Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[NH4+].O.[C:7]([NH:10][CH:11]([CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8]>C(#N)C>[C:7]([NH:10][C@H:11]([CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8]
Reactant: CCOC(=O)C(Cc1ccsc1)NC(C)=O
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@@H](Cc1ccsc1)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
3.95 g of ammonium hydrogen carbonate and 35 cm3 of deionized water are added to a stirred solution, under an inert atmosphere, of 2.41 g of ethyl 2-(acetylamino)-3-(3-thienyl)propanoate in 17 cm3 of acetonitrile. 0.017 g of type-II α-chymotrypsin is added and the pH of the reaction medium is then in the region of 8. This mixture is stirred for 1 hour at room temperature and, after checking that the pH is still at 8, a further 0.017 g of type-II α-chymotrypsin is added. After stirring for 1 hour, with the pH remaining constant, a further 0.017 g of type-II α-chymotrypsin is introduced and stirring of the reaction mixture is continued for 19 hours at room temperature. The acetonitrile is evaporated off under reduced pressure (2 kPa) at a temperature in the region of 33° C. and 25 cm3 of ethyl acetate are then added to the residual aqueous phase. The emulsion obtained is filtered through Celite and the aqueous phase is then extracted with twice 25 cm3 of ethyl acetate. The organic phases are combined, washed with twice 15 cm3 of sodium carbonate solution and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The solid residue is then dried in an oven under vacuum (10 Pa) at room temperature. 1.1 g of ethyl (2R)-2-(acetylamino)-3-(3-thienyl)propanoate are obtained in the form of a beige-colored solid melting at about 75° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.[CH2:12]([Mg]Br)[CH2:13][CH3:14].Cl>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:12][CH2:13][CH3:14])=[N:6][N:5]2[CH:11]=1
Reactant: CCC[Mg]Br
Reactant: Clc1cn2nc(Cl)ccc2n1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1ccc2nc(Cl)cn2n1
Temperature: 5 °C

Procedure:
Under a nitrogen stream, 2,6-dichloroimidazo[1,2-b]pyridazine (0.50 g, 2.66 mmol) and iron(III) acetylacetonate (0.094 g, 0.27 mmol) were added to tetrahydrofuran (5.0 ml), and a solution of n-propylmagnesium bromide in tetrahydrofuran (2 M, 1.99 ml, 3.99 mmol) was added dropwise over 13 minutes to the mixture with stirring at 0 to 10° C. After stirring for 10 minutes under ice-cooling, the reaction mixture was warmed to room temperature and stirred for 6 hours at room temperature. The reaction mixture was poured onto ice-cold water, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated saline. The resulting organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound as pale yellow crystals. The yield was 0.28 g (53.8%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N:8]=O.[S:10](=[O:14])(=[O:13])([OH:12])[OH:11]>[Pd]>[S:10](=[O:12])(=[O:11])([OH:14])[OH:13].[NH2:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH2:1]
Reactant: Cn1ncc(N=O)c1N
Agent: [Pd]
Agent: O=S(=O)(O)O
Product: Cn1ncc(N)c1N
Reaction time: 10 h
Yield: 81 %

Procedure:
To a suspension of 5-amino-1-methyl-4-nitrosopyrazole (117 g) were added sulfuric acid (91 g) and 10% palladium on carbon (58 g) The mixture was hydrogenated under balloon pressure for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. To the concentrate was added isopropyl alcohol (2.3 L), and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give 4,5-diamino-1-methylpyrazole sulfuric acid salt (158 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[C:26]([O:30][C:31]([NH:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[OH-].[Na+]>CN(C=O)C.CO>[C:26]([O:30][C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:39][CH:40]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-tert.butoxycarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+].[Na+].S(=O)(=O)(O)O>O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([OH:10])=[O:9])[CH:2]2[C:11]([OH:13])=[O:12]
Reactant: O=C([O-])C1C2CCC(C2)C1C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)C1C2CCC(C2)C1C(=O)O
Temperature: 25 °C

