Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:30])([CH3:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2([C:17]3[CH:18]=[C:19]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:20]=[CH:21][CH:22]=3)SCCCS2)[CH:8]=[CH:9][CH:10]=1.CC(C)=[O:33]>CN(C=O)C.[Cu]=O.[Cu](Cl)Cl>[OH:1][CH2:2][C:3]([CH3:30])([CH3:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:18]=2)=[O:33])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(CO)Cc1cccc(C2(c3cccc(CC(C)(C)CO)c3)SCCCS2)c1
Reactant: CC(C)=O
Agent: Cl[Cu]Cl
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: CC(C)(CO)Cc1cccc(C(=O)c2cccc(CC(C)(C)CO)c2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A suspension of copper(II) oxide (0.96 g, 12.1 mmol) and anhydrous copper(II) chloride (3.2 g, 23.8 mmol) in acetone (80 mL) was heated to reflux. A solution of 230 (4.44 g, 10.0 mmol) in acetone (20 mL) and DMF (1.2 mL) was added dropwise over 5 min. After 90 min at reflux temperature, the reaction mixture was cooled to room temperature and filtered. The insoluble material was washed with CH2Cl2 (3×20 mL). The combined organic solutions were washed with aqueous 2 N Na2CO3 solution (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; hexanes/acetone=80/20) to give 232 (2.5 g, 71%) as an oil. 1H NMR (CDCl3): δ 7.68-7.30 (m, 8H), 3.31 (s, 4H), 3.03 (s br., 2H), 2.65 (s, 4H), 0.88 (s; 12H). 13C NMR (CDCl3=77.00 ppm): δ 197.42, 139.06, 136.96, 134.60, 131.88, 127.78, 127.55, 70.39, 44.07, 36.30, 23.80. HRMS (LSIMS, nba): Calcd for C23H31O3 (MH+): 355.2273. found: 355.2263. HPLC: 94.5% pure.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[C:59](B(O)O)[CH:58]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][S:25](=[O:28])(=[O:29])[CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[C:3](=[O:30])[C:2]=1[C:59]1[CH:58]=[N:57][C:66]2[C:61]([CH:60]=1)=[CH:62][CH:63]=[CH:64][CH:65]=2
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reactant: OB(O)c1cnc2ccccc2c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cnc3ccccc3c2)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Yield: 74 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 112 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-quinolinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (74%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:32]=[CH:31][C:30]([CH:33]2[C:46]3[CH:45]=[CH:44][C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[C:37]=3[NH:36][S:35](=[O:48])(=[O:47])[N:34]2[CH3:49])=[CH:29][C:25]=1[C:26]([OH:28])=O.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:23][C:24]1[CH:32]=[CH:31][C:30]([CH:33]2[C:46]3[CH:45]=[CH:44][C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[C:37]=3[NH:36][S:35](=[O:47])(=[O:48])[N:34]2[CH3:49])=[CH:29][C:25]=1[C:26]([N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)=[O:28]
Reactant: C1COCCN1
Reactant: CN1C(c2ccc(F)c(C(=O)O)c2)c2ccc3cccnc3c2NS1(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CN1C(c2ccc(F)c(C(=O)N3CCOCC3)c2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.7 %

Procedure:
TBTU (49.73 mg, 0.15 mmol) was added to a suspension of 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzoic acid 424 (60 mg, 0.15 mmol) in DCM (1 ml) and the mixture was stirred at room temperature for 20 min. Morpholine (13.6 μl, 0.15 mmol) and DIPEA (25.6 μl, 0.15 mmol) were added and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water (1 ml) and the mixture was extracted with DCM (3 ml). The organic phase was concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic conditions 1) to give the title compound (32 mg, 45%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].Cl.[CH2:16]([NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[ClH:14].[NH2:29][C:27]1[NH:26][C:24]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:25][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:28]=1
Reactant: N=C(N)NC(=N)NCc1ccccc1
Reactant: CCCCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCC1N=C(N)NC(NCc2ccccc2)=N1

Procedure:
160 ml of ethanol, 13.0 g (70.5 mmol) of 1-dodecanal and 1.5 ml of concentrated hydrochloric acid were added to 8.0 g (35.1 mmol) of N1-benzyl-biguanide hydrochloride. The mixture was refluxed for 16 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography, and the first main fraction eluted with a mixture of chloroform and methanol (9:1.5) was recrystallized from 80% aqueous ethanol to obtain 3.1 g of colorless crystals (1) having a melting point of 152 to 155° C. The second main fraction was recrystallized from 80% aqueous ethanol to obtain 0.9 g of colorless crystals (2) having a melting point of 153 to 156° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.C(O)C.[NH2:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(OC(C)C)(C)C>C(OCC)(=O)C>[N:21]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]=12
