Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:35])([C:13]([F:34])([F:33])[C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH2:10][CH2:11]O.Cl>C(OCC)C>[F:8][C:9]([F:35])([C:13]([F:33])([F:34])[C:14]([F:31])([F:32])[C:15]([F:29])([F:30])[C:16]([F:27])([F:28])[C:17]([F:25])([F:26])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH2:10][CH2:11][O:4][C:3](=[O:5])[CH:2]([Cl:1])[CH2:6][OH:7]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(O)C(Cl)CO
Agent: Cl
Solvent: CCOCC
Product: O=C(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(Cl)CO
Temperature: 65 °C

Procedure:
In a 50 mL RB with a condenser, 2-chloro-3-hydroxypropionic acid (6.0 g, 0.05 mol) and 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-1-decanol (18.0 g, 0.04 mol) and a catalytic amount of hydrochloric acid were taken together and heated up to 65° C. for 36 h. Product was dissolved in 300 mL of ethyl ether and washed twice with 100 mL of dil. NaHCO3 aq. sol. and once with 100 mL of sat. aq. NaCl sol. and then dried over anhy. Na2SO4. Solution was filtered, solvent was removed by rotary evaporation and unreacted alcohol was sublimed off at 70° C. under vacuum. Yield=15.0 g (67%). 1H-NMR (CDCl3, 7.27 ppm): 2.54 (m, —CH2CF2). 3.05-3.35 (broad, —OH), 4.01 (m, —CH2OH), 4.42 (m, —CHCl), 4.52 (m, —CO2CH2CH2).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.Cl>CCOCC>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:11][CH:13]2[O:15][CH2:14]2)=[CH:4][CH:5]=1)[CH3:10]
Reactant: ClCC1CO1
Reactant: CCc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCc1ccc(CC2CO2)cc1
Temperature: 20 °C

Procedure:
A Grignard solution freshly prepared from 12.15 g (0.50 g atom) magnesium chips and 92.5 g (0.50 mole) 1-bromo-4-ethylbenzene in 400 ml dry ether is dripped with agitation into a precooled solution of 92.5 g (1.00 mole) of epichlorohydrin in 100 ml of dry ether, so that the temperature does not exceed -40° C. After addition is complete, the solution is heated slowly to 20° C. and is hydrolyzed after another three hours by the addition of ice water and dilute hydrochloric acid. The ether phase is separated, washed twice with water and dried over sodium sulfate. Following the removal of the ether, the bath temperature is raised to 70° C. and the volatile components carefully removed at 0.1 mbar. The residue is taken up in 185 ml of methanol and a freshly prepared solution of 6.90 g (0.30 g atom) sodium in methanol added at room temperature. After three hours the sodium chloride precipitate is separated, the filtrate concentrated in vacuum and the yellow, oily residue used without purification for further conversion.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH:9]([NH:20]C(=O)OC(C)(C)C)[CH2:10][C:11]2[S:15][C:14]([C:16]([F:19])([F:18])[F:17])=[N:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:20][CH:9]([CH2:10][C:11]1[S:15][C:14]([C:16]([F:19])([F:18])[F:17])=[N:13][CH:12]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:28]
Reactant: CC(C)(C)OC(=O)NC(Cc1cnc(C(F)(F)F)s1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(Cc1cnc(C(F)(F)F)s1)C(O)c1ccc(F)cc1

Procedure:
A solution of tert-butyl N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]ethyl]carbamate (0.711 g, 1.691 mmol) and conc. hydrochloric acid (0.5 ml) in methanol (5 ml) was heated under reflux for 10 min. The reaction solution was diluted with water, alkalified with potassium carbonate and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (ethyl acetate) to give the objective substance.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:11][CH2:12][CH2:13][CH2:14][C:15]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(Cl)CCCCl
Product: O=C(CCCCl)N1CCCc2ccccc21

Procedure:
from 3,4-dihydro-2H-quinoline and 4-chlorobutanoyl chloride
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-acetate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoacetate according to general procedure D.
Reaction SMILES: [K].Cl[B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.O1CCBO1.[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21]C>>[CH2:21]([B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1)[CH:20]=[CH:19][CH:18]=[CH2:17]
Reactant: CC1(C)OB(Cl)OC1(C)C
Reactant: CCCCCC
Agent: B1CCOO1
Agent: [K]
Product: C=CC=CCB1OC(C)(C)C(C)(C)O1
Temperature: -78 °C