Procedure:
100.0 g (438.3 mmoles) of disodium bicyclo[2.2.1]heptane-2,3-dicarboxylate (228.15 g/mole) and 280 ml of water were charged into a 2L Erlenmeyer flask with stirring. To this solution was added fuming sulfuric acid until the pH of the resulting solution was ˜1. As the pH became acidic, a white flocculent precipitate formed. The solution was stirred and cooled to room temperature. The precipitate was removed by vacuum filtration and dried overnight in a vacuum oven at 110° C. The resulting product (melting point of 152.1-153.4° C.) was dried and milled. An IR analysis was consistent with that of the expected structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13](OC)=[O:14])[N:10]=[CH:9]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]1
Reactant: COC(=O)c1cn(-c2ccccc2Cl)cn1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn(-c2ccccc2Cl)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mg (0.21 mmol) of the compound from Example 34A were dissolved in 1 ml of THF, and 222 μl (0.22 mmol) of a 1 N solution of lithium aluminum hydride in THF were added at −10° C. Over a period of one hour, the mixture was then warmed to RT. For work-up, 2 ml of water and 5 ml of saturated potassium sodium tartrate solution were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave 34 mg (56% of theory) of the target compound in a purity of 73%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[C:9]2=[O:36])=[CH:4][C:3]=1[C:37](F)(F)F.CC1(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(=O)N(C2C=CC([N+]([O-])=O)=C(C)C=2)C1=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:31])[F:32])[C:9]2=[O:36])=[CH:4][C:3]=1[CH3:37]
Reactant: CC1(C)C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Agent: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1[N+](=O)[O-]
Product: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1N
Yield: 93 %

Procedure:
The experimental protocol is the same as that described for the compound of Example 16, the compound of Example 23 replacing the compound of Example 1. The expected compound is obtained in the form of a brown oil with a yield of 93%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:26][C:27]([C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=1)=[O:28].C(N(CC)C(C)C)(C)C.I[CH2:46][C:47]([NH2:49])=[O:48]>CN(C)C=O>[NH2:49][C:47](=[O:48])[CH2:46][N:11]1[C:12](=[N:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:4]=2)=[CH:10]1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 72.6 %

Procedure:
In the same manner as in Reference Example 5 and using N-{2-fluoro-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (7.25 g, 14.6 mmol), N,N-diisopropylethylamine (3.31 mL, 19.0 mmol), N,N-dimethylformamide (30 mL) and iodoacetamide (3.51 g, 19.0 mmol) as starting materials, the title compound (5.86 g, 73%) was obtained as a white solid.
Reaction SMILES: [C:1]([S:20][CH2:21][C@@H:22]([C:24]([NH2:26])=[O:25])[NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([S:48]([NH:23][C@H:22]([C:24]([NH2:26])=[O:25])[CH2:21][S:20][C:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Part C: To a solution of 2.93 grams (8.1 mmol) of S-trityl-L-cysteine amide in 50 mL of dry methylene chloride was added 2 equivalents of triethylamine followed by 2.29 grams (8.1 mmol) of 4-(4′-methoxyphenyl)phenylsulfonyl chloride. The solution was stirred at room temperature for one hour, then concentrated on a rotory evaporator. The resulting slurry was partitioned between ethyl acetate and water. The organics were washed with 5% potassium hydrogen sulfate, saturated sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated to give 4.2 grams of crude product. The crude material was purified by silica gel chromatography using 1:1 ethyl acetate:hexane as the eluent to yield 3.36 grams of pure N-(4-(4′methoxyphenyl)-benzenesulfonyl-S-trityl-L-cysteine amide as a white solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH2:18](O)[CH2:19][OH:20]>C1(C)C(S(O)(=O)=O)=CC=CC=1.O>[O:1]([CH2:8][C:9]([O:11][CH2:18][CH2:19][OH:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=C(O)COc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C(COc1ccccc1)OCCO
Reaction time: 8 h