Reactant: CCOC(=O)C(C)c1ccc(C(=O)CCl)cc1
Reactant: Nc1ncccn1
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc(-c2cn3cccnc3n2)cc1
Yield: 28.4 %

Procedure:
A mixture of 25.5 g of ethyl 2-[4-(chloroacetyl)phenyl]propionate, 50 ml of ethanol and 19 g of 2-aminopyrimidine is heated under reflux for 3 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried and concentrated to give a reddish brown oil. To the oil are added ethyl acetate and isopropyl ether, and the crystalline precipitate is filtered off and recrystallized from ethanol to give 8.4 g of ethyl 2-[4-(imidazo[1,2-a]pyrimidin-2-yl)phenyl]propionate as colorless scales melting at 171°-173°C.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6][CH2:7][CH3:8])=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18](C(=O)C)[CH:19]=1.S(=O)(=O)(O)O>C(O)C>[CH2:11]([O:10][C:3]([C:4]1[O:6][C:7]2[C:18]([C:17](=[O:23])[CH:16]=1)=[CH:19][C:14]([Cl:13])=[CH:15][CH:8]=2)=[O:9])[CH3:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an argon atmosphere, ca. 60% oily sodium hydride (1.68 g) was added to ethanol (10 mL). The mixture was stirred at room temperature for 10 minutes. Diethyl oxalate (3.36 mL) was added thereto, 5′-chloro-2′-hydroxyacetophenone (2.82 g) dissolved in ethanol (20 mL) was added dropwise to the resultant mixture, and ethanol (40 mL) was further added, followed by refluxing for 1.5 hours and stirring at 50° C. for 14 hours. To the reaction mixture, concentrated sulfuric acid (1.5 mL) and ethanol (10 mL) were added, and the mixture was refluxed for 4 hours. The resultant mixteure was cooled, concentrated under reduced pressure to reduce the solvent by half, and toluene and 1N aqueous sodium hydroxide (15 mL) were added to the concentrated mixture. The resultant mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1). The resultant solid was washed with hexane, to thereby give the title compound (1.20 g).
Reaction SMILES: [K].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20](Cl)[N:19]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Ba+2].[OH-].[CH2:41]([OH:44])[CH2:42][OH:43].C1(C)C=CC=CC=1>O.C(O)C>[CH3:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20]([O:43][CH2:42][CH2:41][OH:44])[N:19]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCO
Agent: [Ba+2]
Agent: [K]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 110 °C
Reaction time: 4 h

Procedure:
10 gms of p-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-[2,2′-bipyrimidin]-4-yl]benzenesulfonamide potassium salt and barium hydroxide (1.5 gms) were charged to a reaction vessel. Ethylene glycol (30 ml) and toluene (150 ml) were added thereto. The reaction mass was heated at a temperature of 110° C. for 2 hours. Further 1.5 gms of barium hydroxide was added and heating was continued for another 4 hours. After completion of the reaction, toluene was removed by distillation and water (150 ml) was added. The pH of the reaction mass was adjusted to a value ranging from 1 to 2 with a mixture of 1:1 HCl:water and extracted in dichloromethane. The organic layer was collected and washed with water (150 ml) and the solvent was distilled off to obtain a residue. To the residue a mixture of ethanol and water (1:1) was added and stirred. The resulting suspension was heated to reflux to obtain a clear solution. The clear solution was further cooled to 25° C. to isolate bosentan.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)=[CH:4][C:3]=1[CH3:13].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([CH3:12])([CH3:11])[C:8]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:10])=[CH:4][C:3]=1[CH3:13]
Reactant: C1CCNC1
Reactant: Cc1cc(C(C)(C)C(=O)O)sc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C(=O)N2CCCC2)sc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of the 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoic acid in dichloromethane (10 ml) with a catalytic amount of dimethylformamide was added oxalyl chloride (0.30 ml, 0.34 mmol). The mixture was allowed to stir at ambient temperature for 2 hours. The solvent was evaporated and the crude acid chloride dried under vacuum. The crude acid chloride was dissolved in dichloromethane (10 ml) and cooled in an ice-bath. Pyrrolidine (1.2 ml, 14 mmol) was added and the mixture was allowed to stir for 30 minutes while being cooled in an ice-bath. The mixture was poured into ethyl acetate (25 ml) and then extracted with 1N hydrochloric acid. The organic layer was washed with a saturated brine solution, dried over magnesium sulfate and then evaporated to leave 1-[2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoyl]pyrrolidine as a red oil which was used in the next step without purification.