Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[CH2:38]([NH2:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:38]([NH:40][C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=2)=[CH:15][CH:16]=1)[CH3:39]
Reactant: CCN
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCNC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), ethanamine-HCl (5.36 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention 13.4) to provide (R/S)-N-ethyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide (8 mg, 0.015 mmol, 33.5% yield): LCMS=530.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.23 (2 H, m), 7.52-7.74 (7 H, m), 5.11 (1 H, s), 3.43-3.57 (2 H, m), 3.17 (2 H, q, J=7.41 Hz), 2.40 (2 H, t, J=6.71 Hz), 1.09 (3 H, t, J=7.26 Hz); HPLC peak RT=8.6 min (Method A).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4]2[C:7]([NH:9][C:10]3[C:15]([N:16]([C:17]([CH2:19][N:20]4[CH2:25][CH2:24][N:23](C)[CH2:22][CH2:21]4)=[O:18])[C:3]=12)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:8].Cl.Cl.ClC(OC(Cl)C)=O.C(N(C(C)C)CC)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.CO.CCOCC>[CH3:1][C:2]1[S:6][CH:5]=[C:4]2[C:7](=[O:8])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[N:16]([C:17](=[O:18])[CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:3]=12
Reactant: Cc1scc2c1N(C(=O)CN1CCN(C)CC1)c1ccccc1NC2=O
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1scc2c1N(C(=O)CN1CCNCC1)c1ccccc1NC2=O
Yield: 48.8 %

Procedure:
Telenzepine dihydrochloride (0.10 g, 0.23 mmol), α-chloroethyl chloroformate (0.2mL), and N,N,N-diisopropylethylamine (0.3 mL) were suspended in 100 mL anhydrous CHCl3 and the mixture was refluxed for 2 h, treated with an additional 0.1 mL of diisopropylethylamine, and heated 10 min. The CHCl3 was removed in vacuo and the solid (consisting mainly of the N-(α-chloroethyloxycarbonyl) intermediate which was not isolated) was dissolved in 7 mL of methanol and sufficient 1M HCl in ether to lower the pH to 0-1. The solution was refluxed for another 0.5 h and immediately basified with aqueous sodium carbonate and washed with ether. The aqueous layer was saturated with NaCl and extracted into CHCl3 to yield 40 mg (50%) of 38. 1H NMR (CDCl3) spectrum showed a characteristic singlet for the thiophene CH3 at δ 2.43 ppm; MS (Cl/NH3) m/e 353 (MH30, base).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2=[O:15].[C:16](=O)([O-])[O-].[K+].[K+].IC.O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:16])[O:8][C:7]([CH3:13])([CH3:14])[CH2:6][C:5]2=[O:15]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(=O)c2cc(Br)c(O)cc2O1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-7-hydroxy-2,2-dimethyl-chroman-4-one (Compound 3, 2.00 g, 7.4 mmol) in acetone (100 mL) were added potassium carbonate (500 mg) and iodomethane (5.22 g, 36.8 mmol). The mixture was then heated to reflux for 2 h. After cooling to room temperature, water was added to the mixture until all solids dissolved. The resulting solution was then extracted with diethyl ether, washed with brine, dried (MgSO4) and concentrated at reduced pressure to give a yellow residue. Purification by flash chromatography (silica gel, 95:5 hexane/ethyl acetate) gained the title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:23])[CH:6]=[C:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:8]=1.Cl.[CH3:25][N:26]([CH:33]([CH3:35])[CH3:34])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[Cl:2][C:3]1[CH:4]=[C:5]([OH:23])[CH:6]=[C:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:25])[CH:33]([CH3:35])[CH3:34])[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:8]=1
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)cc(Cl)c4)c23)C1

Procedure:
The title compound was prepared in analogy to Example 122 from 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (100 mg, 0.27 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (73 mg, 0.38 mmol) to yield 24 mg (19%) as tan crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:16]=[O:17])[C:7]2[C:12]([C:13]=1[OH:14])=[C:11]([CH3:15])[CH:10]=[CH:9][CH:8]=2)([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].O>N1C=CC=CC=1>[C:18]([O:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:15])[C:6]([CH:16]=[O:17])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: Cc1cccc2c(C=O)cc(C(C)C)c(O)c12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1c(C(C)C)cc(C=O)c2cccc(C)c12

