Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12]([F:13])=[CH:11][N:10]=[C:9]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=4)[N:16]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:15]=3)[N:8]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH2:43]([S:46](Cl)(=[O:48])=[O:47])[CH2:44][CH3:45].N1CCOCC1>C1COCC1>[Cl:23][C:20]1[CH:21]=[C:22]2[C:14]([C:9]3[N:8]=[C:7]([NH:6][CH:4]4[CH2:3][N:2]([S:46]([CH2:43][CH2:44][CH3:45])(=[O:48])=[O:47])[CH2:5]4)[C:12]([F:13])=[CH:11][N:10]=3)=[CH:15][N:16]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:17]2=[N:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCS(=O)(=O)N1CC(Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 50 °C
Yield: 43 %

Procedure:
To a stirred suspension of N-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.055 g, 0.110 mmol) in THF (1 mL) was added iPr2NEt (0.300 mL, 1.720 mmol) followed by propane-1-sulfonyl chloride (0.012 mL, 0.108 mmol). The resulting homogenous light yellow solution mixture was heated at 50° C. for one hour at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube for 10 minutes. The resulting solution was quenched with aqueous saturated NH4Cl solution (0.5 mL) then evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 19.8 mg (43% yield) of the desired product, 423, as a solid.
Reaction SMILES: [ClH:1].[ClH:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C.O>[ClH:17].[Cl:1][C:8]1[CH:9]=[C:10]([Cl:2])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N2CCNCC2)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 530 mg (2.0 mmol) of 1-(3-Methoxyphenyl)piperazine dihydrochloride in 7 mL of acetic acid and 4 mL of water at 0° C. was added 700 mg (4.4 mmol) of N-chlorosuccinimide. The reaction was taken out of the ice/water bath after 2 hours, and allowed to stir overnight. After 12 hours, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ether and water. The phases were separated, the aqueous was basified with 1M NaOH, and was extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, the solution was acidified with 5M HCl in isopropanol and was diluted with ethyl acetate to effect crystallization. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.38 (s, 1H), 6.72 (s, 1H), 3.78 (s, 3H), 3.32 (m, 4H), 3.19 (m, 4H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=1
Reactant: CC(C)(C)CNc1nc(Cl)cc(Cl)n1
Reactant: C1CCNC1
Product: CC(C)(C)CNc1nc(Cl)cc(N2CCCC2)n1
Yield: 96.7 %

Procedure:
The reaction of 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine with pyrrolidine as described in Example 12 gives the title product in a yield of 96.7%, m.p.: 147°-150° C.
Reaction SMILES: O[C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[OH2:21]>N1C=CC=CC=1.ClCCl>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:21][C:5]2[C:6](=[O:7])[CH:2]([CH3:9])[O:3][C:4]=2[CH3:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CC1=CC(=O)C(C)(O)O1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(OS(=O)(=O)c2ccc(C)cc2)C(=O)C(C)O1
Temperature: -10 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
12.8 grams (0.1 m) of 4 hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-one were dissolved in 70 ml of dry pyridine. The solution was stirred and cooled to -10° C in an ice-salt bath. With stirring a cold solution of 22.9 grams (0.12 m) of p-toluene sulfonylchloride in 50 ml of dry dichloromethane was added dropwise (temp. below -5° C). After completion of the addition (1 hour), stirring at 0° C was continued for 3 hours, and water (10 ml) was added in portions at intervals of 5 min., with stirring and cooling, so that the temperature did not rise above 5° C. The solution was then poured into 250 ml of ice-water. The mixture was extracted four times with dichloromethane, the combined extracts were successively washed with portions of ice-cold dilute sulphuric acid, water, sodium hydrogen carbonate solution and water. The dichloromethane solution is then dried with anhydrous solution sulphate and evaporated to dryness. Crystallization from ethanol yielded 21.3 grams = 75.5% of the pure 4-p-toluene-sulfonyloxy-2,5-dimethyl-2,3-dihydrofuran-3-one with m.p. 70°-72° C. 3.5 grams (12.4 mmol) of the tosylate thus otained were dissolved in a mixture of 15 ml of ethanol and 5 ml of water at 40° C. To this solution was added a solution of 1.68 grams (30 mmol) of sodium hydrogensulphide in 20 ml of ethanol, while a gentle stream of hydrogen sulphide was passed through the reaction mixture. AFter completion of the addition, which took one hour, stirring and passing of H2S into the solution were continued for 6 hours at 40° C and the reaction mixture was diluted with 200 ml of water, acidified with aqueous dilute hydrochloric acid (pH 5.5) and continuously extracted with ether for 18 hours. The extract was dried over anhydrous sodium sulphate and evaporated to dryness. From the residue the title compound was isolated in a quantity of 3 grams by preparative gaschromatography, using a column of 600 × 0.4 cm, a support of Diatoport S (a silanated silicagel) ex Hewlett Packard, loaded with 1% Carbowax 20 M (a polyethylene glycol ether with a molecular weight above 20,000) ex Hewlett Packard and 10% Apiezon (a mixture of stable alkanes) ex Shell Comp. Nitrogen was used as a carrier gas at a velocity of 40 ml per minute.
Reaction SMILES: ClC[CH:3]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][CH:14]([N:16]3[CH2:20][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[O:18][C:17]3=[O:28])[CH3:15])=[CH:12][C:5]=2[O:4]1.[SH-].[K+].[OH2:31].C[S:33]([CH3:35])=O>>[Cl:27][C:23]1[CH:22]=[C:21]([CH:19]2[O:18][C:17](=[O:28])[N:16]([CH:14]([CH3:15])[CH2:13][C:11]3[CH:10]=[CH:9][C:6]4[O:7][CH:8]([S:33][CH2:35][OH:31])[CH2:3][O:4][C:5]=4[CH:12]=3)[CH2:20]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CS(C)=O
Reactant: CC(Cc1ccc2c(c1)OC(CCl)CO2)N1CC(c2cccc(Cl)c2)OC1=O
Reactant: O
Agent: [K+]
Agent: [SH-]
Product: CC(Cc1ccc2c(c1)OCC(SCO)O2)N1CC(c2cccc(Cl)c2)OC1=O