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:4].[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)Nc1cccnc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.4 ml, 0.015 mole) was added dropwise (slowly) to a stirred and chilled (25°-30° C.) solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.00 g, 0.0138 mole) in anhydrous dimethylformamide (75 ml). The reaction mixture was heated at 55°-60° C. for 31/2 hrs, cooled to room temperature, and added dropwise to a stirred and chilled (15°-20° C.) solution of 3-aminopyridine (1.50 g, 0.016 mole) and triethylamine (1.62 g, 0.016 mole) in anhydrous dimethylformamide (25 ml). The reaction mixture was stirred at room temperature overnight, filtered, and poured into ice water (500 ml). The mixture was extracted with ethyl acetate (3×75 ml). The combined organic portions were washed with 5% potassium hydroxide solution (2×50 ml), water (50 ml), brine (25 ml), dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in tetrahydrofuran and treated with excess ethereal hydrogen chloride and isopropyl ether giving 2.5 g (41%). Recrystallization from isopropyl alcohol-ethanol-isopropyl ether gave 0.82 g. This was combined with a second crop of 0.43 g to give an off-white solid which underwent a phase change from 157°-163° C. and then decomposed at 186°-192° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Cl-].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][Zn+]>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.C1COCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([F:17])[CH:19]=2)[C:11]=1[CH3:12]
Reactant: Fc1cccc(C[Zn+])c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cccc(F)c2)nc2cc(F)cc(F)c2c1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A screw cap vial was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (500 mg, 2.016 mmol), tetrakis(triphenylphosphine)palladium(0) (233 mg, 0.202 mmol), and THF (5.04 mL). The mixture was sparged with N2, then 3-fluoro-benzylzinc chloride (0.5M in THF, 4.23 mL, 2.116 mmol) was added and the reaction stirred at 60° C. for 2 h. The reaction was then partitioned between EtOAc and water, and the organic layer washed with brine, dried (MgSO4), and concentrated. The crude material was purified by flash chromatography, eluting with a gradient of 0-15% EtOAc in hexane to give 4-chloro-5,7-difluoro-2-(3-fluorobenzyl)-3-methylquinoline. Mass Spectrum (ESI) m/e=322.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([S:11](Cl)(=[O:13])=[O:12])=[CH:5][C:4]=1[C:15]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[CH:23]=1.ClS(O)(=O)=O.[CH3:29][NH:30][CH3:31]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([S:11]([N:30]([CH3:31])[CH3:29])(=[O:13])=[O:12])=[CH:5][C:4]=1[C:15]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[CH:23]=1
Reactant: COc1cc(OC)c(S(=O)(=O)Cl)cc1-c1cn2cccnc2n1
Reactant: CNC
Agent: O=S(=O)(O)Cl
Product: COc1cc(OC)c(S(=O)(=O)N(C)C)cc1-c1cn2cccnc2n1

Procedure:
Prepared from 2-(2,4-dimethoxy-5-chlorosulphonyl-phenyl)-imidazo[1,2-a]pyrimidine (prepared from 2-(2,4-dimethoxyphenyl[1,2-a]pyrimidine and chlorosulphonic acid) and 40% dimethylamine analogously to Example 25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[C:17](Cl)=[N:18][CH:19]=[C:20](Br)[N:15]2[N:14]=1)(=[O:12])=[O:11].[CH3:24][O-:25].[Na+].[CH3:27][OH:28]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[C:17]([O:28][CH3:27])=[N:18][CH:19]=[C:20]([O:25][CH3:24])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2c(Cl)ncc(Br)n2n1
Reactant: CO
Reactant: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ncc(OC)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 0.42 g (0.92 mmol) of N-(2,6-dichlorophenyl)-5-bromo-8-chloro[1,2,4]triazolo[1,5-a]-pyrazine-2-sulfonamide in 30 mL of dry acetonitrile was combined with 2.8 mL (5.6 mmol) of a 2M solution of sodium methoxide in methanol and the mixture was warmed to 40° C. under a nitrogen atmosphere with stirring. After 24 hours, the reaction was quenched with 1 mL of glacial acetic acid and the solvent was removed under reduced pressure. The residue was extracted portionwise with up to 100mL of tetrahydrofuran and the cloudy extract obtained was filtered and concentrated by evaporation under