Procedure:
About 0.55 moles of potassium piperylide is placed in a 2 liter, 3-neck flask with a mechanical stirrer, nitrogen bubbler, and a septum on the third neck. Approximately 340 ml of hexane is added and the flask is cooled to −78° C. in a dry ice/isopropyl alcohol bath. A dioxaborolane solution is prepared by dissolving 89.3 grams of 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.55 moles) in 750 ml of hexane. The dioxaborolane solution is added to the flask over about 2 hours while stirring. The mixture is stirred continuously overnight and is slowly warmed to room temperature. The flask contents are filtered and the solids are washed with about 250 ml of hexane. The resulting solution is concentrated by distilling off the hexane at atmospheric pressure. The product is 2-(2,4-pentadienyl)4,4,5,5-tetramethyl-1,3,2-dioxaborolane which is then vacuum distilled at 58° C. and 3 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)CCl
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CSc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
20 g (105.7 mmol) of 2-bromothiophenol, 19 g (137.5 mmol) of potassium carbonate, 27.8 g (165.5 mmol) of potassium iodide, 200 ml of dimethylformamide and 14.68 g (158.6 mmol) of chloroacetone are introduced into a 500 ml three-necked flask. The mixture is stirred for 2 hours at room temperature and is then poured into 800 ml of water. Extraction is carried out with ethyl acetate (3×400 ml). The organic phases are combined, washed with a molar sodium hydroxide solution (2×400 ml), dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a silica column (elution solution: 10% ethyl acetate in cyclohexane). 24.1 g (Yield: 93%) of (2-bromothiophenoxy)acetone are obtained (yellow oil).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1>CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:12][NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][N:23]=2)[CH:7]=1
Reactant: Nc1nccc2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1nccc2ccccc12)C(F)(F)F
Yield: 21.9 %

Procedure:
Analogously to Example 1, 200 mg (0.68 mmol) of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)oxirane and 99 mg (0.68 mmol) of 1-aminoisoquinoline are reacted. After chromatography on silica gel with hexane-ethyl acetate (0-60%), 65 mg of product is obtained.
Reaction SMILES: [CH2:1]([C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:14]([NH:16][CH2:17][CH:18]=[O:19])[CH3:15]>C1C=CC=CC=1>[CH2:14]([N:16]([CH2:17][CH:18]=[O:19])[C:12]([NH:11][C:9]1[S:10][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:7][N:8]=1)=[O:13])[CH3:15]
Reactant: CCNCC=O
Reactant: CCCCCc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCCCCc1nnc(NC(=O)N(CC)CC=O)s1

Procedure:
A mixture of 5-pentyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-ethylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-pentyl-1,3,4-thiadiazol-2-yl)ureido] acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:20][CH2:21][NH:22][CH:23]([CH3:25])[CH3:24])([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:9]([NH2:11])=[O:10].[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([N:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:20][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:9]([NH2:11])=[O:10])(=[O:28])[CH3:27]
Reactant: CC(C)NCCC(CCN1CCCCC1)(C(N)=O)c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(CCC(CCN1CCCCC1)(C(N)=O)c1ccccc1Cl)C(C)C