Procedure:
One equivalent of product from Example 6, 2-isomer, and 2 equivalents of potassium hydrosulfide in dimethylsulfoxide is heated at 60° C. for 8 hours. The reaction mixture is poured into water, the precipitated product is collected and recrystallized from ethyl alcohol to give 6-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,4-benzodioxan-2-yl-thiomethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][OH:18]>>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][O:18][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: OCc1cccs1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: O=[N+]([O-])c1ccc(OCc2cccs2)c(Cl)c1
Yield: 40 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 2-thienylmethanol to give 2-chloro-4-nitrophenyl 2-thienylmethyl ether in 40% yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][CH3:12])[C:5]=1[OH:13])(=[O:3])[CH3:2].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl>C(O)C.CO>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][CH3:12])[C:5]=1[OH:13])(=[O:3])[CH:2]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC=Cc1cccc(C(C)=O)c1O
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CC=Cc1cccc(C(=O)C=Cc2ccccc2)c1O
Reaction time: 8 h

Procedure:
3.5 g (20 mmol) of 2-acetyl-6-(1-propenyl)phenol and 2.1 g (20 mmol) of benzaldehyde are dissolved in 20 ml of ethanol, 4 ml of concentrated NaOH are added, the mixture is stirred overnight, the red crystal slurry is diluted with methanol and acidified with concentrated HCl and, after cooling, the product is filtered off with suction. Orange-red crystals of melting point 95°-98° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][OH:25])[CH2:20][CH2:19]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:33][S:34]([O:25][CH2:24][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:19][CH2:20]1)(=[O:36])=[O:35]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CO)CC1)C1CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reaction time: 2 h

Procedure:
To a suspension of (6-bromo-4-((trans-4-(hydroxymethyl)cyclohexyl)amino)quinolin-3-yl) (cyclopropyl)methanone (1.23 g, 3.05 mmol) in dichloromethane (60 mL) was added triethylamine (2.09 mL, 15 mmol) and methanesulfonyl chloride (0.35 mL, 4.5 mmol) was added dropwise. The reaction mixture was stirred for 2 h. The solution was then diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acteate/hexanes) afforded the desired product (0.98 g, 67%) as a white solid. ESI MS m/z 481 [C21H25BrN2O4S+H]+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:18][C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.[H-].[Na+].CN(C)C=O>O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:18]2[C:9]3=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:13]=[C:8]3[CH:7]=[C:6]2[C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ncco3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncco1)n2Cc1ccc(F)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
A mixture of 2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.19 g), 4-fluorobenzyl bromide (0.16 g), sodium hydride (32 mg, 60% purity) and dimethylformamide (10 ml) was stirred at 15 to 30° C. for 30 minutes. To the reaction mixture was added water, and the precipitated crystals were filtered off and dissolved in ethyl acetate. The solution was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue (0.14 g) was recrystallized (ethyl acetate/hexane) to obtain 92 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[H][H]>C(O)(=O)C.[Pt]=O>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: Nc1cccc2cnccc12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Nc1cccc2c1CCNC2

