulting solution was washed with sodium hydroxide solution, Mohr's salt solution and then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 1.1 g (yield 19%) of m-methylallylbenzene oxide having a boiling point of 90° C/7 mmHg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[N:32][NH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:15][C:16]=1[F:21]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Fc1cc(C2(c3ccc(Br)cc3)CCNCC2)ccc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1cc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)ccc1Cl

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst, to obtain the title compound. LCMS (PS-A3) Rt 7.11 mm [M+H]+ 356. 1H NMR (Me-d3-OD) δ 2.62-2.80 (4H, m), 3.18-3.30 (partially overlaps with solvent, 4H, m), 7.23 (1H, t), 7.34-7.39 (1H, m), 7.22 (1H, dd), 7.30 (1H, dd), 7.43-7.49 (3H, m), 7.71 (2H, d), 8.55 (2H, s).
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:18])[C@@H:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH3:10])[CH2:2][CH2:3][C:4]#[CH:5].I[C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(NCC)C>[Cu](I)I>[NH2:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[C:5]#[C:4][CH2:3][CH2:2][CH2:1][NH:6][C:7](=[O:18])[C@@H:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH3:10]
Reactant: C#CCCCNC(=O)[C@H](CC)NC(=O)C(F)(F)F
Reactant: Nc1ccccc1I
Agent: I[Cu]I
Solvent: CCNCC
Product: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 50 mL round bottom flask was charged with (S)—N-(pent-4-ynyl)-2-(2,2,2-trifluoroacetamido)butanamide (110 mg, 0.42 mmol), 2-iodoaniline (89.0 mg, 0.41 mmol), copper iodide (13.0 mg, 0.068 mmol), palladium tetrakistriphenylphosphine (47 mg, 0.041 mmol), and diethylamine (12.6 mL). The resulting mixture was stirred at room temperature for 4 h, concentrated in vacuo and the resulting residue purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-10:90 Heptane:EtOAc) to yield N-[5-(2-aminophenyl)pent-4-ynyl]-2-(S)-(2,2,2-trifluoroacetylamino)butyramide. 1H NMR (300 MHz, CDCl3) δ 7.21-7.24 (m, 1H), 7.07-7.12 (m, 1H), 6.64-6.71 (m, 1H), 6.42-6.46 (m, 1H), 4.38-4.45 (m, 1H), 3.39-3.53 (m, 2H), 2.53 (t, J=6.8 Hz, 2H), 1.67-1.96 (m, 4H), and 0.88-0.93 (m, 3H).
Reaction SMILES: [CH2:1]([O:6][C:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(N=C=NC2CCCCC2)CCCCC1.[F:43][C:44]1[C:49](O)=[C:48]([F:51])[C:47]([F:52])=[C:46]([F:53])[C:45]=1[F:54]>C(OCC)(=O)C>[CH2:1]([O:6][C:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][C:49]4[C:48]([F:51])=[C:47]([F:52])[C:46]([F:53])=[C:45]([F:54])[C:44]=4[F:43])=[O:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOC1(c2ccc(-c3ccc(C(=O)O)cc3)cc2)C=CC=CC1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCOC1(c2ccc(-c3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc3)cc2)C=CC=CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4"-(n-pentyloxy)-[1,1':4',4"-terphenyl]-4-carboxylic acid (10.5 mmol) and dicyclohexylcarbodiimide (10.5 mmol) in ethyl acetate at 0° C. is added pentafluorophenol (11.5 mmol). The mixture is stirred at 25° C. for a period of 18 h, producing a precipitate. The mixture is filtered. The filtrate is washed with water and brine and dried with magnesium sulfate. The solvent is removed in vacuo to obtain pentafluorophenyl 4"-(n-pentyloxy)-[1,1':4',4"-terphenyl]-4-carboxylate, C30H23F5O3, M.W.=526.5.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2].S[CH2:22][C:23]([OH:25])=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1]([C:4]1[C:5]([CH:13]([CH2:22][C:23]([OH:25])=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)CS
Reactant: CC(C)c1cc2c(cc1C(O)c1ccccc1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)c1cc2c(cc1C(CC(=O)O)c1ccccc1)OCO2
Yield: 102.4 %

Procedure:
1.2 g of α-(6-isopropyl-1,3-benzodioxol-5-yl)-benzyl alcohol was dissolved in 10 ml of benzene, followed by the addition of 490 mg of mercaptoacetic acid and a catalytic amount of p-toluenesulfonic acid monohydrate. The obtained mixture was heated under reflux for one hour and cooled, followed by the addition of benzene. The mixture was washed with water, followed by the addition of a 1N aqueous solution of sodium hydroxide. The alkaline layer was separated, acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane/chloroform=3:7) to obtain 1.42 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH3:22][O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH3:22][O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[N:32]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:25]
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL). (1R,2S)-2-(4-Fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester (0.79 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.07 mL, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 2 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, (1R,2S)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid methyl ester (0.3 mmol), as a yellow oil. LC-MS (ESI) calcd for C25H29FN4O7S2 580.15, found 581.3 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[CH2:20](I)[CH2:21][CH3:22].O>CS(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][CH2:21][CH3:22])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCCI
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCn1c(C(=O)OCC)cc2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under argon, 937 mg (4.00 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate (A. Guy, J. -P. Guetté, Synthesis 1980, 222–223) are initially charged in 12 ml of dimethyl sulphoxide. 4.40 mmol of sodium hydride (176 mg of a 60% dispersion in paraffin) are added a little at a time, and the mixture is stirred at 50° C. for 30 min. After cooling to RT, 170 mg (4.40 mmol) of propyl iodide are added, and the mixture is stirred at RT for another 3 h. The reaction mixture is poured into 30 ml of water and extracted with ethyl acetate (6×30 ml). The combined organic phases are washed with 50 ml of sat. sodium chloride sol., dried over sodium sulphate and freed from the solvent using a rotary evaporator. The resulting brown crude product is purified by column chromatography (silica gel 60, mobile phase gradient cyclohexane→cyclohexane-ethyl acetate 3:1), giving the product as second fraction.