Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][C@H:16]([CH3:20])[C:17](O)=[O:18])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][C@H:16]([CH3:20])[C:17]([Cl:24])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a mixture of 675 m9 (2.2 mmol) of (2R)-2-(2,4-di-t-butylphenyloxy)propanoic acid (18) and 4 drops of N,N-dimethylformamide in methylene chloride (20 mL) at 0° C. under a nitrogen atmophere was added 1.21 mL (2.4 mmol) of a 2M solution of oxalyl chloride in methylene chloride dropwise over a 10 min period. The reaction mixture was allowed to stir at room temperature overnight. The solvent and any excess oxalyl chloride was removed by rotary evaporation and dried (under vacuum) to afford 715 mg (99%) of (2R)-2-(2,4-di-t-butylphenyloxy)propanoyl chloride (16) as a crude yellow liquid: 1H NMR (CDCl3) δ1.29 (s, 9 H), 1.42 (s, 9 H), 1.76-1.79 (d, 3 H), 4.94-5.00 (q, 1 H), 6.50-6.(d, 1 H), 7.12-7.16 (d, 1 H), 7.36 (s, 1 H); 13C NMR (CDCl3) δ175.0, 152.8, 144.1, 137.4, 124.6, 123.4, 110.6, 78.6, 35.1, 34.3, 1.5, 30.0, 18.0.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[O:25])=[CH:22][CH:21]=1
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43.70 g (258 mol) 2-aminoindane hydrochloride and 53.43 g (528 mmol) triethylamine were mixed with 250 ml of tetrahydrofuran, 42.89 g (270 mmol) 4-fluorobenzoylchloride were added, and the mixture was stirred for 2 h at RT.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[C:9]([CH2:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])#[N:10].C(N(CC)CC)C>C(Cl)Cl>[OH:5]/[C:4](/[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[C:11](/[C:9]#[N:10])\[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]
Reactant: CCC(CC)C(=O)Cl
Reactant: CC(C)OC(=O)CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)/C(O)=C(\C#N)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
22.2 g (0.16 mol) of 2-ethylbutyryl chloride were added to a solution of 21 g (0.16 mol) of isopropyl cyanoacetate in CH2Cl2, and the reaction mixture was cooled to 0° C. At this temperature, with ice-cooling, 33.5 g (0.33 mol) of triethylamine were added dropwise, and the mixture was then stirred at 25° C. for 2 h. Following subsequent acidic hydrolysis, the organic phase was washed, dried and concentrated. Purification by customary methods gave 24.4 g of the title compound (68% of theory) as a colorless oil (b.p. 70-75° C./1.5 mbar).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:35])[C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)[CH2:16][C@H:15]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:42](OC1(O[Si](C)(C)C)CC1)[CH3:43]>C(Cl)(Cl)Cl>[F:32][C:31]([F:33])([F:34])[C:23]1[CH:22]=[C:21]([C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[CH2:12][CH2:13][N:8]([CH:6]4[CH2:43][CH2:42]4)[CH2:9][CH2:10]3)[CH:15]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:16]2)=[O:35])[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(C3CC3)CC2)C(c2ccccc2)C1

Procedure:
The title compound, MS: m/e=526.2 (M+H+), [α]58920=−6.17, [α]43620=−23.81, [α]36520=−74.09 (c=0.1134, chloroform), was prepared in accordance with the general method of example 114 (step1) and example 110 (step 2) from (3S,4R) or (3R,4S)-4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester and [(1-ethoxycyclopropyl)-oxy]trimethylsilane.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:24][NH:25][C:26]([C:28]2[C:29]([CH3:38])=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][N:32]=3)=[O:27])[CH:16]=[CH:17][C:18]=1[CH2:19][O:20][CH2:21][CH2:22][OH:23].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:23][CH2:22][CH2:21][O:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([CH2:24][NH:25][C:26]([C:28]3[C:29]([CH3:38])=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:27])=[CH:14][C:13]=2[F:12])(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2ncccc2cc1C(=O)NCc1ccc(COCCO)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccc(CNC(=O)c3cc4cccnc4nc3C)cc2F)cc1
Reaction time: 2 h

