Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([SH:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([S:13][CH2:15][C:16]([OH:18])=[O:17])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCl
Reactant: Sc1nc(-c2ccc(Cl)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CSc1nc(-c2ccc(Cl)cc2)no1
Yield: 67 %

Procedure:
A mixture of 3-(p-chlorophenyl)-5-mercapto-1,2,4-oxadiazole (106 parts), chloroacetic acid (48 parts), potassium carbonate (75 parts) and water (100 parts) was heated at reflux for one hour. The solution was filtered hot, cooled, acidified and the solid separated to give [3-(p-chlorophenyl)-1,2,4-oxadiazol-5-ylthio]acetic acid (91 parts, 67% yield), melting point 112°-114° C. (as monohydrate).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH2:13][CH2:14][CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][CH2:21][P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24].C(N(CC)CC)C.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([CH:21]([P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24])[NH2:20])=[O:18])[CH2:13][CH2:14][CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COP(=O)(CN)OC
Reactant: CCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@H](NC(=O)OCc1ccccc1)C(=O)C(N)P(=O)(OC)OC
Temperature: -12 °C
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
(i)(b) 45.4 g (180 mmol) of N-benzyloxycarbonyl-L-norvaline were stirred in 200 ml of methylene chloride while 31.76 g (180 mmol) of dimethyl aminomethylphosphonate hydrochloride were added. The resulting suspension was cooled to -12° C. and 25.3 ml (180 mmol) of dry triethylamine were added dropwise. After completion of the addition, the cold mixture was stirred for 0.25 hour. 56.8 g (230 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline in 100 ml of methylene chloride were then added rapidly. The mixture was stirred in the cold for 2 hours and then at room temperature overnight. The mixture was washed with 100 ml of water and then with four 100 ml portions of 1-N hydrochloric acid. The combined acid washings were back-extracted with two 50 ml portions of methylene chloride. The combined organic solutions were washed with 100 ml of water and finally with three 100 ml portions of 15% potassium bicarbonate solution, then dried over anhydrous sodium sulphate, filtered and evaporated. The residual oil was re-evaporated with benzene to give an oil which was triturated with 200 ml of anhydrous ether. There were obtained 58.2 g of crude product of melting point 77°-80° C. Recrystallization from 200 ml of ethyl acetate gave 50.6 g of dimethyl N-benzyloxycarbonyl-L-norvalyl-aminomethylphosphonate of melting point 82°-84° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1C=C[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[C:14]1([S:13][C:10]2[N:11]=[CH:12][C:4]([CH:5]=[O:1])=[CH:3][CH:2]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(Sc2ccccc2)nc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Sc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
To a tetrahydrofuran (40 mL) solution of 5-bromo-2-phenylsulfanyl-pyridine (2.24 g, 8.42 mmol) described in Manufacturing Example 97-1-1 was added n-butyl lithium (6.35 mL, 1.6 M hexane solution, 10.1 mmol) under nitrogen atmosphere at −78° C., which was stirred for 45 minutes at −78°. Next, N,N-dimethylformamide (848 μL, 10.9 mmol) was added to this reaction mixture, and stirred for 35 minutes as the temperature was gradually raised to room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (583 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=O.C1(C)C=CC=CC=1.[CH3:28][NH:29][NH2:30]>O>[CH3:28][N:29]1[N:30]=[C:5]([C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([Cl:1])[CH:3]=2)[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:10]
Reactant: CNN
Reactant: COc1ccc(C(=O)c2ccccc2C(=O)O)cc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nn(C)c(=O)c3ccccc23)cc1Cl
Yield: 68.7 %

Procedure:
A mixture of 2-(3-chloro-4-methoxybenzoyl)benzoic acid (10.46 g, 0,036 mol), toluene (50 mL) and methyl hydrazine (2.1 mL) was refluxed in the presence of a Dean Stark trap until the theoretical amount of water had been collected. The reaction mixture was cooled, and the product was collected by filtration to afford 7.42 g (68.7%) of 2-methyl-4-(3-chloro-4-methoxyphenyl)-1-(2H)-phthalazinone, m.p. 195°-195° C. An additional 1.89 g of product was also collected from the filtrate for a total of 9.31 g (86.2%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH2:9][C:10]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:24])C.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH2:9][CH:10]=[O:24]
Reactant: CC(=O)O
Reactant: CC1CC(C)(C)CC1CC#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)CC1CC=O
Temperature: 25 °C

