Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:12]=[C:11]([Cl:21])[C:10]=1[F:22])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:21])[C:10]=1[F:22])[CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: CCN(CC)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCN(CC)Cc1cc(Cl)c(F)c(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (3-chloro-5-diethylaminomethyl-2-fluoro-benzyl)-carbamic acid tert-butyl ester (115 mg, 0.33 mmol) in MeOH (1 mL) was added a solution of 4N HCl in dioxane (3 mL). The reaction mixture was stirred for 2 h at ambient temperature and the solvent was removed in vacuo to give the title compound. MS (LC/MS): 245.0 [M]+; tR (HPLC conditions c): 2.13 min.
Reaction SMILES: C([C:3]1[Se:7][C:6]([C@@H:8]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C3C=CC=CC=3)[C@@H:19]([O:20]C(=O)C3C=CC=CC=3)[C@H:9]2[O:10]C(=O)C2C=CC=CC=2)=[N:5]C=1C(N)=O)C.C[O-].[Na+].C1(C)C=CC=CC=1.[C:54]([O:57][CH2:58]C)(=[O:56])[CH3:55]>CO>[C@@H:8]1([C:6]2[Se:7][CH:3]=[C:55]([C:54]([O:57][CH3:58])=[O:56])[N:5]=2)[O:30][C@H:29]([CH2:31][OH:32])[C@@H:19]([OH:20])[C@H:9]1[OH:10]
Reactant: CCc1[se]c([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)nc1C(N)=O
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C

Procedure:
A gummy suspension of 206.3 g (75.1% pure by HPLC; 0.239 mol) of the blocked ethyl ester, IV, in 700 ml of methanol was heated and stirred on the steam bath until solution occurred. The solution was allowed to cool to room temperature during which time a finely dispersed oily suspension formed. To this suspension was added 17.2 g (318 mmol) of sodium methoxide. The addition was slightly exothermic and resulted in a brown solution. The solution was stirred at room temperature overnight. TLC (SiO2, toluene-ethyl acetate, 10:1) indicated that no starting material remained. To the reaction solution was added 100 g of Dowex 50 W×4 resin (H+) (washed with methanol) and the suspension was stirred for one hour. The resin was filtered off, washed well with methanol, and discarded. The filtrate and washings were evaporated under reduced pressure to give a two phase mixture. The upper, more liquid phase (mainly methyl benzoate) was decanted. The remaining brown viscous gum was triturated two times with ether. (The methyl benzoate was combined with the ether triturates and upon standing yielded some desired product as a solid). The brown viscous gum was treated with approximately 1 l of warm ethanol and triturated. A dark brown material was filtered from the suspension. TLC (SiO2; dichloromethane-methanol, 10:1) indicated that the dark brown material was mostly slower moving impurities in the filtrate and was discarded.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:8]1[CH:17]=[CH:16][C:15]2[C:14]([C:18]([NH:20][CH2:21][C@:22]3([OH:29])[CH2:27][CH2:26][CH2:25][C@H:24]([CH3:28])[CH2:23]3)=[O:19])=[C:13]([Cl:30])[CH:12]=[CH:11][C:10]=2[N:9]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:30][C:13]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]([N:4]3[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]3)[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:20][CH2:21][C@:22]1([OH:29])[CH2:27][CH2:26][CH2:25][C@H:24]([CH3:28])[CH2:23]1)=[O:19]
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: O[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](O)C4)ccc23)C1
Temperature: 120 °C