Procedure:
25 mg tosylchloride (0.13 mmol) was added to a solution of 40 mg N-[[3-fluoro-4-(2-hydroxyethoxymethyl)phenyl]methyl]-2-methyl-1,8-naphthyridine-3-carboxamide (0.11 mmol), 23 μl diisopropylethylamine (6.13 mmol) and 13 mg DMAP (0.11 mmol) in 1.0 ml CH2Cl2 at room temperature. The solution was stirred for 2 h. The reaction mixture was placed directly on a SiO2 column and purified by flash chromatography (CH2Cl2/MeOH 50:1). Gave 52 mg (90%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:13]([C:15]2[CH:16]=[CH:17][C:18](=[S:21])[NH:19][N:20]=2)[CH:14]=1>>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[C:13]([C:15]2[CH:16]=[CH:17][C:18](=[S:21])[NH:19][N:20]=2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)NCC(O)COc1ccc(N)cc1-c1ccc(=S)[nH]n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(=S)[nH]n2)c1

Procedure:
Addition of acetic anhydride to a stirred suspension of 6-[5-amino-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(2H)-pyridazinethione in an aqueous buffer solution at pH 5.5 gave 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3-(2H)-pyridazinethione.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>>[CH3:6][Si:7]([CH3:9])([CH3:8])[O:5][CH:2]([C:3]#[CH:4])[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC(C)O
Product: C#CC(C)O[Si](C)(C)C
Yield: 60 %

Procedure:
The above compound was prepared in a 60% yield from 35 g of but-3-yn-2-ol and 50.4 g of trimethylsilyl chloride according to the method given in Can. J. Chem. 43, 2004 (1965); b.p. 117°/760 Torr.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[OH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][O:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[N:4]=2)=[CH:9][CH:10]=1
Reactant: O=C(CO)c1ccccc1
Reactant: Fc1ccc(-c2nc(CCl)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: O=C(COCc1csc(-c2ccc(F)cc2)n1)c1ccccc1
Yield: 74.1 %

Procedure:
11.2 g (0.05 mol) of 4-chloromethyl-2-(4-fluorophenyl)thiazole (see Example 4), 5.4 g (0.04 mol) of 2-hydroxyacetophenone, 7.5 g (0.055 mol) of potassium carbonate and 0.5 g of potassium iodide in 20 ml ethanol are refluxed for 24 hours. The mixture is filtered, the filtrate is concentrated, the residue is taken up in dichloromethane, the solution is extracted with dilute sodium hydroxide solution and then with water, and the organic phase is dried over MgSO4. Removal of the solvent by distillation under reduced pressure results in a solid residue which is washed with diisopropyl ether to give 9.7 g (59% yield) of 2-[2-(4-fluorophenyl)-4-thiazolylmethyloxy]acetophenone as yellowish crystals of melting point 104°-106° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@@H:19]1[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@H:21]([C:32]([O:34][CH3:35])=[O:33])[CH2:20]1)=[O:17].C(OCC)(=O)C.Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@@H:19]1[CH2:24][NH:23][CH2:22][C@H:21]([C:32]([O:34][CH3:35])=[O:33])[CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)OC)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.8 %

Procedure:
1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (247 mg), 1-tert-butyl 3-methyl (3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (314 mg) and diisopropylethylamine (862 μl) were dissolved in methylene chloride (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (337 mg) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give 1-tert-butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) as an oil. The obtained 1-tert-butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) was dissolved in methanol (2 ml), 4M hydrogen chloride-ethyl acetate (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the object product (13 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([S:22]([CH3:25])(=[O:24])=[O:23])=[N:15]2.[OH:26]OS([O-])=O.[K+]>CO.C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([S:22]([CH3:25])(=[O:23])=[O:24])=[N:15]2)=[O:26]
Reactant: O=S([O-])OO
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1F
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2nc(S(C)(=O)=O)ccc2c1S(=O)c1ccc(F)cc1F
Yield: 45.9 %

Procedure:
5-(2,4-Difluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 101 (230 mg) was dissolved in 9 mL (1:1:1 MeOH/THF/H2O) and was treated with 1 gram of OXONE™. After 3 hours the mixture was partitioned between CH2Cl2 and water. The product was purified by chromatography (10% MeOH/CH2Cl2) to afford 110 mg of 5-(2,4-difluoro-benzenesulfinyl)-2-methanesulfonyl-6-methoxy-quinoline 301; ([M+H]+)=398.
Reaction SMILES: [I-].[Na+].[CH3:3][S:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:19][CH2:20][CH2:21][Cl:22])[C:7]=2[CH:6]=1.C(N(CC)CC)C.[NH:30]1[CH2:35][CH2:34][CH:33]([O:36][CH2:37][CH2:38][OH:39])[CH2:32][CH2:31]1>C(C(C)=O)C>[ClH:22].[CH3:3][S:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:19][CH2:20][CH2:21][N:30]3[CH2:35][CH2:34][CH:33]([O:36][CH2:37][CH2:38][OH:39])[CH2:32][CH2:31]3)[C:7]=2[CH:6]=1
Reactant: OCCOC1CCNCC1
Reactant: CSc1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ccc2c(c1)N(CCCN1CCC(OCCO)CC1)c1ccccc1S2
Product: Cl
Yield: 41.1 %