Procedure:
2-(2,4,4-Trimethylcyclopentyl)acetonitrile 4 is placed in toluene at 10° C. under an inert atmosphere. 1.2 eq. of Dibal (diisobutylaluminum hydride) are added thereto dropwise. The reaction medium is stirred at ambient temperature for a few hours and then poured onto a 20:40:40 mixture of acetic acid, water and ice. The aqueous phase is extracted once with toluene. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of two diastereomers in proportions of 70:30, is distilled under reduced pressure.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1.[C:17]([C:19]1[CH:20]=[C:21]([S:26]([N:29]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[O:44][CH3:45])[C:30]2[S:31][CH:32]=[CH:33][N:34]=2)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1F)#[N:18]>CN(C=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:24]2[CH:23]=[CH:22][C:21]([S:26]([N:29]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=3[O:44][CH3:45])[C:30]3[S:31][CH:32]=[CH:33][N:34]=3)(=[O:28])=[O:27])=[CH:20][C:19]=2[C:17]#[N:18])=[C:6]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Cn1nccc1-c1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Oc3ccc(Br)cc3-c3ccnn3C)c(C#N)c2)c(OC)c1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a slurry of sodium hydride (54 mg, 1.4 mmol, 60% in mineral oil) in DMF (1 mL) was added 4-bromo-2-(1-methyl-1H-pyrazol-5-yl)phenol (Preparation 89, 210 mg, 0.83 mmol) as a solution in DMF (3 mL). After stirring for 30 minutes, 3-cyano-N-(2,4-dimethoxy-benzyl)-4-fluoro-N-thiazol-2-yl-benzenesulfonamide (Preparation 90, 415 mg, 0.957 mmol) was added. After 3 hours the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by automated flash column chromatography using a 0-100% ethyl acetate/dichloromethane gradient provided the title compound (482 mg, 87%) as a yellow foam.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O(C1C2N=C(C3C=CC(F)=CC=3)C=CC=2N=CN=1)C1C=CC=CC=1.[CH3:43][O:44][CH2:45][CH2:46][OH:47]>>[CH3:43][O:44][CH2:45][CH2:46][O:47][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Reactant: COCCO
Agent: Fc1ccc(-c2ccc3ncnc(Oc4ccccc4)c3n2)cc1
Product: COCCOc1ncnc2ccc(-c3ccc(F)cc3)nc12
Yield: 78 %

Procedure:
was synthesized from 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine and 2-methoxyethanol in 78% yield, using the procedure described for the synthesis of 4-phenoxy-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine The mass spectrum characterising data is as follows: MS (m/z): 300 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:18]=[C:17](O)[C:16]([S:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:15][N:14]=1)(=[O:11])=[O:10].O=P(Cl)(Cl)[Cl:38]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:18]=[C:17]([Cl:38])[C:16]([S:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(O)n1)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(Cl)n1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A solution of 10 (150 mg, 0.26 mmol) in POCl3 (0.24 mL, 2.6 mmol) was heated to 90° C. for 3.5 hours. The mixture was cooled to room temperature and poured onto ice. The precipitate was collected by filtration, washed with water and dried under vacuum to afford 11 as a pale yellow solid (143 mg), which was used without further purification. Mass Spectrum m/e=594.8 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]=[CH:18][C:19]([OH:21])=[O:20].[H][H]>[Pd].O1CCOCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: [H][H]
Reactant: COc1c(C=CC(=O)O)cccc1Oc1ccccc1Cl
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1c(CCC(=O)O)cccc1Oc1ccccc1Cl
Yield: 99.3 %

Procedure:
Palladium on carbon (500 mg) was added to a solution of 3-[2-methoxy-3-(2-chlorophenoxy)phenyl]acrylic acid (5.0 g) in dioxan (80 ml), and hydrogen gas (400 ml) was introduced into the mixture. After filtration, the filtrate was evaporated to give oily 3-[2-methoxy-3-(2-chlorophenoxy)phenyl]propionic acid (5.0 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH:10]=1)[CH2:8]O.P(Br)(Br)[Br:15]>CCOCC>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH:10]=1)[CH2:8][Br:15]
Reactant: BrP(Br)Br
Reactant: OCc1cc(C(F)(F)F)ccc1I
Solvent: CCOCC
Product: FC(F)(F)c1ccc(I)c(CBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Trifluoromethyl-2-iodobenzyl alcohol (45 g, 0.15 mol) is dissolved in anhydrous Et2O (400 mL) and treated with phosphorous tribromide (41 mL, 0.15 mol) by dropwise addition. The reaction mixture is stirred at room temperature overnight and quenched by slow addition of water (150 mL). The organic layer is separated, washed with saturated aqueous NaHCO3 (250 mL), brine (250 mL), dried (MgSO4) and concentrated by rotary evaporator to give 5-trifluoromethyl-2-iodobenzyl bromide as an oil.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]([O:7][C:8]([CH:10]1[CH:18]2[C:13]3([CH:22]=[CH:21][CH:20]=[CH:19][C:14]3=[N:15][CH2:16][CH2:17]2)[S:12][CH2:11]1)=[O:9])[CH3:6].[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH2:5]([O:7][C:8]([CH:10]1[CH:18]2[C:13]3([CH:22]=[CH:21][CH:20]=[CH:19][C:14]3=[N:15][CH2:16][CH2:17]2)[S:12][CH:11]1[C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23])=[O:9])[CH3:6]
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(C(=O)c2ccccc2Cl)SC23C=CC=CC2=NCCC13
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To 30 ml of chloroform were added 0.60 g of 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester synthesized in Example 1, 0.64 ml of triethylamine, and 523 mg of 2-chlorobenzoyl chloride, and the mixture was stirred for one hour at room temperature. The reaction mixture was washed with ml of water and then with 30 ml of an aqueous sodium hydrogencarbonate solution having a pH of 9.0, and also with 30 ml of water. The chloroform layer was dried by sodium sulfate and the solvent was distilled off under reduced pressure to provide 614 mg (yield of 67%) of 2 -(2-chlorobenzoyl)-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=[O:3].[CH3:22][NH2:23]>>[CH2:22]([NH:23][C:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: CN
Product: O=C(NCc1ccccc1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12

