Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([CH2:11][OH:12])([F:10])[CH:5]([F:13])[C:4]=1[F:14].[BrH:15]>>[OH:12][CH2:11][C:6]1([F:10])[C:7]([F:9])=[CH:8][C:3]([CH2:2][Br:15])=[C:4]([F:14])[CH:5]1[F:13]
Reactant: OCC1=C(F)C(F)C(F)(CO)C(F)=C1
Reactant: Br
Product: OCC1(F)C(F)=CC(CBr)=C(F)C1F
Yield: 90 %

Procedure:
A 90% yield of 4-hydroxymethyl-2,3,4,5-tetrafluorobenzyl bromide obtained from 1,4-bis(hydroxymethyl)-2,3,4,5-tetrafluorobenzene by treatment with 48% hydrobromic acid was reported by Costello and Milner in Synthetic Communications, 17, 219-221 (1987). However, it has since been shown that treatment of benzenedimethanols lacking nuclear halogen substituents shows no particular selectivity, and accordingly, the unusually high yield in this isolated example is believed to be an anomaly due to insolubility of the monohalogenated product in the reaction media.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18]/[C:19](/[CH3:26])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:26])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)C=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using ethyl 2-chloro-5-isocyanatobenzoate and ethyl 3-aminocrotonate there is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-methylvinyl]ureido}-benzoate, using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 3-aminocrotonate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methylvinyl]ureido}benzoate, m.p. 147°-150° C.,
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[CH2:4][CH:3]1[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[CH3:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>O1CCCC1>[Cl:1][C:2]1([Cl:13])[CH2:4][CH:3]1[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=2[CH3:14])=[O:21])=[CH:8][CH:7]=1
Reactant: Nc1ccc(OC2CC2(Cl)Cl)cc1
Reactant: Cc1ccccc1C(=O)N=C=O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)NC(=O)Nc1ccc(OC2CC2(Cl)Cl)cc1

Procedure:
6.54 g (0.03 Mol) of 4-(2,2-dichlorcyclopropyloxy)-aniline, dissolved in 50 ml dry tetrahydrofuran, are added dropwise with 4.84 g (0.03 Mol) of 2-methylbenzoyl-isocyanate, with stirring. The temperature increases mildly therewith. After cooling, the product is precipitated with pentane, withdrawn by suction, after-washed with pentane and dried.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][C:13]3[CH2:19][CH2:18][CH2:17][CH:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]=3[N:15]=2)=[CH:6][CH:5]=1.O.[NH2:28][NH2:29].[CH2:30]([OH:32])C>>[CH3:30][O:32][C:9]1[CH:8]=[C:7]([NH:10][C:11]2[S:12][C:13]3[CH2:19][CH2:18][CH2:17][CH:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:14]=3[N:15]=2)[CH:6]=[CH:5][C:4]=1[C:3]([NH:28][NH2:29])=[O:26]
Reactant: CCO
Reactant: NN
Reactant: COC(=O)c1ccc(Nc2nc3c(s2)CCCC3c2ccccc2)cc1
Solvent: O
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1C(=O)NN
Temperature: 90 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
To a suspension of 4-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-benzoic acid methyl ester (200 mg, 0.50 mmol) in ethanol (4 mL) was added hydrazine hydrate (0.6 mL) and the mixture was stirred for 7 hours at 90° C. The formed white precipitate was filtered off, washed with ethanol and dried to yield the title compound (130 mg, 65%) as a white solid which was used without further purification in the next step. mp 297-299° C. MS ISP (m/e): 393.5 (100) (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.[Cl:16][C:17]1[C:24]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=[C:21]([Cl:31])[C:18]=1[CH:19]=[O:20].[OH-].[K+].O>CO>[Cl:16][C:17]1[C:24]([O:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=[C:21]([Cl:31])[C:18]=1[CH:19]([C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)[NH:13][CH:14]=1)[OH:20]
Reactant: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1Cl
Reactant: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(-c2cnc3[nH]cc(C(O)c4c(Cl)ccc(OCC(F)(F)F)c4Cl)c3c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (109, 100.0 mg, 0.51 mmol, prepared as described in Example 35) in methanol (30 mL) were added 2,6-dichloro-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde (115, 154 mg, 0.56 mmol) and potassium hydroxide (596.0 mg, 10.62 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 25% methanol in dichloromethane to give the desired compound (116, 0.18 g, 75.7%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].O.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:14]([O:13][CH:10]1[CH2:11][CH2:12][C:7]([C:36]2[C:31]([F:30])=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:8][CH2:9]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16]
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2cccnc2F)CC1
Temperature: 80 °C