Procedure:
(S)-3-hydroxypyrrolidine (80 mg) was added to a suspension of the product of step d) (0.2 g) and diisopropylethylamine (300 μl) in acetonitrile (3 ml). The reaction mixture was heated in a microwave (100 W) for 30 minutes at 120° C. before being concentrated in vacuo. Water (15 ml) was added and the suspension sonicated for 10 minutes. The solid was filtered and dried in vacuo overnight to afford the title compound as a cream solid (180 mg). m.p. 222° C. (acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:30][C:31]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([CH:40]([CH3:42])[CH3:41])[O:33][N:32]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:30][C:31]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([CH:40]([CH3:42])[CH3:41])[O:33][N:32]=1
Reactant: COC(=O)c1c(CO)noc1C(C)C
Reactant: Cc1cccc(C)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(COc2c(C)cccc2C)noc1C(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 2,6-dimethylphenol (184 mg, 1.51 mmol), triphenylphosphine (396 mg, 1.51 mmol), and methyl 3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (300 mg, 1.51 mmol) in toluene (4 mL) was slowly added diisopropyl azodicarboxylate (0.272 mL, 1.51 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes and then allowed to stand at ambient temperature overnight. The solution was concentrated and purified by chromatography (silica gel, 2.5% acetone in hexanes) to afford methyl 3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (329 mg, 72%). 1H-NMR (400 MHz, DMSO-d6) δ 7.02-6.90 (m, 3H), 5.00 (s, 2H), 3.74 (s, 3H), 3.72 (septet, J=7 Hz, 1H), 2.17 (s, 6H), 1.28 (d, J=7 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:17][N:8]1[C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:10]=[C:9]1[C:11]([F:14])([F:13])[F:12]
Reactant: O=[N+]([O-])c1ccc2[nH]c(C(F)(F)F)nc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C(F)(F)F)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
5-Nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (4.45 g, 19.1 mmol, 1.0 eq.), K2CO3 (3.2 g, 23.0 mmol, 1.2 eq.) and methyliodide (1.2 ml, 19.1 mmol, 1.0 eq.) were dissolved in DMF (anhydrous, 50 ml). The reaction was stirred at RT for 2 h. TLC showed mostly starting material. The mixture was stirred at RT for another 16 h. The DMF was removed in vacuo and the residue redissolved in a minimum of hot EtOAc and recrystallized (gave mixture). Crystals and mother liquor were combined and evaporated down. Purification by column chromatography (0-25% EtOAc/Hex) yielded 1-methyl-5-Nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (1 g) and 1-methyl-6-Nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole. Structures confirmed by NOESY NMR.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=O)=[O:14])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:20])(=[O:16])=[O:14])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC#CCOc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: -10 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
30 g (107 mmol) of the sodium salt of 4-but-2-ynyloxybenzenesulfonic acid in 120 ml of dimethylformamide are added dropwise to a solution of 28 ml (321 mmol) of oxalyl chloride in 120 ml of dichloromethane, cooled beforehand to −10° C., and then the reaction medium is stirred at ambient temperature for 18 h. 800 ml of ice are added and the medium is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. 22 g (84%) of 4-but-2-ynyloxybenzenesulfonyl chloride are obtained in the form of a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[N:5]([C:7]2[C:12]([Br:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:17][C:18]1[C:26]([Br:27])=[CH:25][C:24]([Br:28])=[CH:23][C:19]=1[C:20](O)=[O:21].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:28][C:24]1[CH:25]=[C:26]([Br:27])[C:18]2[N:17]=[C:14]([C:4]3[N:5]([C:7]4[C:12]([Br:13])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH:6]=[C:2]([Br:1])[CH:3]=3)[O:16][C:20](=[O:21])[C:19]=2[CH:23]=1
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Reactant: O=C(O)c1cc(Br)cn1-c1ncccc1Br
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Br)cn2-c2ncccc2Br)nc2c(Br)cc(Br)cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-1-(3-bromo-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[4-bromo-1-(3-bromo-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C[O-].[Na+].[C:22](=O)(OCC)[O:23]CC>C1(C)C=CC=CC=1>[OH:23][C:22]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(=O)c2c(ncn2Cc2noc(O)n2)n(C)c1=O
Yield: 82 %

Procedure:
5.04 g. of 2-(theophylline-7-yl)-acetamidoxime, 2.16 g. of sodium methylate, 4.72 g. of diethyl carbonate and 100 cm3 of toluene are heated for 2 hours to boiling, the mixture is then evaporated and the residue crystallized from water. 4.3 g. (82% yield) of 7-[(5-hydroxy-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. M.p.: 206°-207° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.O[C@H]1CCNC1.Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([C:24]([NH:26][CH2:27][C@:28]3([OH:35])[CH2:33][CH2:32][CH2:31][C@H:30]([CH3:34])[CH2:29]3)=[O:25])=[C:19]([Cl:36])[CH:18]=[CH:17][C:16]=2[N:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:36][C:19]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)[CH:23]=[CH:22][C:21]=2[C:20]=1[C:24]([NH:26][CH2:27][C@:28]1([OH:35])[CH2:33][CH2:32][CH2:31][C@H:30]([CH3:34])[CH2:29]1)=[O:25]
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: O[C@@H]1CCNC1
Agent: O[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](O)C4)ccc23)C1

