Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH2:13][S:14][CH3:15])=[CH:3]1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH2:13][S:14]([CH3:15])=[O:24])=[CH:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cn(C)c2ccccc2c1=O
Solvent: ClCCl
Product: Cn1cc(CS(C)=O)c(=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of the above 1-methyl-3-methylthiomethyl-4-quinolone (4.86 g.) in dichloromethane (220 ml.) at -20° was added a solution of 3-chloroperbenzoic acid (85%, 4.86 g.) in dichloromethane (220 ml.) during 1 hour. The solution was allowed to warm to room temperature and extracted with saturated aqueous sodium bicarbonate until free of per-acid. The organic phase was dried over anhydrous magnesium sulphate and evaporated to give a solid product. The product was crystallized from acetone to give the novel 1-methyl-3-methylsulphinylmethyl-4-quinolone, m.p. 93°-95°.
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>Cl.CO.O>[O:24]1[CH2:23][CH2:22][N:21]([CH:18]2[C:13]3[C:12]4[CH:11]([CH:10]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[NH:9][C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:19]2)[CH2:26][CH2:25]1
Reactant: O=C(c1ccccc1)N1c2cccc3c2C(CCC3N2CCOCC2)C1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: c1ccc(C2Nc3cccc4c3C2CCC4N2CCOCC2)cc1
Yield: 89.9 %

Procedure:
A portion (0.56 g) of the compound obtained in Example 134 was dissolved in a solution (15 ml) of 10% hydrochloric acid in methanol and to the solution was added 6N hyrdochloric acid (15 ml). The mixture was heated to reflux for 3 hours and allowed to cool. The reaction mixture was diluted with water, adjusted to pH 9 with potassium carbonate and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from an ether/hexane mixed solvent to yield 0.38 g (90%) of the titled compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7](S([O-])(=O)=O)=[CH:6][CH:5]=1.[K+].[NH2-:15].[K+].N>>[NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:15])=[CH:6][CH:5]=1
Reactant: [NH2-]
Reactant: NCCc1ccc(S(=O)(=O)[O-])cc1
Agent: N
Agent: [K+]
Product: NCCc1ccc(N)cc1
Yield: 82.2 %

Procedure:
In a 200-ml autoclave were placed 12 grams (0.05 mole) of anhydrous potassium p-(2-aminoethyl)benzene sulfonate, 6.1 grams (0.11 mole) of potassium amide and 55 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 135° C for 5 hours. The reaction pressure in the autoclave was 115 atm. during the reaction. After the ammonia was removed, 10 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 4-(2-aminoethyl)aniline. The recrystallization thereof from ether gave 5.6 grams of 4-(2-aminoethyl)aniline having a melting point of 62° to 63° C and boiling point of 140° to 142° C/12 mm Hg. Yield was 82.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][CH2:12][CH2:13][OH:14])([O-:3])=[O:2].[OH:15]S(O)(=O)=O>O1CCCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][OH:14])([O-:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccccc1C#CCCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCO)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of HgO (0.21 g, 1.0 mmol) in 50 ml of 0.12N H2SO4 is heated to 60° C., treated dropwise with a solution of 4-(o-nitrophenyl)-3-butyne-1-ol (3.70 g, 19.4 mmol) in 25 ml of tetrahydrofuran over a 10 minute period, held at 60° C. for 3 hours, treated with additional HgO (0.84 g, 3.9 mmol) suspended in 25 ml of 0.12N H2SO4, held at 60° C. for 4 hours, cooled to room temperature and diluted with water. The resultant aqueous mixture is extracted with ether. The extracts are combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give a residue. The residue is purified by flash column chromatography (silica gel; gradient 1:1→2:1 ethyl acetate: hexanes as eluent) to give the title product as a brown oil, 1.48 g, 37% yield, identified by NMR and mass spectral analyses.
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)CCC.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:2]1[S:3][C:4]([C:21]2[S:20][CH:19]=[CH:23][CH:22]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOC(=O)Cc1cc(Br)sc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(-c2cccs2)sc1-c1cccs1
Temperature: 100 °C
Yield: 85 %