Procedure:
acetylating α-(2-chlorophenyl)-α-[2-[(1-methylethyl)amino]ethyl]-1-piperidinebutanamide in the presence of acetic anhydride to give α-[2-[acetyl(1-methylethyl)amino]ethyl]-α-(2-chlorophenyl)-1-piperidinebutanamide.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li].CN(C)P(N(C)C)(N(C)C)=O.[CH3:20][C:21]1([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:25][CH2:24][CH2:23][O:22]1.C(I)CC>C1COCC1>[CH3:20][C:21]1([CH2:26][CH:27]([CH2:7][CH2:5][CH3:6])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:22][CH2:23][CH2:24][O:25]1
Reactant: CCOC(=O)CCC1(C)OCCO1
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCI
Product: CCCC(CC1(C)OCCO1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a cooled (−78° C.) solution of lithium diisopropylamine (30 mL; 60 mmol; 2N in THF) in THF (8 mL) was added hexamethylphosphoramide (12 mL) and the solution was stirred for 30 min. A solution of ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate (9.4 g; 50 mmol), in tetrahydrofurane (9 mL), was added over 30 min and stirring was continued for 1 h. Propyl iodide (6.84 mL; 70 mmol) was slowly added and the solution was allowed to warm to room temperature for 4 h. the reaction was quenched by adding a saturated aqueous solution of ammonium chloride. The two phases were separated and the aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were dried with sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash-chromatography on silica gel using a gradient of ethyl acetate (0-40%) in heptane to furnish 9.8 g (85%) of ethyl 2-((2-methyl-1,3-dioxolan-2-yl)methyl)pentanoate as an oil. ESI/APCI(+): 231 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:25]O)[CH2:10][C:11]1([OH:24])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][CH:9]1[CH2:10][C:11]2([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[O:24][CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC(CO)OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OCc1ccccc1)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
4.81 g of tert-butyl 4-[2-(benzyloxy)-3-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate was dissolved in 20 ml pyridine, 2.76 g of tosyl chloride was added thereto, and the mixture was stirred at room temperature for 2 hr. Further, 1.00 g of tosyl chloride was added thereto, and the mixture was stirred at room temperature for 30 min, and at 50° C. for 35 min. The reaction solution was partitioned into ethyl acetate and water, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 3.72 g of tert-butyl 3-(benzyloxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][C:12]([CH3:30])=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)[CH:14]=3)[C:9]2=[O:31])=CC=1.FC(F)(F)C(O)=O.Cl>>[CH3:30][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[CH:17][NH:8][C:9]2=[O:31])=[CH:14][C:13]=1[O:18][CH:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH2:24]1
Reactant: COc1ccc(Cn2ccc3cc(OC4CCC(N5CCCC5)CC4)c(C)cc3c2=O)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(=O)[nH]ccc2cc1OC1CCC(N2CCCC2)CC1
Yield: 44.4 %

Procedure:
180 mg (0.4 mmol) of 2-(4-methoxy-benzyl)-7-methyl-6-(4-pyrrolidin-1-yl-cyclohexyloxy)-2H-isoquinolin-1-one were heated with 0.9 g trifluoro acetic acid in a microwave oven at 150° C. After aqueous workup, 58 mg of 7-methyl-6-(4-pyrrolidin-1-yl-cyclohexyloxy)-2H-isoquinolin-1-one were obtained as hydrochloride. Rt=1.07 min (Method B). Detected mass: 327.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:21](=[O:23])[CH3:22])=[N:12][C:11]=2[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Solvent: O
Product: CC(=O)Nc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C

Procedure:
A mixture of 0.28 g of 2-(3-aminopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 3 ml of acetic anhydride was stirred while heating at 60° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate to give 0.17 g of N-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]acetamide (hereinafter, referred to as “active compound 82”).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:27]1[C:28]([CH3:33])=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[C:28]([CH3:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Reactant: Cc1ncccc1Br
Product: Cc1cc(-c2cccnc2C)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 3-Bromo-2-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=325.2 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:23]([CH3:24])=[CH:22][C:7]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=C(C#N)[CH:18]=4)[NH:13][N:12]=3)=[N:10][C:6]=2[CH:5]=1.[C:25]([OH:28])(=[O:27])[CH3:26]>>[CH3:24][C:23]1[C:4]([CH3:3])=[CH:5][C:6]2[NH:10][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:26]([C:25]([OH:28])=[O:27])[CH:18]=4)[NH:13][N:12]=3)=[N:8][C:7]=2[CH:22]=1
Reactant: Cc1cc2nc(-c3n[nH]c4ccc(C#N)cc34)[nH]c2cc1C
Reactant: CC(=O)O
Agent: Cl
Product: Cc1cc2nc(-c3n[nH]c4ccc(C(=O)O)cc34)[nH]c2cc1C
Temperature: 100 °C