Procedure:
Reaction of 3-chlorocarbonyl-1-(phenylsulfonyl)indole [XXIII] with an excess of methylamine as above gave N-methyl-1-(phenylsulfonyl)indole-3-carboxamide [XXIV: R8 =Me]; mp (MeOH) 192.5°-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[C:4]=1[Cl:11].[CH3:12][O:13]C(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:11][C:4]1[C:3]([O:2][CH3:1])=[C:10]([CH:9]=[CH:8][C:5]=1[O:6][CH3:7])[CH:12]=[O:13]
Reactant: COc1cccc(OC)c1Cl
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C=O)c(OC)c1Cl

Procedure:
2-chlororesorcinol dimethyl ether (3.4 g) is dissolved in 20 ml of CH2Cl2 and TiCl4 (4.3 ml) is added. To this solution is added dichloromethyl methyl ether (2.3 g). After 30 minutes the reaction mixture is poured into H2O into H2O and extracted with ether. Drying and evaporation gives 3-chloro-2,4-dimethoxybenzaldehyde, mp 107°-108° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.C(O)C>[C:8]1(/[CH:7]=[CH:3]/[C:4](=[O:5])/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1

Procedure:
(3) Hill and Barbaro, Experiments in Organic Chemistry. Contemporary Publishing Co. of Raleigh, Inc., Raleigh, 1996. 5 g of sodium hydroxide, dissolved in 25 ml of water and 25 ml of 95% ethanol, was cooled to 20 to 25° C. 2.9 g (50 mmol) of acetone and 10.6 g (100 mmol) of benzaldehyde were added, and a yellow precipitate formed. After 20 minutes the solution was filtered, and the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets: mp 111.9-112.5° C. (lit. mp 112° C., Hill and Barbaro, supra). 1H NMR (250 MHz) δ 7.79-7.73 (d, 1 H), 7.65-7.61 (m, 4 H), 7.44-7.41 (t, 6 H), 7.13-7.07 (d, 1 H) ppm.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:29]=[CH:30][C:31]=4[C:32](O)=[O:33])[C:20]=3[NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:29]=[CH:30][C:31]=4[C:32]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:33])[C:20]=3[NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:14])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3cccnc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3cccnc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12

Procedure:
In the same manner as in Example 1, step 6 and using 6-(4-phenylpiperidine-1-carbonyl)-7-(pyridin-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.11 mmol) obtained in step 2 and methanesulfonamide (0.052 g, 0.550 mmol), compound a-9 (0.03 g, 58%) was obtained.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:12]=[C:11]([C:13](=[O:17])[CH:14]=[N+]=[N-])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>CCOCC>[Br:1][CH2:14][C:13]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([Cl:2])[CH:12]=1)=[O:17]
Reactant: Br
Reactant: COC(=O)c1ccc(C(=O)C=[N+]=[N-])cc1Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(C(=O)CBr)cc1Cl
Yield: 79 %

Procedure:
Hydrogen bromide gas was bubbled through a suspension of 2-chloro-4-(diazoacetyl)benzoic acid, methyl ester (400 mg, 1.7 mmol) in ether (30 mL) for 10 min. The solvent was evaporated and the residue was triturated with ether/hexane and filtered to give 4-(bromoacetyl)-2-chlorobenzoic acid, methyl ester (385 mg, 79%) as a colorless solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.[BrH:10]>>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:10])=[N:4][CH:5]=1
Reactant: Br
Reactant: OCc1ccc(Br)cn1
Product: BrCc1ccc(Br)cn1
Temperature: 150 °C
Yield: 87 %