Procedure:
The synthesis of 3T-ET is carried by first synthesizing ethyl 2-(2,5-dibromothiophen-3-yl)acetate using known methods and is performed as follows. Ethyl 2-(2,5-dibromothiophen-3-yl)acetate (6.4 g, 10 mmol) and 2-(tributylstannyl)thiophene (15 g, 20 mmol) are added to a 30 mL dry DMF solution of dichlorobis-(triphenylphosphine)palladium (1.3 g, 1.5 mmol). After three freeze thaw cycles, the mixture is heated at 100° C. for 48 hours. The mixture is cooled to room temperature and poured into a beaker containing 150 mL of water and subsequently extracted with CH2Cl2. The extracted CH2Cl2 mixture is dried with Na2SO4. After filtering and evaporation of solvent, the crude product is purified by chromatography on silica gel using toluene as eluent. The final product is obtained in 85% yield as pale yellow oil. The characterization of the compound is consistent with that published in the literature.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][N:11]([CH3:30])[C:12](=[O:29])/[CH:13]=[CH:14]/[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1.O>CS(C)=O>[CH3:9][O:10][N:11]([CH3:30])[C:12]([CH:13]1[CH2:2][CH:14]1[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)=[O:29]
Reactant: CON(C)C(=O)/C=C/c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CON(C)C(=O)C1CC1c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
660 mg (3.3 mmol) of trimethylsulphoxonium iodide and 3 ml of DMSO are introduced into a three-necked flask under a stream of nitrogen. 100 mg (4.12 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. A solution of 900 mg (3 mmol) of (E)-N-methoxy-N-methyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)acrylamide in 15 ml of DMSO is then added dropwise and the mixture is stirred at room temperature for two hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (80/20). After evaporating the solvents, 400 mg (43%) of N-methoxy-N-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropanecarboxamide are collected in the form of an oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.CC[O-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
12 ml of diethyl malonate were introduced into 120 ml of ethanol and then 5.5 grams of sodium ethylate at 98% were added over 10 minutes at 0° to +5° C. The mixture was stirred for 15 minutes at 0°+5° C. and then 8.8 ml of ethyl bromoacetate were added over 30 minutes. The mixture was stirred for 48 hours at ambient temperature and then the mixture was poured into 600 ml of water and extracted 3 times with 300 ml of methylene chloride. The organic phase was washed twice with 300 ml of water, then evaporated to dryness. The oil obtained was distilled under reduced pressure to obtain 12.4 grams of the expected product with a boiling point of 110° to 120° C. at 1.0 mm of Hg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[OH-].[K+].S(O[CH:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:22])(C1C=CC(C)=CC=1)(=O)=O.O>O1CCOCC1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Reactant: OCCOCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(COCc1ccccc1)OCCOCCO
Temperature: 63 °C
Reaction time: 13.5 h
Yield: 36.7 %

Procedure:
HO(CH2)2O(CH2)2OH (21.2 g), potassium hydroxide (11.2 g) and dioxane (100 ml) were charged into a four necked flask and heated to an internal temperature of 63° C. to dissolve potassium hydroxide. A solution obtained by dissolving 32.0 g of TsOCH(CH3)CH2OCH2Ph obtained in Example 2-1 in dioxane (50 ml), was dropwise added over a period of 30 minutes, and while maintaining the internal temperature within a range of from 60 to 100° C., stirring was continued for 13.5 hours. The mixture was left to cool, then added to water (200 ml) and extracted three times with dichloromethane (50 ml). The organic layer was washed with water (20 ml). It was dried over magnesium sulfate, filtered and then concentrated by an evaporator to obtain a crude product (52 g). it was purified by silica gel chromatography to obtain 9.32 g of the above-identified compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>CCOCC.C1COCC1.II>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([OH:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
A mixture of 2.3 g of magnesium and 0.01 g of iodine in 20 ml of ether is heated to reflux, a solution of 26 g of 1-bromo-2-trifluoromethylbenzene in 20 ml of ether is added dropwise and the resulting mixture is refluxed for 60 minutes. A solution of 9 g of 5-chloro-1H-indole-2,3-dione in 40 ml of THF is then added and refluxing is continued for 30 minutes. After cooling to RT, the reaction mixture is poured into an ice/concentrated HCl mixture and extracted with ether, the organic phase is washed with 1N NaOH solution and with water, and dried over Na2SO4, and the solvent is evaporated off under vacuum. 5.3 g of the expected product are obtained after crystallization from heptane, m.p.=205–208° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5](Cl)=[O:6])=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]=1[OH:26])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[CH3:15][C:12]([C:16]1[CH:21]=[C:20]([C:5](=[O:6])[C:3]([O:2][CH3:1])=[O:4])[CH:19]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]=1[OH:26])([CH3:13])[CH3:14]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A dichloromethane (50 mL) solution of 13.6 g (106.5 mmol, 1.1 equiv.) of methyloxalylchloride is added over 15 minutes to a 0° C. stirred slurry of 14.2 g (106.5 mmol, 1.1 equiv.) of AlCl3 in 100 mL of dichloromethane under nitrogen atmosphere. The reaction is stirred at 0° C. for 5 minutes and treated with a dichloromethane (50 mL) solution of 20.0 g (96.9 mmol) of 2,6-di-t-butylphenol over 30 minutes. The reaction is stirred for 3 hours and poured onto 700 mL of ice water and the layers separated. The aqueous layer is extracted with diethyl ether (3×200 mL). The combined organic layers are washed with aqueous 1N HCl (200 mL), water (4×200 mL) and saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give a yellow solid. Recrystallizing from n-pentane gives a first crop of 8.40 g (mp 85°-86° C.) and a second crop of 4.45 g (mp 82.5°-84° C.). The total yield is 12.85 g (28.33 g theor., 45%).
Reaction SMILES: [Na].CO[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=3)(=[O:21])=[O:20])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)=[NH:5].[H-].[Na+].O>CN(C=O)C>[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=3)(=[O:21])=[O:20])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)#[N:5]
Reactant: COC(=N)c1cc(-c2nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccnc(C#N)c2)nc1OC
Temperature: 0 °C