Procedure:
0.7 g of 3-isopropyl-4-hydroxy-5-methyl-1-naphthalenecarbaldehyde and 10 ml of acetic anhydride were dissolved in 10 ml of pyridine and reacted at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with dilute hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, thereby obtaining 0.5 g of the captioned compound as a black oily substances.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:28])[CH2:10][C@@H:11]([CH2:26][OH:27])[C:12]([N:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[I:35]I>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:28][I:35])[O:27][CH2:26][C@@H:11]([C:12]([N:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])[CH2:10]1
Reactant: II
Reactant: C=C(C[C@@H](CO)C(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OC[C@@H](c2ccccc2)N1C(=O)[C@@H]1CO[C@@](CI)(c2ccc(F)cc2F)C1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
To the above obtained dichloromethane layer containing (R)-3-((S)-4-(2,4-difluoro phenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5, added sodium carbonate (59.4 g) followed by iodine (177.8 g) and the reaction mixture was stirred for 3 hours at 25-35° C. After completion of the reaction, the reaction mixture was quenched with 30% hypo solution and the reaction mixture was extracted with methyl tertiary butyl ether. Both organic and aqueous layers were separated and the organic layer was washed with 30% hypo solution, followed by 10% sodium chloride solution. Distilled off the solvent completely from the organic layer. Isopropanol (600 ml) was added to the obtained compound and the reaction mixture was stirred for 1½ hour at 25-30° C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 65 g; Chiral purity: 99.5%
Reaction SMILES: O1CCCC1.[CH2:6]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([Li])CCC.[C:28]1([C:34]2[CH:43]=[CH:42][CH:41]=[C:36]([C:37](OC)=[O:38])[C:35]=2[OH:44])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:6]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:37]([C:36]2[C:35]([OH:44])=[C:34]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:43]=[CH:42][CH:41]=2)=[O:38])=[CH:21][CH:22]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCc1ccc(N)cc1
Reactant: COC(=O)c1cccc(-c2ccccc2)c1O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc(NC(=O)c2cccc(-c3ccccc3)c2O)cc1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a tetrahydrofuran (20 ml) solution of 4-decylaniline (3.07 g, 13.14 mmol), cooled to 0°-5° C. (inert atmosphere), is added n-butyllithium (2.3 M, 13.14 mmol). The deeply colored solution is stirred for ten minutes, after which a tetrahydrofuran (20 ml) solution of methyl 3-phenylsalicylate (1.00 g, 4.38 mmol) is added. The temperature is allowed to rise to 25° C. over a 30 minute period. The reaction is quenched by pouring the contents into 10% hydrochloric acid (100 ml). The organics are extracted into ethyl acetate, washed with 10% hydrochloric acid, dried (sodium sulfate), and concentrated to give 2.77 g of crude solid. Chromatography (Kieselgel 60, dichloromethane) affords N-(4-decylphenyl)-2-hydroxy-[1,1'-biphenyl]-3-carboxamide (1.69 g, 90%), mp 74°-75° C.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Cl:7][C:8]1[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][S:18][C:12]=2[CH:11]=[CH:10][CH:9]=1.Cl.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([N:15]1[CH2:14][C:13]2[C:8]([Cl:7])=[CH:9][CH:10]=[CH:11][C:12]=2[S:18][CH2:17][CH2:16]1)(=[O:5])=[O:4])[CH3:2]
Reactant: Clc1cccc2c1CNCCS2
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethanesulphonyl chloride (1.28 g) in dichloromethane (10 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-ethylsulphonyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethyl acetate/hexane. Yield 2.53 g (m.p. 126°-128° C.).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[CH:7]=1)[CH3:2].[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>>[CH2:1]([C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[C:7]=1[CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1[nH]c(CC)cc1C
Product: CCOC(=O)c1[nH]c(CC)c(CC(C)C)c1C

Procedure:
The crude product, obtained as in Example 74 but using 2-ethyl-4-methyl-5-carbethoxypyrrole and isobutyraldehyde was sublimed (80° C. 1 × 10-4 mm) and recrystallized from aqueous ethanol, m.p. 94°-96° C (44%).