Procedure:
Into a 5000 ml. 3-necked flask, equipped with thermometer, stirrer, condenser and Dean-Stark trap were weighed 924 gms. of phenoxyacetic acid. There were added 2 gms. toluene sulfonic acid as catalyst and 100 mls. of benzene. Heating was started with stirring and there were added 2270 gms. of ethylene glycol. At reflux temperature water was collected and taken off. After 11 and 1/2 hours of refluxing the reaction mixture was transferred to a 6 liter separatory funnel where excess ethylene glycol was separated and recovered. The benzene layer was extracted with hot water and sodium bicarbonate and the benzene layer was filtered warm through a molecular sieve to remove residual water. The benzene extract was allowed to stand overnight and the crystals which formed were removed by filtration and dried in a vacuum oven. A total of 370.2 gms. product was recovered, m.p. 61°-63° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[C:15](Cl)=[N:16][C:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:18][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>O1CCCC1.[Zn]>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[N:16][C:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:18][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(Cc2nc(Cl)c3c(n2)CCN(Cc2ccccc2)CC3)c1
Agent: N
Agent: [Zn]
Solvent: C1CCOC1
Product: Clc1cccc(Cc2ncc3c(n2)CCN(Cc2ccccc2)CC3)c1
Yield: 66.9 %

Procedure:
Zinc dust (943 mg, 14.4 mmol) was added to a mixture of the product from Step B (221 mg, 0.56 mmol) and 0.880 ammonia (20 ml) in tetrahydrofuran (5 ml). This was heated to reflux for 5 h. The reaction mixture was filtered then filtrate was extracted with ethyl acetate (15 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on a silica cartridge, eluting with DCM:MeOH (100:0 to 95:5), to afford the title compound as a pale orange oil in 66.9% yield, 135 mg.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([C:17]([OH:19])=O)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C(C)=CC=CC=1C>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([C:17](=[O:19])[NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)O)OC2
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)NCc1ccccc1)OC2
Reaction time: 72 h
Yield: 54.5 %

Procedure:
To a solution of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester (101 mg, 0.34 mmol, prepared in Example 31) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.41 mmol) in distilled dichloromethane (4 ml) under nitrogen was added benzylamine (40 μl, 0.37 mmol) followed by 2,6-lutidine (0.12 ml, 1.02 mmol). The reaction was stirred for 72 h., concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (Na2SO4) over sodium sulfate, filtered, and the solvent evaporated in vacuo to give 72 mg (56%) of 2-amino-5-benzylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1C(C2C=CC(C#N)=CC=2)O1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Reactant: CC(C)(N)CO
Solvent: CCOCC
Product: CC(C)(CO)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-3-(4-cyanophenyl)-oxaziridine (CAS #: 150884-56-3, purchased from Acros, 5.17 g, 21 mmol) in anhydrous diethyl ether (20 mL) was added to a solution of 2-amino-2-methyl-propan-1-ol (1.78 g, 20 mmol) in anhydrous diethyl ether (20 mL) at room temperature. The reaction mixture stirred at room temperature for 2 hours. Diethyl ether was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of 3-5% methanol/dichloromethane to give N′-(2-hydroxy-1,1-dimethyl-ethyl)-hydrazinecarboxylic acid tert-butyl ester (1.63 g, 40%) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:17]=1>N1C=CC=CC=1.C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(N2CCN(S(=O)(=O)c3cccnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of 1-(4-nitrophenyl)-piperazine (2.50 g, 12.1 mmol) in pyridine (15 mL) was added a solution of pyridine-3-sulfonyl chloride (2.78 g, 15.7 mmol) in THF (30 mL) under an argon atmosphere at 0° C. The reaction was warmed to r.t. and stirred for 2 h, before the mixture was evaporated to dryness. The residue was partitioned between water and dichloromethane, the organic layer separated and washed successively with sat. sodium bicarbonate solution, water and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was subjected to column chromatography over neutral alumina using 5% to 70% ethyl acetate in petroleum ether as eluent to afford 1-(4-nitrophenyl)-4-(pyridine-3-sulfonyl)-piperazine (1.63 g, 39%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13]3=[C:14]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=N[CH:23]=[CH:24][CH:25]=4)=[CH:18][N:12]3[C:11]3[CH:10]=[CH:9][C:8]([Cl:27])=[CH:7][C:6]=3[O:5]2)[CH:15]=1.[CH:28](=O)C1C=CC=CC=1>>[Cl:27][C:8]1[CH:7]=[C:6]2[C:11]3=[C:10]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=[CH:28][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:12]3[C:13]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=3[O:5]2)[CH:9]=1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(Cl)cc13)Oc1cc(Cl)ccc1-2
Reactant: O=Cc1ccccc1
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(Cl)cc13)Oc1cc(Cl)ccc1-2
Yield: 81 %