Procedure:
To a solution of 2.93 g of 4-[4-(5-isopropyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboximidic acid methyl ester sodium salt in DMF (60 ml) was added under ice cooling NaH (0.8 g of a 60% NaH suspension in oil). The mixture was stirred for 1,5 h at 0° C. The mixture was poured into water, the pH adjusted to pH=6 and the product extracted into EtOAc. The organic layer was washed with water, dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/EtOAc: 5/1). Combination of the purified fractions and evacuation in vacuo afforded 5-isopropyl-pyridine-2-sulfonic acid [2-(2-cyano-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a light yellow crystalline solid. ISN mass spectrum, m/e 531.1 (M−1 calculated for C26H24N6O5S: 531).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]([CH2:16][CH2:17][CH2:18]O)[C:14]3[C:20]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=[C:23]([Cl:24])[C:13]=3[N:12]=2)=[C:6]([CH3:29])[CH:5]=1)(=[O:3])[NH2:2]>C1C(Cl)=CC=C(Cl)C=1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3=[N:12][C:13]4[C:14](=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:21]=[CH:22][C:23]=4[Cl:24])[N:15]3[CH2:16][CH2:17][CH2:18]2)=[C:6]([CH3:29])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(C(N)=O)cc3C)n(CCCO)c12
Solvent: Clc1ccc(Cl)cc1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(N)=O)cc1C
Temperature: 110 °C
Reaction time: 23 h
Yield: 61.2 %

Procedure:
Tsunoda reagent (904 mg, 3.74 mmol) was added to a stirred suspension of methyl 2-[(4-carbamoyl-2-methylphenyl)amino]-4-chloro-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (1.30 g, 3.12 mmol) in dichlorobenzene (30 mL) at room temperature, and the mixture was stirred at 110° C. for 23 hr. The mixture was concentrated in vacuo, crystallized from ethyl acetate/diisopropyl ether and washed with diisopropyl ether to give the title compound as a pale yellow powder (761 mg, 1.91 mmol, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([O:65][C:66]([C@H:68]1[CH2:72][CH2:71][CH2:70][NH:69]1)=[O:67])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][C@@H:68]1[C:66]([O:65][CH2:63][CH3:64])=[O:67])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)[C@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (R)-2-ethyloxycarbonyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:12])[N:9](S(C3C=CC=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1.[Na].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:12])[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: COc1cnc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1cnc2[nH]c(C)cc2c1
Yield: 90.7 %

Procedure:
A solution of 5-methoxy-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (950 mg, 3.14 mmol) and 40% aqueous sodium hydroxyde (106 ml) in methanol (160 ml) was heated at reflux for 30 minutes. After cooling, the mixture was poured onto cooled water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1/1). The fractions containing the expected product were combined and evaporated to give 5-methoxy-2-methyl-1H-pyrrolo[2,3-b]pyridine (462 mg, 91%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>ClCCl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([Cl:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Solvent: ClCCl
Product: Cc1ccc(C(=O)Cl)c2ccccc12