Reaction SMILES: [NH:1]([CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]2[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12](=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:16][CH:17]=1
Reactant: O=C(O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccccc1
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
(2)-(b) To a suspended solution of 2.0 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid in 10 ml of toluene and 520 mg of pyridine was added 1.21 g of acetic anhydride at 25° C., and the solution was stirred at same temperature for 1.5 hours. Then, the reaction solution was treated in the same manner as in Example 1-(2)-(a) to give 1.51 g of 6-(4-chlorophenyl)-1-phenyl-2-piperidone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:19])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N)=O)cc1Br
Temperature: 25 °C

Procedure:
3-Bromo-4-methylbenzoic acid (5 g, 23.25 mmol) was suspended in CH2Cl2 (100 mL) and stirred under argon at room temperature. Oxalyl chloride (5.9 g, 46.5 mmol) was added followed by DMF (20 μL). Gas evolution began, and the mixture was stirred for 2 days during which time complete solution occurred. The solvents were pumped off and toluene was added and stripped off to remove excess oxalyl chloride. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (20 mL). This was stirred for thirty mins. The phases were separated and the organic phase washed 1× with brine, dried over anhydrous Na2SO4, filtered, and evaporated. The residue was crystallized from EtOAc/hexane and dried under vacuum to afford the title compound as a white crystalline solid. LC-MS m/z 213.8 (M+H)+, 1.41 min (ret time).
Reaction SMILES: [CH2:1]([C:5]1([CH:9]([OH:12])C#C)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C.CN(C=[O:30])C>>[CH2:1]([C:5]1([C:9]([OH:12])=[O:30])[CH2:6][CH2:7][CH2:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CC(O)C1(CCCC)CCC1
Reactant: CN(C)C=O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CCCCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To 6.26 g (37.6 mmol) of crude 1-(1-butylcyclobutyl)prop-2-yn-1-ol in DMF (20 mL) were added imidazole (3.1 g, 45.2 mmol) and tert-butyldimethylsilyl chloride (6.8 g, 45.2 mmol). The reaction mixture was stirred at RT overnight, then concentrated to remove DMF, diluted with 100 ml of EtOAc, and added 100 mL of sat. aq. NH4Cl. After separation, the aq. phase was extracted with EtOAc (2×100 mL). The combined organic phase was washed with 50 mL of brine, dried (Na2SO4), concentrated. Flash chromatography over silica gel of the crude product (eluted with hexanes) afforded the title intermediate (6.82 g, 58% 3 steps) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][C:26]=1[O:25][CH3:24]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Reactant: Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(Cl)n1
Product: COC(=O)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cnc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 2-methoxy-3-(carbomethoxy)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 2.75 min (Method A); M+H=479 MS-ES).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]([CH3:9])([CH:7]=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 2,2-dimethyl-3-hydroxypropionate (1 g, 7.57 mmol) in DCM (50 ml) at 0° C. under nitrogen was added Dess-Martin periodinane (3.21 g, 7.57 mmol) in one portion and the reaction mixture was stirred at 0° C. for 1 h then rt for 45 min. The reaction mixture was cooled down to 0° C. and poured into 1N NaOH solution (30 mL) and extracted with DCM. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and partially evaporated (at around 25° C.) under reduced pressure, to afford a solution of 567 that was stored in the freezer and used in the next step without any further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:14][CH3:15])[N:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[C:12]([O:14][CH3:15])[N:13]=[C:3]([CH2:2][NH:1][C:34]([NH:33][C:31]([O:30][CH2:29][CH:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:28]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:32])=[S:35])[CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cc(CN)nc(OC)c1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)nc(OC)c1
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