reduced pressure. The title compound was isolated from the residue obtained by flash column chromatography on silica gel using a 2 to 10 percent ethanol/dichloromethane gradient as eluent. The title compound, which was the least polar of the three compounds present, was further purified by extraction with warm methanol and diethyl ether mixtures to obtain 46 mg (12 percent of theory) as a white powder melting above 250° C. with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@H:6]([NH:13][C:14](=[O:25])[CH2:15][N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]1=[O:24])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[N:27]1[C:36]2[NH:35][CH2:34][CH2:33][CH2:32][C:31]=2[CH:30]=[CH:29][C:28]=1[CH:37]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@H:6]([NH:13][C:14](=[O:25])[CH2:15][N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH:23][CH2:37][C:28]2[CH:29]=[CH:30][C:31]3[CH2:32][CH2:33][CH2:34][NH:35][C:36]=3[N:27]=2)[C:17]1=[O:24])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](NC(=O)Cn1c(C)ccc(N)c1=O)c1cccnc1
Reactant: O=Cc1ccc2c(n1)NCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@H](NC(=O)Cn1c(C)ccc(NCc2ccc3c(n2)NCCC3)c1=O)c1cccnc1
Reaction time: 48 h

Procedure:
##STR55## To a solution of the amine 16-6 (155 mg, 0.433 mmol), the aldehyde 14-3 (70 mg, 0.433 mmol) in CH2ClCH2Cl was added crushed 4A seives, AcOH (20 μL) and then NaB(OAc)3H (184 mg, 0.866 mmol). After stirring for 48 hours, the mixture was filtered through celite, poured into EtOAc and washed with saturated NaHCO3 then brine. The dried (MgSO4) solution was concentrated in vacuo to give a foam type solid. Column chromatography (5%MeOH in CHCl3) afforded the title compound 16-7 as a foam type solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)=[O:11])=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=2)=[CH:18][C:17]=1[O:45][CH3:46]>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)[CH2:34][CH2:33]3)[N:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:10](=[O:11])[C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)=[C:17]([O:45][CH3:46])[CH:18]=3)[C:30]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Trifluoromethoxy)-1-benzenecarbonyl chloride (283 mg, 1.256 mmol) in dichloromethane (1 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.145 mmol) in pyridine (8 mL) at 0° C. After 30 minutes, the ice bath was removed the reaction mixture was stirred at room temperature for 1.5 hour. Solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide (526 mg, 74%). 1H NMR (CDCl3) δ 1.57 (m, 2H), 1.74 (m, 2H), 2.10-2.27 (m, 6H), 2.30 (s, 3H), 2.51 (m, 4H), 2.66 (m, 3H), 4.03 (s, 3H), 4.77 (m, 3H), 5.56 (bs, 2H), 7.26-7.37 (m, 4H), 7.99 (m, 2H), 8.38 (s, 1H), 8.59 (s, 1H), 8.67 (d, J=8.21 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]3[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.C1(O[C:34](Cl)=[O:35])C=CC=CC=1.[Br:37][C:38]1[S:42][C:41]([NH2:43])=[N:40][CH:39]=1>C(#N)C>[Br:37][C:38]1[S:42][C:41]([NH:43][C:34]([NH:19][S:16]([C:14]2[S:13][C:12]3[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:8][CH:9]=[CH:10][C:11]=3[CH:15]=2)(=[O:18])=[O:17])=[O:35])=[N:40][CH:39]=1
Reactant: Nc1ncc(Br)s1
Reactant: NS(=O)(=O)c1cc2cccc(-c3ccncc3)c2s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ncc(Br)s1)NS(=O)(=O)c1cc2cccc(-c3ccncc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
To a suspension of 7-pyridin-4-yl-benzo[b]thiophene-2-sulfonic acid amide (0.10 g, 0.34 mmol) in acetonitrile (3 mL) were added triethylamine (0.11 mL, 0.8 mmol) and at 0-5° C. phenylchloroformate (0.065 g, 0.40 mmol). The mixture was stirred at rt for 2 h, and 5-bromo-thiazol-2-yl-amine (0.092 g, 0.50 mmol) was added. The reaction mixture was stirred at 55-60° C. for 3 h. After cooling down to rt, the solution was chromatographed over silica gel using dichloromethane/methanol as eluent to obtain the title compound (0.045 g) as a light brown solid. MS (ISN) m/e 492.8, 494.8 (M−H)−
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[ClH:19].[CH3:18][C@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: C[C@H]1CCCN1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CCCN1[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a chilled solution of Intermediate (v), (2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester, (2.51 g, 9.87 mmol) in 1,4-dioxane (9 mL) at 0° C. was added 4N HCl in dioxane (6 mL) and allowed to stir for 20 h at ambient temperature. The reaction mixture was concentrated to afford an oil which was dried under high vacuum to obtain 2.29 g of the title compound.