Procedure:
A stirred suspension of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile dihydrochloride [200 mg, Reference Example 6(aq)] in acetic acid/concentrated hydrochloric acid (4 ml, 1:1 v/v) was heated at 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature and filtered. The precipitate was washed with water and dried in vacuo to give 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid (195 mg) as a white solid. LC-MS (METHOD B): RT=2.52 minutes, 307 (M+H)+.
Reaction SMILES: C([O:8][N:9]([CH2:20][CH2:21][CH2:22][P:23](=[O:30])([O:27]CC)[O:24]CC)S(C1C=CC(C)=CC=1)(=O)=O)C1C=CC=CC=1.Cl.C(O)(=O)C.C>O>[OH:8][NH:9][CH2:20][CH2:21][CH2:22][P:23](=[O:24])([OH:30])[OH:27]
Reactant: CCOP(=O)(CCCN(OCc1ccccc1)S(=O)(=O)c1ccc(C)cc1)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=P(O)(O)CCCNO
Reaction time: 45 h
Yield: 1831.2 %

Procedure:
A mixture of diethyl 3-(N-benzyloxy-N-tosylamino)propylphosphonate (13.2 g), conc. hydrochloric acid (130 ml) and acetic acid (130 ml) was refluxed with stirring for 45 hours. The resultant mixture was concentrated under reduced pressure to give a residue and then water and an activated charcoal was added thereto, whereafter the mixture was filtered. The filtrate was concentrated under reduced pressure, and the resultant residual oil (8.59 g) was dissolved in water (25 ml). To the solution were added pyridine (2.08 g) and ethanol (5 ml), and then the mixture was allowed to stand overnight at 4° C. to give 3-(N-hydroxyamino)propylphosphonic acid 82.30 g) in the form of crystals. MP: 160°~166° C. (dec.).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([Cl:12])=[N:8][S:9](=[O:11])(=[O:10])[C:4]2=[CH:3][CH:2]=1.[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>CC(C)=O>[Cl-:12].[CH2:13]([N+:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH3:14]
Reactant: CCN(CC)CC
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: CC(C)=O
Product: CC[N+](CC)(CC)C1=NS(=O)(=O)c2ccccc21
Product: [Cl-]
Reaction time: 10 h

Procedure:
10.0 g of pseudosaccharine chloride are dissolved in 40 ml of acetone, and 5.1 g of triethylamine (diluted with 5 ml of acetone) are added. The reaction temperature is held at room temperature by ice cooling. After stirring for 10 hours, the resultant precipitate is isolated to give 5.3 g (35%) of 3-triethyl-ammoniobenzoisothiazole 1,1-dioxide chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 79 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (87 mg, 79%) which was obtained as an off white solid. MS: m/e=370.0 [M+H]+.
Reaction SMILES: O[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:30].C(N(C(C)C)CC)(C)C>CCOC(C)=O>[Cl:30][C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n3cnnc23)c1
Temperature: 25 °C

Procedure:
5-hydroxy-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine (0.3 g, 0.76 mmol), POCl3 (0.459 g, 3 mmol), and diisopropylethylamine (0.387 g, 3 mmol) in a 50-ml r.b.flask with a stir bar was stirred at 120° C. overnight. The reaction solution was cooled to room temperature and 20 ml of EtOAc and 5 g of SiO2 gel were added into the cooled solution. The solvents were evaporated in vacuo at 40° C. The resulting brown solid was placed on a cake of SiO2 gel (˜20 g) and washed with 250 ml of EtOAc. The brown filtrate was evaporated in vacuo to give 5-chloro-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine; MS m/z (M)+ 410; C17H8Cl2F3N5 requir. 410.2.
Reaction SMILES: [Br:1][C:2](Br)=[N:3][OH:4].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].C(=O)(O)[O-].[K+]>CCO.O>[Br:1][C:2]1[CH:8]=[C:7]([C:6]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1
Reactant: ON=C(Br)Br
Reactant: C#CC(=O)OCC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(Br)no1
Yield: 78 %

Procedure:
Dibromoformaldoxime (407 mg, 2.07 mmol) (prepared via the procedure of J C Rohloff, et. al., Tetrahedron Lett 1992, 33:3113-6), and ethyl propiolate (311 mg, 3.17 mmol) were dissolved in 10 ml of 50% aqueous EtOH. While stirring, a solution of 243 mg (2.43 mmol) of potassium bicarbonate in 5 ml of water was added dropwise over 1 h. The resulting solution was stirred for an additional 4 h, diluted with 25 ml of water, and extracted with chloroform (3×25 ml). The combined organic extract was dried over sodium sulfate and concentrated in vacuo to a colourless oil, 345 mg (78% yield) as a 7:1 mixture of the 5- and 4-carboxylates.