Procedure:
To a sealable vessel was added 4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl trifluoromethanesulfonate (1.90 g, 5.27 mmol), sodium carbonate as a 2N solution in water (7.91 mL, 15.81 mmol), and 2-fluoropyridin-3-ylboronic acid (0.891 g, 6.33 mmol) before adding tetrakis(triphenylphosphine)palladium(0) (0.305 g, 0.264 mmol) under argon. The reaction mixture was sealed and set stirring at 80° C. After complete consumption of starting material, the black mixture was diluted with water before extracting with dichloromethane, drying over sodium sulfate, filtering, and concentrating under reduced pressure to an orange oil, which was used without purification. MS (ESI, pos. ion) m/z: 308.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH:9]1([N+:15]#[C-:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:17](=O)[CH3:18]>Cl(O)(=O)(=O)=O>[CH:9]1([NH:15][C:16]2[N:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]3=[N:1][C:17]=2[CH3:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: CC=O
Reactant: Cc1ccnc(N)c1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccn2c(NC3CCCCC3)c(C)nc2c1

Procedure:
Compound (18) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-4-methylpyridine solution (0.1 M, DCM), 0.575 ml of cyclohexyl isocyanide solution (0.2 M, DCM), 0.500 ml of acetaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH:30]([CH3:34])[CH2:29]1>C(O)C>[ClH:1].[CH3:34][CH:30]1[CH2:29][N:28]([CH3:27])[CH2:33][CH2:32][N:31]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4]
Reactant: CC1CN(C)CCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1CN(C)CCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Product: Cl
Yield: 20 %

Procedure:
8.6 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiaze-pin-6-one, 3.1 gm of sodium carbonate and 4.5 gm of 1,3-dimethyl-piperazine were refluxed in 100 ml of absolute ethanol for 3.5 hours. After suction filtration the filtrate was evaporated to dryness. The residue was then purified on a silica gel column. The obtained base was dissolved in ethanol by addition of hydrochloric acid to form the hydrochloride. After recrystallization from ethanol: M.p.: 301°-303° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18].[CH:35](N(C(C)C)CC)(C)C.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1CCl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:35][C:48]3[CH:49]=[N:44][CH:45]=[CH:46][CH:47]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18]
Reactant: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Reactant: CCN(C(C)C)C(C)C
Reactant: ClCc1ccccn1
Solvent: CN(C)C=O
Product: COc1cc(OC2CCN(Cc3cccnc3)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Methoxy-4-(4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl) piperazine-2-carboxamide (110 mg, 0.236 mmole) was dissolved in 3 ml of dry N,N-dimethylformamide. To this solution was added 86 μL (0.496 mmole) of diisopropylethylamine (DIEA) and 43 mg (0.26 mmole) of picolyl chloride. The reaction mixture was stirred at ambient temperature overnight and then was treated with an additional 20 mg of picolyl chloride. The pH of the reaction mixture was adjusted to 9 with DIEA and stirring was continued for 24 hr more. All volatiles were removed under reduced pressure and the residual material was partitioned between ethyl acetate and water. The organic phase was washed with 5% sodium carbonate solution and brine, then dried and concentrated. The crude product mixture was purified via preparative thick layer chromatography on precoated silica gel plates (80:20 chloroform-methanol elution) to give the title compound in homogeneous form: m.p. 78°-81° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])C[CH2:9][CH3:10].[Br:12][C:13]1[CH:26]=[CH:25][C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:28])[CH:21]=3)[C:16](=O)[C:15]=2[CH:14]=1.[Sn](Cl)Cl>C1COCC1.Cl.O.CCCCCC>[Br:12][C:13]1[CH:26]=[CH:25][C:24]2[C:15](=[C:16]([C:10]#[C:9][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:17]3[C:22]([C:23]=2[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:21][C:20]([Br:28])=[CH:19][CH:18]=3)[CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Reactant: [Li]CCCC
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C[Si](C)(C)C#Cc1c2ccc(Br)cc2c(C#C[Si](C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Trimethylsilylacetylene (13.51 g, 137.5 mmol) and dry hexane (300 mL) were charged to an oven-dried round bottom flask (1 L) under dry nitrogen. Butyl lithium (2.7 M in hexane, 46.3 mL, 125.1 mmol) was added dropwise under dry nitrogen through a syringe with water bath cooling. A white precipitate appeared immediately. The mixture was stirred at room temperature for 2 hours. It was then added to a suspension of 2,6-dibromoanthraquinone (18.30 g, 50.0 mmol) in dry THF (600 mL) under dry nitrogen. All of the solids dissolved after the addition and a dark red solution was obtained. A precipitate appeared after about 1 hour. The reaction mixture was stirred at room temperature for 16 hours. DI water (10.0 mL) was added and a white precipitate appeared. Tin (II) chloride (22.8 g, 120 mmol) in HCl (50 mL, 6 M) aqueous solution was then added. The mixture was heated to 70° C. for 2 hours and then cooled to room temperature. The solvent was removed by rotary evaporation. The residue washed with water and then extracted with warm CHCl3 (300 mL). After removal of the CHCl3 solvent, the residue was recrystallized from CHCl3. An orange solid (22.1 g, yield 84%) was obtained as the product. 1H NMR (400 MHz, CDCl3). δ ppm 9.061-9.100 (d, 2H, J=2.4 Hz), 8.757-8.812 (d, 2H, J=9.2 Hz), 8.030-8.091 (dd, 2H, J=9.2 Hz, J=2.0 Hz), 0.851 (s, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O>C1C=CC=CC=1>[Cl-:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([O-:9])=[O:8]
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C([O-])C=Cc1cccc(Cl)c1
Product: [Cl-]