Procedure:
A solution of 5-aminoisoquinoline (20 g) in glacial acetic acid (500 ml) was shaken under hydrogen in the presence of a platinum oxide catalyst (2.0 g) at room temperature and approximately 345 kilopascals pressure until uptake of hydrogen stopped. The catalyst was removed by filtration and the filtrate was evaporated to a small volume under reduced pressure. Residual solvent was removed by co-evaporation with water, then isopropyl alcohol, and the resulting solid was recrystallized from isopropyl alcohol to give 5-amino-1,2,3,4-tetrahydroisoquinoline as a white solid, 19 g, m.p. 153°-154° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[O-2:10].[Ca+2:11]>O>[C:1]([O:9][OH:10])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Ca+2:11].[Ca+2:11].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: [O-2]
Reactant: O=C(O)CC(O)C(=O)O
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
A large batch of dicalciumhydroxy malate is produced by mixing 19.16 kg of malic acid in 68.19 L of water. In a separate tank, 16.33 kg of calcium oxide is mixed in 68.19 L of water. These two aqueous solutions are slowly mixed together and stirred continuously. A milky solution containing the product resulted, which is spray dried to obtain a powdered product of dicalciumhydroxy malate.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1.[O:34]1CCCC1>C(OCC)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:34])(=[O:4])[CH:2]=[CH2:3]
Reactant: C1CCOC1
Reactant: C=CC(=O)Cl
Reactant: OCCCCCCCCCCCc1ccc(O)cc1
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: C=CC(=O)OCCCCCCCCCCCc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
2.5 ml of acryloylchloride was added to a solution of 7.4 g of 4-(11-hydroxyundecyl)-phenol (D) and 3.9 ml of N,N-dimethylaniline in 60 ml of tetrahydrofuran, cooled in an ice bath. After stirring for three hours at room temperature, the solution was diluted with 60 ml of diethyl ether and extracted subsequently with 100 ml of water, 100 ml of 2.4 N HCl and 100 ml of a saturated NaCl solution. 4.74 g of 4-(11-acryloyloxyundecyl phenol (G, 53%) was obtained as a brown powder after drying over magnesium sulphate, evaporating and washing with ligroin.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[I-].[CH3:26][CH2:27][CH3:28].[CH3:29][C:30]([CH2:32]C)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH2:27][CH3:28])=[C:13]([O:18][CH2:29][CH2:30][CH3:32])[CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCC(C)=O
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(O)c2)cc1
Reactant: CCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCOc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1OCCC
Temperature: 100 °C
Yield: 90 %

Procedure:
4′-methanesulfonyl-biphenyl-3,4-diol (30 mg) and potassium carbonate (38 mg) were dissolved in methylethylketone. Afterward, propane iodide (0.032 ml) was added and refluxed for 3 hours at 100° C. After filtering just potassium carbonate, the residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/1, v/v). As a result, the present compound (30 mg, productive yield 90%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([O:35][CH2:36][C:37](O)=[O:38])=[O:34].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:37](=[O:38])[CH2:36][O:35][C:33]([C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)=[O:34]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)COC(=O)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(COC(=O)c1cccs1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (150 mg, 0.357 mmol), 2-(thiophene-2-carbonyloxy)acetic acid (80 mg, 0.428 mmol), EDC (205 mg, 1.071 mmol), and DMAP (43.6 mg, 0.357 mmol) were dissolved in DCM (15 ml), and the solution was stirred at room temperature overnight. The solution was diluted with DCM, washed with 1N HCl and 5% NaHCO3, then with brine. The organic phase was dried over Na2SO4, and the solvent was evaporated. The crude so obtained (233 mg of a pale yellow solid) was triturated with MeOH and sonicated; the fine solid so obtained was filtered and dried in vacuum oven overnight. The desired product was obtained as a white powder (133 mg, 0.226 mmol, 63.3% yield, LC-MS/ESI+ 588.04 [MH]+, [αD]=−24.78, c=0.51, CHCl3).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[F:30].[OH-].[Li+].C1COCC1.Cl>CO.O>[F:30][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:9][C:4]=1[C:3]([OH:31])=[O:2]
Reactant: COC(=O)c1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a solution of Example 204 (0.080 g, 0.193 mmol) in methanol (1 ml), lithium hydroxide (0.075 g, 1.80 mmol) in water (1 ml) and THF (2 ml) were added and stirred at RT. After 12 h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.060 g, 78%). The acid was used without further purification in the next step.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=[O:7])C=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][C:15]=1[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[N:27]=1.[CH:35]([N:38]([CH2:42]C)[CH:39](C)C)(C)[CH3:36]>C(#N)C>[NH:30]1[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[N:27]=[C:26]1[C:15]1[CH:16]=[C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:36](=[O:7])[CH2:35][N:38]([CH3:42])[CH3:39])[CH2:22][CH2:21]2)[CH:18]=[CH:19][C:14]=1[F:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Fc1ccc(N2CCNCC2)cc1-c1nc2ccccc2[nH]1
Solvent: CC#N
Product: CN(C)CC(=O)N1CCN(c2ccc(F)c(-c3nc4ccccc4[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.6 %