Procedure:
The title compound was prepared by the method of Example 1, step e) by reacting (R)-3-hydroxypyrrolidine (80 mg) (instead of (S)-3-hydroxypyrrolidine) with the product of Example 1, step d) (0.2 g) and diisopropylethylamine (300 μl) in acetonitrile (3 ml) to afford the title compound as a cream solid (190 mg). m.p. 222-223° C. (acetonitrile).
Reaction SMILES: IC1C=CC=C(C)C=1C(O)=O.[NH2:12][CH2:13][C@@H:14]1[C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][N:15]1[C:21]([C:23]1[C:28]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:35])=[O:22].F[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[CH3:20][C@@H:19]1[CH2:18][CH2:17][CH2:16][N:15]([C:21]([C:23]2[C:28]([C:29]3[N:30]=[CH:31][CH:32]=[CH:33][N:34]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:35])=[O:22])[C@@H:14]1[CH2:13][NH:12][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Cc1cccc(-c2ncccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN
Agent: Cc1cccc(I)c1C(=O)O
Product: Cc1cccc(-c2ncccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A230 using 2-iodo-6-methylbenzoic acid to make ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-6-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13]2([CH3:16])[CH2:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:17]2[NH:21][C:20]3[CH2:22][NH:23][C:24](=[O:25])[C:19]=3[CH:18]=2)[N:3]=1.[Cl:26]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:26][C:18]1[C:19]2[C:24](=[O:25])[NH:23][CH2:22][C:20]=2[NH:21][C:17]=1[C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[C:2]([CH3:1])=[N:3]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CNC4=O)c2nc1NC1(C)CC1
Solvent: ClC(Cl)Cl
Product: Cc1nc2cccc(-c3[nH]c4c(c3Cl)C(=O)NC4)c2nc1NC1(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.2 %

Procedure:
To a 25-mL round-bottomed flask was added 2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (357) (68 mg, 0.20 mmol), N-chlorosuccinimide (33 mg, 0.24 mmol) (Alfa-Aesar, Ward Hill, Mass.), and CHCl3 (3 mL). The reaction mixture was stirred at RT for 16 h and partitioned between water (5 mL) and EtOAc (5 mL). The organic extract was washed with brine (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0-3% MeOH in DCM to provide 3-chloro-2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (358) (9 mg, 12% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.40 (dd, J=1.27, 7.73 Hz, 1H), 7.75 (s, 2H), 7.70 (dd, J=1.27, 8.12 Hz, 1H), 7.44 (t, J=7.82 Hz, 1H), 4.32 (s, 2H), 2.51 (s, 3H), 1.45 (s, 3H), 0.90-0.95 (m, 2H), 0.73-0.79 (m, 2H). m/z (ESI, +ve) 368.1 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:20](C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:31](O)C>>[CH2:2]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][CH3:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCO
Reactant: CCCCCCCCCCCCCCCCCCN(C)c1ccccc1[N+](=O)[O-]
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCNc1ccccc1NC

Procedure:
Add 23.6 g (0.22 mol) N-methylaniline into 92 g (0.2 mol) 14% hexane solution of N-butyllithium and stir it for 10-20 minutes. Add 33.3 g (0.1 mol) octadecylbromide into the above solution, while stirring it. Add 200 ml water into the solution, after heating and refluxing the solution for about 17 hours and cooling it down to room temperature. Add 6N hydrochloric acid to the solution after concentrating the solution extracted by 300 ml diethyl ether and deposit it. 32.3 g (0.09 mol) N, N-methyloctadecyl-aniline is obtained by refinement through crystaiization with ethyl alcohol and water. Dissolve the obtained 32.3 g (0.09 mol) N, N-methyloctadecyl-aniline into 250 ml concentrated sulfuric acid. Add 30 ml concentrated nitric acid into the solution while stirring it in an ice water bath. Leave it about one hour after adding the nitric acid. Add the solution into ice water, filter off the deposit from it, and refine it by crystallization with ethyl alcohol and water. With the above step, 14.5 g (0.036 mol) N, N-octadecylmethyl-o -nitroaniline is obtained. Add 100 ml 2N hydrochloric acid into this 14.5 g (0.036 mol) N, N-octadecylmethyl-o-nitroaniline which is dissolved into 200 ml ethyl alcohol. 11.7 g (0.031 mol) N, N-octadecylmethyl-o-phenylene-diamine is obtained after adding 11.75 (0.18 mol) zinc dust into the above solution to be heated and refluxed for one hour.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:3]=1[O:13][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(I)cc(Br)c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1c(Br)cc(I)cc1C(C)(C)C

Procedure:
A solution of 2-bromo-6-tert-butyl-4-iodophenol (5.0 g, 14.08 mmol) in acetone (50 mL) was treated with potassium carbonate (2.92 g, 21.13 mmol) and dimethylsulfate (1.95 g, 15.49 mmol) at reflux for 16 hours, cooled and concentrated. The residue was dissolved in ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified on an Isco 40 g silica cartridge eluting with 2% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C@@H:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7](O)=[O:8])(=[O:4])=[O:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:42]([NH:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(CC)CC>>[CH2:42]([NH:49][NH:50][C:7]([C@@H:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)[C@H](NS(C)(=O)=O)C(=O)O
Reactant: NNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](NS(C)(=O)=O)C(=O)NNCc1ccccc1
Yield: 58 %