6.67 g (31.7 mmol) of ethyl 2-aminomethyl-6-methoxyisonicotinate (20d) were dissolved in 175 ml of toluene and treated at RT with 8.93 g (281.3 mmol) of fluoren-9-ylmethyloxycarbonyl isothiocyanate. After 15 minutes, the resulting precipitate was filtered off and dried at 50° C., 4.6 g of the title compound being isolated. The filtrate was concentrated, and the residue was taken up in DCM and washed three times with water. The organic phase was dried with MgSO4 and concentrated. The crude product thus obtained was chromatographed on silica gel (heptane/ethyl acetate 90:10→75:25), it being possible to isolate a further 8.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13](OC(Cl)(Cl)Cl)=[O:14].O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:13](=[O:14])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=c1[nH]nc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
To a suspension of 4-chlorobenzhydrazide (8.53 grams (g), 0.05 mole) in methylene chloride (100 milliliters (ml)), was dropwise added trichloromethyl chloroformate (5.94 g, 0.03 mole). After addition, the reaction mixture was heated to reflux for 2 hours. The reaction was cooled down to room temperature and poured into a mixture of water (500 ml) and hexane (200 ml) and stirred for 10 to 20 min. The resultant precipitate was collected by suction-filtration and was washed with hexane to give a solid product. The product was dried in air at room temperature overnight yielding 5.5 g (60% yield) of 2-(4-chlorophenyl)-1,3,4-oxadiazolin-5one as a solid, m.p. 225°-227° C. NMR and IR spectra showed the desired structure. Without further purification, this product was subjected to the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:41]=[CH:40][C:20]([C:21]([N:23]([CH3:39])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30]C(=O)C4C=CC=CC=4)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:39])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[OH:30])=[O:22])=[CH:40][CH:41]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OC(=O)c3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-benzoyloxyphenyl)benzamide (350 mg) in methanol (10 ml) was added potassium carbonate (89.5 mg) and the mixture was stirred at ambient temperature overnight. Chloroform was added to the mixture and the solution was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oil and the oil was subjected to silica gel column (30 g, 1% methanol in chloroform) to give an oil. The oil was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-hydroxyphenyl)benzamide (228 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH3:10].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C[Si]([N:31]=[N+:32]=[N-:33])(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]([CH3:10])=[N:33][N:32]=[N:31]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)Nc1ccccc1Br
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: Cc1nnnn1-c1ccccc1Br
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
To a solution of N-(2-bromophenyl)acetamide (1.0 equiv.) in acetonitrile (0.4 M) at −5° C., was added trifluoromethanesulfonic anhydride (2.0 equiv.) dropwise and the mixture was stirred for 5 min. Trimethylsilyl azide (4.0 equiv.) was added slowly while maintaining the temperature at −5° C., then the mixture was stirred at 0° C. for 80 mins. The mixture was poured into ice-cold sodium bicarbonate solution, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude residue. The residue was purified by silica gel column chromatography (16% ethyl acetate in petroleum ether) to give the desired product (44% yield) as a yellow solid. MS (ESI) m/z 239.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Cl[C:27]1[S:28][C:29]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:30]([CH3:32])[N:31]=1>>[CH3:32][C:30]1[N:31]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[S:28][C:29]=1[S:33]([NH2:36])(=[O:35])=[O:34]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(Cl)sc1S(N)(=O)=O
Product: Cc1nc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(N)(=O)=O

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-Chloro-4-methyl-thiazole-5-sulfonic acid amide (example B.23) (191 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (160 mg, 30%). MS (ISP) 532.1 [(M+H)+]; mp 245-246° C.