Procedure:
Dissolve 2-hydroxymethyl-5-bromopyridine (5.21 g, 27.7 mmol) in 48% aqueous hydrobromic acid (20 mL). Heat the mixture at 150° C. for 2 h. Cool to ambient temperature and remove excess hydrobromic acid under vacuum. Dilute with water, add cautiously saturated aqueous NaHCO3 and extract three times with EtOAc. Dry over anhydrous Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the title compound as pink oil (6.0 g, 87%) that crystallizes in the freezer.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:20][C:19]3[C:18](=[O:21])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[CH:9]2[C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)CCC>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:39]1[CH:40]=[CH:41][C:36]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:20][C:19]4[C:18](=[O:21])[C:17]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[NH:11][C:10]=4[CH:9]3[C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)=[N:6][CH:7]=2)=[CH:37][CH:38]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncc(Br)cn1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncc(-c3ccncc3)cn1)C2
Temperature: 140 °C

Procedure:
A stirred mixture of 1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (46 mg, 0.1 mmol) (prepared as in Example 53), (PPh3)4Pd (3.5 mg, 3.0 μmol) and 4-tri-n-butylstannylpyridine (37 mg, 0.1 mmol) in dry DMF (2.0 ml) was heated at 140° C. for 12 h. More catalyst (3.5 mg) was added and the mixture was refluxed for 4 h and then cooled. The solution was diluted with ethyl acetate and filtered through filter paper. The organic phase was washed with brine and water, then dried over Na2SO4. A small amount of silica gel was added into the solution and dried in vacuo. Purification by flash column (silica gel, neat acetonitrile followed by 10% ammonium hydroxide in water:actonitrile=1:10, v/v) yielded the product as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([NH2:14])[CH3:13]>O>[NH2:14][CH2:12][CH2:13][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCN
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: O
Product: NCCc1nc(Cl)ccc1C(=O)O
Yield: 62 %

Procedure:
A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml of a solution of ethylamine at 70% in water is stirred at ambient temperature for 72 hours. The excess amine is then evaporated off under reduced pressure, and an aqueous solution of acetic acid at 10% is then added until the product precipitates. The beige solid is spin-filter-dried, rinsed with cold water and dried in an oven. 10.5 g of the expected product are obtained. Melting point: 158-160° C. Yield=62%.
Reaction SMILES: C([O:3][C:4](=[O:35])/[C:5](/[CH3:34])=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14](=[O:32])[NH:15][C:16]2[S:17][C:18]3[CH2:28][O:27][C:26]4[C:25]([CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=4[C:19]=3[N:20]=2)=[CH:9][C:8]=1[F:33])C.CO.[OH-].[Na+].Cl>C1COCC1>[F:33][C:8]1[CH:9]=[C:10]([C:14](=[O:32])[NH:15][C:16]2[S:17][C:18]3[CH2:28][O:27][C:26]4[C:25]([CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=4[C:19]=3[N:20]=2)[CH:11]=[C:12]([F:13])[C:7]=1/[CH:6]=[C:5](\[CH3:34])/[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)/C(C)=C/c1c(F)cc(C(=O)Nc2nc3c(s2)COc2c-3cccc2C(C)C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C/C(=C\c1c(F)cc(C(=O)Nc2nc3c(s2)COc2c-3cccc2C(C)C)cc1F)C(=O)O

Procedure:
(E)-3-[2,6-difluoro-4-(6-isopropyl-4H-chromeno[4,3-d]thiazol-2-ylcarbamoyl)phenyl]-2-methylacrylic acid ethyl ester (620 mg) was dissolved in THF (2 mL), methanol (2 ml), and 2N sodium hydroxide aqueous solution (2 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate to obtain the compound (A1309) 460 mg.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:28])[O:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Br[CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45]>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CC(C)CCBr
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CCC(C)C)c2ccc(C(C)C)cn2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To a stirred solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (150 mg, 0.37 mmol) in acetonitrile (4 mL) was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (128 mg, 0.75 mmol). The reaction mixture was stirred at 20° C. for 1 hour. 1-Bromo-3-methylbutane (0.09 mL, 0.75 mmol) was then added and the reaction vessel sealed and heated by microwaves to 150° C. for 30 minutes. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate. The organic phase was washed with water, dried using a hydrophobic frit and evaporated in vacuo to give the crude product. The crude was then purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title compound (48 mg) as a yellow oil. LCMS (2 min, HpH) Rt 1.50 min, m/z (ES+) 472 (M+H).