Procedure:
A solution of methanesulfonyl chloride (0.593 mL, 7.62 mmol) in 1M NaOH (7.60 mL, 15.2 mmol) and THF (10 mL) was added drop wise to a stirred mixture of (L)-tert-leucine (1.0 g, 7.6 mmol), dissolved in THF (7.6 mL) and H2O (12 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The mixture was acidified with 4M HCl and extracted with EtOAc. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give (2S)-2-methanesulphonylamino-3,3-dimethyl-butyric acid (0.486 g, 30%), which was analyzed by NMR and then used without further purification. The general procedure for the preparation of hydrazides described above was then followed using the crude (2S)-2-methanesulfonylamino-3,3-dimethyl-butyric acid (0.476 g, 2.27 mmol), EDAC (0.481 g, 2.51 mmol), HOBT (0.338 g, 2.50 mmol), NMM (0.275 mL, 2.50 mmol), benzylhydrazine×2HCl (0.489 g, 2.51 mmol) and Et3N (0.700 mL, 4.98 mmol) which gave the title compound (0.416 g, 58%) as a white solid.
Reaction SMILES: [H][H].[CH3:3][C:4]1([CH3:20])[C@@H:6]([C:7]#[C:8][C:9](=[O:16])[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C@H:5]1[C:17]([OH:19])=[O:18].N1C2C(=CC=CC=2)C=CC=1>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:3][C:4]1([CH3:20])[C@@H:6](/[CH:7]=[CH:8]\[C:9](=[O:16])[O:10][CH2:11][C:12]([F:15])([F:13])[F:14])[C@H:5]1[C:17]([OH:19])=[O:18]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(F)(F)F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Yield: 64.5 %

Procedure:
500 mg of 10% palladium hydroxide on barium sulfate and 5 ml of ethyl acetate were placed in a round flask connected to a hydrogen apparatus and 2 g of the product of Step C, 45 ml of ethyl acetate and 0.5 ml of quinoline were added thereto. Hydrogenation was carried out until hydrogen absorption ceased and the mixture was filtered. The filtrate was washed with N hydrochloric acid, then with water and evaporated to dryness. The 2 g of residue were chromatographed over silica gel and eluted with a 70-20-1 cyclohexane-ethyl acetate-acetic acid mixture to obtain 1.3 g of (1R,cis) 2,2-dimethyl-3-[(Z )-3-oxo-3-(2,2,2-trifluoro-ethoxy)-1-propenyl]cyclopropane-carboxylic acid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C:12]1[C:16]([CH3:17])=[C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[S:14][C:13]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][C:24]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:16]([CH3:17])[C:12]=2[CH2:11][F:7])=[CH:25][CH:26]=1
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CF
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of diethylaminosulfer trifluoride (DAST, 0.06 mL) in CH2Cl2 (5 mL) was added 3-hydroxymethyl-2,5-di(4-pyridyl)-4-methylthiophene (0.144 g) at 0° C. under nitrogen. The resulting mixture was stirred at room temperature for 1 hour. DAST (0.06 mL) was additionally added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water and the whole was extracted with CH2Cl2 (50 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-CH2Cl2 (1:1). The resulting solid was recrystallized from diisoplopanol-diisopropyl ether to give the title compound (0.056 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](Cl)=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([N:33]6[CH2:38][CH2:37][O:36][CH2:35][CH2:34]6)=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)Cl)s5)nn34)ccnc2c1
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)N6CCOCC6)s5)nn34)ccnc2c1
Temperature: 25 °C

Procedure:
To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carbonyl chloride (0.100 g, 0.21 mmol) in dichloromethane (2 mL) at 0° C. was added morpholine (0.19 g, 2.1 mmol). The solution was stirred at room temperature twenty minutes, then was concentrated and purified by MPLC chromatography (eluted with 3% methanol in dichloromethane) to yield a yellow solid. Trituration in acetonitrile and filtration afforded the product as a white solid. MS m/z=517.2 [M+1]+. Calc'd for C26H24N6O4S: 516.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1C=CC=CC=1>[C:30](=[O:31])([O:29][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCCOC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 1.07 g. of chloroformic acid n-heptyl ester as in Example 1. The 1.8 g. of yellow oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.782 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-heptyl carbonate obtained melts at 50.2°-50.5° and has a clearing point of 65.2°. UV (EtOH): ε 270 = 25900.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])(O)=O.[Na+]>CCO>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH3:17])[CH3:16]
Reactant: CCOC(=O)C(C)Br
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Yield: 83 %

Procedure:
A mixture of 3,4-dichloroaniline (20.0 g, 120 mmol), ethyl 2-bromopropionate (26.0 g, 144 mmoL), and NaHCO3 (15.1 g, 180 mmol) in EtOH (200 mL) was heated at reflux. After 16 h another portion of ethyl 2-bromopropionate (13.9 g, 96.7 mmol) and NaHCO3 (8.00 g, 95 mmol) was added, and the mixture heated at reflux for an additional 24 h, then evaporated under vacuum. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 1:1) afforded the title compound (26.1 g, 83%). Yellow oil, MS: 262.0 (M+H)+.