Procedure:
According to Example 1<step 4>, the compound (500 mg) produced in Example 1<step 3> was reacted with benzaldehyde (260 μl) to obtain the title compound (508 mg; 81%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc([N+](=O)[O-])ccc2Cl)n1
Temperature: 150 °C
Yield: 67.6 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-chloro-5-nitrobenzoyl chloride (0.086 g, 0.390 mmol) and triethylamine (0.5 mL, 6.81 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.051 g (68% yield) of pure product: MS (ES) m/z 489 (M+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[C:8]1(=O)[CH2:11][CH2:10][CH2:9]1.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[CH2:8]1[C:11]2([O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]2)[CH2:10][CH2:9]1
Reactant: O=C1CCC1
Reactant: OCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: OCC1COC2(CCC2)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (5.58 g, 52.6 mmol), cyclobutanone (3.69 g, 52.6 mmol), p-toluenesulfonic acid monohydrate (550 mg, 2.89 mmol) and benzene (92.9 ml) was refluxed in a round-bottom flask equipped with a cooling tube and Dean-Stark for 8 hours and 35 minutes. After the reaction mixture was cooled to room temperature, triethylamine (1 ml) was added to the reaction mixture and the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel: 300 g, elution solvent: heptane, heptane/ethyl acetate=1/1). The fractions containing the title compound were collected with ethyl acetate and concentrated. The residue was dissolved in diethyl ether and then the mixture was concentrated to obtain the title compound (6.08 g, yield: 73.1%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH:11]=[O:12]
Reactant: COc1cc(F)cc(F)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)cc(F)c1C=O
Temperature: 0 °C
Yield: 57.3 %

Procedure:
3,5-Difluoroanisole (50 g, 0.35 mol) was charged to a 3-neck flask fitted with thermometer, dropping funnel and argon bubbler. Dichloromethane (200 mL) was added and the solution was cooled in ice-water. Titanium (IV) chloride (61.5 mL, 0.56 mol) was added dropwise (15 min), followed by dropwise addition of α,α-dichloromethyl methyl ether (31.5 mL, 0.35 mol) so that the temperature was maintained <10° C. (approx 20 min). The reaction was stirred in ice-water for a further 140 min, poured into ice-water (1 L), then extracted thrice with DCM. The organic solutions were washed with water, brine then dried (MgSO4) and evaporated. The crude product was purified using the Versaflash (80×300 mm SiO2 cartridge, gradient from DCM to 5% EtOAc) in 7 separate batches to give the title compound (34.5 g, 57%) as an orange solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)O1.Br[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=1>>[CH3:46][O:45][C:43]([CH2:42][C:39]1[CH:40]=[CH:41][C:36]([C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:16]=3[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:11][CH:10]=2)=[CH:37][CH:38]=1)=[O:44]
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)cc3C(=O)OC(C)(C)C)cc2)cc1
Yield: 52 %

Procedure:
According to a method similar to Example (8-1), from tert-butyl 2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-5-(trifluoromethyl)benzoate (100 mg, 0.21 mmol) obtained in Example (2-4) and methyl (4-bromophenyl)acetate (62 mg, 0.27 mmol) obtained in Example (3-1), tert-butyl 2-[({4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-5-(trifluoromethyl)benzoate was obtained (54 mg, yield: 52%).