Procedure:
To a solution of 0.35 g (1.89 mmol) of 4-methyl-1-napthoic acid in 3 mL of dry dichloromethane under argon, was added 2.5 ml (34.3 mmol) of thionyl chloride. The solution was refluxed for 4 hrs and the solvent and excess thionyl chloride were removed by vacuum distillation to give a red oil, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Br[CH2:22][CH2:23][CH2:24][OH:25]>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:22][CH2:23][CH2:24][OH:25])[CH:10]=3
Reactant: OCCCBr
Reactant: O=c1ccn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Product: O=c1ccn2c3c(cc(OCCCO)cc13)Sc1ccc(Br)cc1-2
Yield: 36 %

Procedure:
According to Example 34, the compound (145 mg) produced in Example 58 was reacted with 3-bromopropanol (65 μl) to obtain the title compound (62 mg; 36%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH3:25])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C)c1OC
Temperature: 160 °C
Yield: 18.5 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.332 g), potassium methyltrifluoro borate (0.0675 g), palladium chloride dppf adduct with DCM (0.066 g) and cesium carbonate (0.786 g) in THF (9 ml) and water (1 ml) was sealed in a microwave vial and degassed. The mixture was then heated in the microwave at 160° C. for 30 minutes. After cooling, the mixture was dried (MgSO4) and filtered through Celite, and the pad was washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-50% to give ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-methylbenzoate (0.05 g) as a colourless gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]=2[CH:2]=1)=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.FC1C=CC(F)=CC=1C(C1C(C(O)=O)=CN=CC=1)=O>[N+](C1C=CC=CC=1)([O-])=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:10]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:7]([OH:9])=[O:8])=[O:11]
Reactant: O=C1OC(=O)c2cnccc21
Reactant: Fc1ccc(F)cc1
Agent: O=C(O)c1cnccc1C(=O)c1cc(F)ccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccncc1C(=O)c1cc(F)ccc1F
Reaction time: 3 h
Yield: 84 %

Procedure:
3,4-Pyridine dicarboxylic acid anhydride (95.7 g, 0.67 mol) and AlCl3 (367.3 g, 2.67 mol) were simultaneously, but separately, added in five portions (one every 15') to boiling 1,4-difluorobenzene (650 mL, 90° C.). After about 1 hour from the last addition, the majority of the 1,4-difluorobenzene was removed by distillation at normal pressure until a thick mass was obtained. The temperature was lowered to 80° C. and nitrobenzene (150 mL) was added in order to dissolve the residual mass. While still hot, the resulting solution was cautiously quenched into ice-cooled and stirred water (1000 g of ice and 530 g of demineralized water) (i.e., slowly drop the solution into the ice water). Then concentrated HCl (37%, 160 mL) was added to the poured mixture at 0°-5° C. and stirring was continued for about 3 hours. A greasy beige precipitate (about 150 g wet) was collected by filtration while the aqueous layer was separated from nitrobenzene and extracted with AcOEt (6x500 mL). Nitrobenzene layer was diluted with petroleum ether (400 mL) and the resulting little amount of precipitate was collected by filtration (about 2 g). Combined extracts were concentrated under vacuum, and the residual crude solid (about 45 g), together with the previously collected precipitates, was suspended into a mixture of AcOEt/petroleum ether (1/1) (600 mL). After about 2 hours at room temperature the suspension was filtered and dried in vacuum to give the mixture of 4-(2',5'-difluorobenzoyl)nicotinic acid and 3-(2',5'-difluorobenzoyl) isonicotinic acid (147.3 g, 84% yield) as a pale beige solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1ccc2snnc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4snnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzo[d][1,2,3]thiadiazole-5-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 8.51 (dt, J=8.2, 1.9, 1.7 Hz, 1 H), 8.57 (dd, J=8.5, 1.7 Hz, 1 H), 8.73 (d, J=7.8 Hz, 1 H), 8.85 (dd, J=4.9, 1.5 Hz, 1 H), 9.32 (dd, J=2.4, 1.0 Hz, 1 H), 9.51 (dd, J=1.7, 0.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 282 (M+H)+.