Procedure:
100 ml of benzene was added to 18.3 grams of m-chlorocinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 80° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23]1[C:28](=[O:29])[CH:27]=[CH:26][NH:25][C:24]=1[CH3:30])[CH3:21].[CH2:31]([O:33][CH2:34][CH2:35]O)[CH3:32].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:20]([O:22][C:23]1[C:24]([CH3:30])=[N:25][CH:26]=[CH:27][C:28]=1[O:29][CH2:32][CH2:31][O:33][CH2:34][CH3:35])[CH3:21]
Reactant: CCOCCO
Reactant: CCOc1c(C)[nH]ccc1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCCOc1ccnc(C)c1OCC
Yield: 43.9 %

Procedure:
Triphenylphosphine (2.93 g, 11.2 mmol) was added to a stirred solution of 3-ethoxy-2-methylpyridin-4(1H)-one (1.42 g, 9.3 mmol, obtained from Example 4(b)) in THF (15 mL). 2-Ethoxy ethanol (2.93 g, 11.2 mmol) was added dropwise, followed by dropwise addition of DEAD (1.76 mL, 11.2 mmol). The reaction mixture was then stirred under reflux overnight. The solvent was evaporated in vacuo and the residue was dissolved in water (15 mL). The aqueous solution was adjusted to pH 1 with 2M hydrochloric acid, then extracted with ethyl acetate (3×20 mL). The combined organic phases were dried (MgSO4) and concentrated, and the crude product was purified by flash chromatography (CHCl3/MeOH; 9:1), giving the title compound (0.92 g, 44%).
Reaction SMILES: [CH3:1][O:2][N:3](C)[C:4](=O)C1C=CC(CCC2C=CC3C(=CC=CC=3)N=2)=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[C:29]([OH:31])=O>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[C:29]([N:3]([O:2][CH3:1])[CH3:4])=[O:31]
Reactant: CON(C)C(=O)c1ccc(CCc2ccc3ccccc3n2)cc1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(2-quinolin-2-yl-ethyl)-benzamide but substituting 3-Chloro-4-(quinolin-2-ylmethoxy)-benzoic acid provided the title compound. (M+H m/z=356.9).
Reaction SMILES: ClC1C=CC=CC=1Cl.[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH2:12].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH:12][S:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=1)(=[O:30])=[O:29]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: Clc1ccccc1Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
In a 400 ml flask, 200 ml of o-dichlorobenzene, 1 ml of pyridine and 1.7 g (0.01 mole) of 2-chloro-4-nitroaniline were charged. While stirring the contents at room temperature, 2.5 g (0.01 mole) of 3-trifluoromethylbenzenesulfonylchloride was added gradually over 30 minutes. Thereafter, the reaction mixture was heated and stirred for 8 hours under reflux (175°-180° C.) to complete the reaction. After cooling the reaction mixture to room temperature, it was thoroughly washed first with dilute hydrochloric acid and then with water. Subsequent to its dehydration with sodium sulfate, o-dichlorobenzene was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: benzene) to isolate the intended Compound 1. m.p. 126°-127° C., yield 1.9 g (50%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K].[I-].[Na+].O>CN(C)C=O>[CH3:8][N:7]1[C:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])=[N:4][N:5]=[N:6]1
Reactant: Cn1nnnc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnnc1CN1C(=O)c2ccccc2C1=O
Yield: 4 %