Procedure:
7 g (0.0469 mole) of sodium iodide were added to a solution of 15.1 g (0.0469 mole) of 2-methylthio-10-(3-chloropropyl)-phenothiazine in 250 ml of methyl ethyl ketone followed by the addition of 4.74 g (0.0469 mole) of triethylamine and then 6.8 g (0.0469 mole) of 2-(4-piperidyloxy)-ethanol. The mixture was refluxed for 20 hours and after cooling, the precipitate formed was removed by filtration. The filtrate was evaporated to dryness and the oil residue was dissolved in methylene chloride. The organic phase was washed with aqueous sodium bicarbonate, then with water, dried and concentrated. The resulting oil was dissolved in ethanol and an ether solution of hydrogen chloride was added thereto. The precipitate formed was recovered by vacuum filtration and twice crystallized from an ether-absolute ethanol mixture to obtain 9 g (41% yield) of 2-methylthio-10-[3-(4-β-hydroxyethoxypiperidino)propyl]-phenothiazine hydrochloride in the form of white crystals melting at 158°-160° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50].Cl>CN(C=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:23](=[O:25])[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:22][CH:21]=1
Reactant: O=C(O)c1ccc(Nc2ccccc2)nc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
DIPEA (126 mg, 0.17 mL, 0.98 mmol) was added drop wise to 6-(phenyl-amino)-pyridine-3-carboxylic acid (70 mg, 0.32 mmol) in DMF (5 mL). EDCI (74 mg, 0.39 mmol) and HOBT (53 mg, 0.39 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (137 mg, 0.39 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated to afford 110 mg (65% yield) of N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-6-phenylamino-nicotinamide. LC-MS purity: 93.71%. 1H-NMR (DMSO-d6): δ 9.4 (s, 1H), 8.7 (s, 1H), 8.5 (t, 1H), 8.0 (d, 1H), 7.8 (m, 2H), 7.7 (d, 3H), 7.6 (m, 1H), 6.9 (t, 1H), 6.8 (d, 1H), 4.2 (dd, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[N:31]=[CH:30][C:29]([NH:32][C:33](=[O:38])[CH2:34][C:35]([OH:37])=O)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.O>[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([N:61]1[CH2:62][CH2:63][N:64]([C:35](=[O:37])[CH2:34][C:33]([NH:32][C:29]2[CH:30]=[N:31][C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:27][CH:28]=2)=[O:38])[CH2:65][CH2:66]1)=[O:60]
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)nc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
HOBt (41 mg, 0.3 mmol) and DIEA (98 mg, 0.76 mmol) were added to a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (65 mg, 0.25 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (58 mg, 0.3 mmol) followed by (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (93 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 58.5 mg (46%) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LCMS: 507.1 (M+1)+ 98.54%, 1H NMR: (DMSO-d6): δ 10.5 (d, 1H), 8.8 (dd, 1H), 8.2-7.86 (m, 4H), 7.5 (d, 1H), 7.34 (m, 6H), 3.8-3.4 (m, 8H), 3.2-3.1 (m. 2H).
Reaction SMILES: [N+:1]([C:4]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[N+:1]([C:4]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:5]=1[C:6]([Cl:20])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.7 g (28 mmoles) of 2-nitro-3,4,5,6-tetrafluorobenzoic acid [Tetrahedron, 23, 4719, (1967)], 3.8 g (30 mmoles) of oxalyl chloride and 50 ml of dichloromethane was treated with four drops of N,N-dimethylformamide and stirred at room temperature overnight. The solvent was removed and the residue was used as is without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([C:21]2[O:25][N:24]=[C:23]([OH:26])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:15]1([C:21]2[O:25][N:24]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[C:23](=[O:26])[CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1cc(-c2ccccc2)on1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(-c2ccccc2)on1-c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 80.9 %