Procedure:
CDI (0.052 g, 0.32 mmol) was added to a solution of N,N-dimethylglicine (0.033 g, 0.32 mmol) in acetonitrile (2.50 mL). The resulting solution was stirred at room temperature for 5 hours. Then 2-(2-Fluoro-5-piperazin-1-yl-phenyl)-1H-benzoimidazole (0.10 g, 0.27 mmol) and N,N-diisopropylethylamine (DIPEA) (0.11 mL, 0.6 mmol) were added and reaction was heated at 65° C. overnight. Reaction was cooled to room temperature and solvent was removed under reduced pressure. DCM (2 mL) was added to the crude, organic solution was washed with water (2×4 mL) and with saturated Na2CO3 solution (2×4 mL) and concentrated. The crude reaction mixture was purified by flash chromatography (eluent: MeOH:AcOEt gradient from 100% of AcOEt to MeOH 0.6:AcOEt 4) to afford 0.049 g of the title compound (43%).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:15](O)=[O:16]>O>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][CH:15]=[O:16])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=CO
Reactant: CCCCc1ccc(N)c([N+](=O)[O-])c1
Solvent: O
Product: CCCCc1ccc(NC=O)c([N+](=O)[O-])c1
Yield: 69.2 %

Procedure:
4-n-Butyl-2-nitroaniline (25-g; 0.13 mole) and formic acid (25 g; 0.54 mole) were mixed together at laboratory temperature and the mixture was then refluxed for forty minutes. After cooling to laboratory temperature the clear solution was poured into water (500 ml) and the orange solid which separated was filtered off, washed with water, dried and crystallised from light petroleum (b.p. 60°-80° C.) to give 5-n-butyl-2-formamido-1-nitrobenzene (20 g), m.p. 72°-73° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)=[C:8]([N+:25]([O-])=O)[CH:7]=1>CO.C(Cl)Cl>[CH3:3][O:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)=[C:8]([NH2:25])[CH:7]=1
Reactant: COC(=O)c1ccc(NCc2cc(-c3ccc(Cl)s3)on2)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(NCc2cc(-c3ccc(Cl)s3)on2)c(N)c1

Procedure:
97.1 mg (0.41 mmol) NiCl2.6H2O were dissolved in 10 mL MeOH and treated under ultrasonic conditions. 46.4 mg (1.24 mmol) NaBH4 were added. After 15 minutes a solution of 214.0 mg (0.54 mmol) 4-{[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-amino}-3-nitro-benzoic acid methyl ester in 20 mL CH2Cl2 was added. After further 15 minutes 55.6 mg (1.48 mmol) NaBH4 were added in three portions. The reaction mixture was treated under ultrasonic conditions for 2 h. Addition of NaBH4 (55.6 mg each time) and treatment under ultrasonic conditions had to be repeated three times to achieve complete conversion. The reaction mixture was filtered over “Celite” and the filtrate was concentrated under reduced pressure. The residue was suspended in 30 mL MeOH. After filtration the filtrate was concentrated under vacuo and the residue was taken up in 100 mL CH2Cl2. The organic layer was washed four times with water, dried over anhydrous MgSO4 and concentrated under reduced pressure to afford crude 3-Amino-4-{[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-amino}-benzoic acid methyl ester as a brown oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH3:22])[C:11]([NH:13][C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[NH:13][C:11]1[N:10]([CH3:22])[C:9]2[CH:23]=[CH:24][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[N:12]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(Nc1c(F)cccc1F)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(Nc2c(F)cccc2F)nc2cc(C(=O)O)ccc21

Procedure:
Prepared analogously to example 3b from 2-(2,6-difluoro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid ethyl ester and NaOH in ethanol and water.