Procedure:
5-(Chloromethyl)-1-methyl-1H-tetrazole (a crude product 6.9 g prepared in accordance with Chemical & Pharmaceutical Bulletin, 37(2), 322-6:1989), was dissolved in 50 mL of dimethylformamide and stirred with potassium phthalimide (5.00 g, 27.0 mmol) and sodium iodide (391 mg, 2.60 mmol) at room temperature for 17 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the desired product (550 mg, 4% yield, two steps).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Br:23][C:24]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:25]=1[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:26]([C:25]1[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:24]=1[Br:23])=[O:27]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccn(C)c2=O)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)c1cc(OC)ccc1Br
Yield: 67.6 %

Procedure:
A solution of 4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (52 mg, 0.16 mmol), 2-bromo-5-methoxybenzoic acid (45 mg, 0.19 mmol), DIEA (140 μL, 0.80 mmol) and HBTU (85 mg, 0.22 mmol) in DMF (3 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation (85 mg) was chromatographed on 25 g of silica gel, eluting with ethyl acetate to give N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (54 mg, 68%). HRMS: Obs. Mass 499.0872. Calcd. Mass 15 499.0869 (M+H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]1([C:16]2[CH:17]=[N:18][NH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:10]1([C:16]2[CH:17]=[N:18][N:19]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCBr
Reactant: c1ccc(-c2cn[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCn1cc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
The mixture of ethyl 4-bromobutyrate (0.400 g, 2.05 mmole), 4-phenyl-1H-pyrazole (0.296 g, 2.05 mmole) and K2CO3 (0.567 g, 4.10 mmole) in DMF (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×). The combined organic phases were washed with water and then brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative to afford the desired product (73 mg, 52%) as colorless oil. LCMS calculated for C15H19N2O2 (M+H): 259. found: 259.1.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[F:21][C:22]([F:39])([F:38])[C:23]1[N:28]=[CH:27][C:26]([NH:29][NH:30]C(OC(C)(C)C)=O)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:26]2[CH:27]=[N:28][C:23]([C:22]([F:21])([F:38])[F:39])=[CH:24][CH:25]=2)[N:30]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)nc1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 69.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-[6-(trifluoromethyl)pyridin-3-yl]hydrazinecarboxylate (Intermediate-61, 0.431 g, 1.55 mmol), DCM (50 mL) and trifluoro acetic acid (5.0 mL) to afford 0.500 g of the desired product.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[OH:19])[CH2:13][CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1.[Cr](O)(O)(=O)=O.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[O:19])[CH2:13][CH:14]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: OC(CCCN1CC=C(c2noc(C3CC3)n2)CC1)c1ccc(F)cc1
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CCCN1CC=C(c2noc(C3CC3)n2)CC1)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
A 0.36 g. portion of 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-3,6-dihydro-α-(p-flurophenyl)-1(2H)-pyridinebutanol, prepared as described in Example 11, in 10 ml. of acetic acid is stirred at room temperature. A 6 ml. portion of chromic acid in acetic acid solution is added dropwise. The mixture is stirred for 2 hours and then allowed to stand overnight. A few drops of methanol and some water is added and the solution is neutralized with solid sodium bicarbonate. The mixture is extracted 3 times with ether. The extracts are dried over magnesium sulfate, filtered and evaporated, yielding a white solid which is recrystallized from aqueous methanol, m.p. 67°-68°C.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@H:5]([CH:24]([CH3:26])[CH3:25])[NH:6][C:7](=[O:23])[C@H:8]([CH3:22])[NH:9][C:10](=[O:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)C>C(Cl)(Cl)Cl.CO>[N+:18]([C:14]1[CH:13]=[C:12]([CH2:11][C:10]([NH:9][C@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:27])=[O:3])[CH:24]([CH3:25])[CH3:26])=[O:23])[CH3:22])=[O:21])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O

Procedure:
Following General Procedure AF and using N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester (from Example 143 above), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.05 in 9:1 CHCl3/MeOH).