Procedure:
After mixing 22.6 g of 4-chloro-3-nitrobenzotrifluoride, 19.3 g of 5-phenyl-3-hydroxyisoxazole, 16.8 g of potassium carbonate, and 150 ml of dimethyl sulfoxide, the reaction was performed for 3 hours at 70° C. After the reaction was over, the reaction mixture was cooled and poured into water. Crystals thus deposited were recovered by filtration and recrystallized from a mixture of dimethylformamide and methanol to provide 28.4 g of the desired product with a yield of 95.0%. The melting point thereof was 185° C. to 187° C.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=O)[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][CH:23]=1>CCOCC>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
In a 2 L three-necked round-bottomed flask equipped with an overhead stirrer and reflux condenser, anthranilamide (20.0 g, 147 mmol) and potassium carbonate (28.4 g, 206 mmol) were suspended in 1 L dry ether and heated to reflux. o-Anisoyl chloride (32.5 g, 191 mmol) was added slowly to the refluxing mixture. After 3 hours at reflux, the reaction mixture was allowed to cool to room temperature, the ether was removed under reduced pressure, and the resulting residue was filtered and washed with water. The resulting solid was then suspended in 600 mL of 5% aq. NaOH solution and boiled for one hour. The reaction was allowed to cool to room temperature, and it was neutralized with acetic acid, upon which 2-(2-methoxyphenyl)quinazolin-4(3H)-one was precipitated. The product was collected by filtration, washed with water, and dried overnight in vacuo to yield 27 g (73%) of pure 2-(2-methoxyphenyl)quinazolin-4(3H)-one. LC/MS: m/z 253.0 (M+H)+ at 3.22 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (DMSO) 63.86 (s, 3H), δ 7.09 (t, 1H), δ 7.18 (d, 1H), δ 7.53 (m, 2H), δ 7.70 (m, 2H), δ 7.80 (m, 1H), δ 8.14 (d, 1H), δ 12.11 (s, 1H) ppm; 13C NMR (DMSO) δ 55.75, δ 111.86, δ 120.89, δ 120.97, δ 122.74, δ 125.75, δ 126.45, δ 127.26, δ 130.41, δ 132.13, δ 134.32, δ 148.97, δ 152.48, δ157.12, δ 161.35.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[NH:4][S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI.[C:18](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH3:18])[S:5](=[O:13])(=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NS(=O)(=O)C(c2ccccc2)=C1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 104 %

Procedure:
A solution of 4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (2.0 g, 8.21 mmol) and MeI (3.5 g, 24.6 mmol) in DMF (30 ml) was cooled with an ice bath, and anhydrous potassium carbonate (1.13 g, 8.21 mmol) was added. The mixture was then allowed to warm to rt and stirred for 21 h. Water (60 ml) was added and the white precipitate formed, was filtered off and washed with water. Toluene was added to the precipitate and the mixture was evaporated and the residue was dried for three days under vacuum to give the title compound (2.2 g, 102%) containing traces of water and toluene. 1H NMR (400 MHz, CDCl3): δ 3.23 (s, 3H), 7.52-7.56 (m, 3H), 7.86-7.88 (m, 2H); 13C-NMR (100 MHz, CD3CN): δ 24.5, 123.8, 1291, 129.5, 130.7, 133.0, 143.1, 157.6.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9]>ClCCl>[OH:10][S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:7].[CH3:6][CH:2]1[CH2:3][CH2:4][CH2:5][S:1]1
Reactant: C1CCSC1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCCS1
Product: O=S(=O)(O)C(F)(F)F

Procedure:
11 mmol of tetrahydrothiophene was dissolved in 10 ml of dichloromethane at 0° C., and about 12 mmol of methyltrifluoromethane sulfonate was slowly dripped to the mixture. As a result, a white solid product in a salt form was obtained after about 5 minutes. The solid product was filtered and dried for 1 hour in an oven at 50° C. to obtain the following product:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)[OH:10].[CH3:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].CO[CH2:21][CH2:22][O:23][CH3:24]>>[CH2:13]([NH:14][C:24](=[O:23])[O-:10])[CH3:12].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:2]1[CH:3]=[CH:4][C:5]2[CH:21]([CH3:22])[CH:16]3[CH2:15][NH:14][CH2:17][CH:18]3[C:6]=2[CH:7]=1
Reactant: CCN(CC)CC
Reactant: COCCOC
Reactant: OB(O)c1c(F)cccc1F
Product: CC1c2ccc(-c3c(F)cccc3F)cc2C2CNCC12
Product: CCNC(=O)[O-]
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2,6-Difluorophenylboronic acid (41 mg, 0.26 mmol), Pd(dppf) (5 mg), and Et3N (0.2 mL) were added to a solution of N-ethylcarbamate-5-triflate-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (52 mg, 0.13 mmol) in DME (2.6 mL), and stirred overnight at 90° C. The solution was cooled to room temperature, partitioned between CH2Cl2 and H2O, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C21H21F2NO2+H: 358, observed: 358.