Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][SH:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12]Cl)=[C:8]([C:14]([Cl:17])([Cl:16])[Cl:15])[CH:7]=1)([O-:5])=[O:4]>C(OCC)C>[CH3:1][S:2][S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=1[C:14]([Cl:17])([Cl:16])[Cl:15]
Reactant: CS
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Solvent: CCOCC
Product: CSSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Reaction time: 2 h
Yield: 88.1 %

Procedure:
At 5° C., 7.2 g of methyl mercaptan is passed over a period of 20 minutes into a solution of 46 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 750 ml of diethyl ether. The reaction mixture is kept at 5° to 10° C. for 2 hours. After the solvent has been distilled off, the residue is recrystallized from ligroin. There is obtained 42 g (88% of theory) of methyldithio-4-nitro-2-trichloromethylbenzene; m.p.: 76° C.
Reaction SMILES: N([O-])=O.[Na+].[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11]([NH-])=[O:12].[OH2:21]>S(=O)(=O)(O)O>[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11]([OH:21])=[O:12]
Reactant: [NH-]C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Reactant: O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Temperature: 25 °C

Procedure:
30 ml of an aqueous solution containing 6.60 g (0.096 moles) of sodium nitrite were slowly added dropwise, whilst stirring and ice-cooling, to a suspension of 15.53 g (0.064 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoyl amide [(XXVI), X=X'=F, R16 =NH2 ] [prepared as described in step (b) above] in 20 ml of concentrated aqueous sulfuric acid, and the mixture was heated under reflux for 30 minutes. At the end of this time, it was cooled to room temperature, and then 50 ml of water were added it. The reaction mixture was then extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to give 15.59 g of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid as a colorless powder.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:5])C.[OH-].[Na+]>CO.O>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCc1cc2ccccc2n1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCc1cc2ccccc2n1-c1cccnc1

Procedure:
A solution of 1.0 g of 2-[4-(ethoxycarbonyl)butyl]-N-(3-pyridyl)indole and 0.25 g of sodium hydroxide in 5 ml of methanol and 5 ml of water is stirred for 17 hours at room temperature. The solvent is evaporated and the residue is redissolved in 10 ml of water and neutralized with 0.515 ml of concentrated hydrochloric acid. The resulting product is recrystallized from methanol to yield 2-(4-carboxybutyl)-N-(3-pyridyl)indole, m.p. 143°-144°.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20]1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[O:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:17])[CH2:20]2)=[CH:27][CH:28]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1c2ccccc2Oc2ccccc21

Procedure:
9-Xanthenylcarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-9-xanthenylcarboxamide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C@H:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]2.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][CH3:30])[CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C@H:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]3)=[C:24]([O:29][CH3:30])[CH:23]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(Br)cc3OC)ccc21
Temperature: 80 °C

Procedure:
To a solution of ethyl [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (1.4 g, 4.10 mmol) (Example 45) in DMF (130 mL, containing 1 vol % water) was added 4-bromo-2-methoxyphenol (832.9 mg, 4.10 mmol) followed by Cs2CO3 (2.66 g, 8.18 mmol). The reaction mixture was heated for 12 h at 80° C. Upon cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (gradient 1:4 to 1:1 (v/v) EtOAc/hexane) to give the product as a colorless oil. 1H NMR (400 MHz, acetone-d6) δ 7.11-7.07 (m, 2H), 7.03-7.01 (m, 1H), 6.94-6.92 (m, 1H), 6.82-6.81 (m, 1H), 6.75-6.72 (m, 1H), 4.20-4.11 (m, 6H), 3.84 (s, 3H), 3.48-3.44 (m, 1H), 2.89-2.69 (m, 3H), 2.42-2.30 (m, 2H), 2.07 (q, 2H), 1.75-1.70 (m, 1H), 1.25 (t, 3H).
Reaction SMILES: BrC1C=CC(N2CCN([CH:14]3[CH2:23][CH2:22][C:17]4[N:18]=[C:19](N)[S:20][C:16]=4[CH2:15]3)CC2)=NC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:30]1CCC[CH2:31]1>>[S:20]1[C:16]2[CH2:15][CH:14]([CH2:31][OH:30])[CH2:23][CH2:22][C:17]=2[N:18]=[CH:19]1
Reactant: Nc1nc2c(s1)CC(N1CCN(c3ccc(Br)cn3)CC1)CC2
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1CCc2ncsc2C1
Reaction time: 1 h

Procedure:
A solution of (±)-ethyl 2-amino-4,5,6,7-tetrahydro-6-benzothiazolecarboxylate (13.5 g) (Example C) in 700 ml of anhydrous tetrahydrofuran is cooled in an ice bath and lithium aluminum hydride (4.56 g) is added in small portions. A thick suspension forms which is kept at room temperature for one hour. The reaction mixture is quenched by careful addition of a 10% solution of hydrochloric acid. The volatile components are evaporated in vacuo and the residue is stirred with a 25% solution of sodium hydroxide and dichloromethane for 30 minutes. An emulsion forms which is filtered through Celite. The aqueous phase is extracted with dichloromethane several times. The pooled organic extracts are dried and evaporated. The residue is recrystallized from ethyl acetate to give (±)-4,5,6,7-tetrahydro-6-benzothiazolemethanol as a colorless solid, mp 176°-182° C. A solution of this compound (5.0 g) in 500 ml of chloroform is treated with 25 ml of a 1 M hydrochloric acid-diethyl ether solution, followed by 50 ml of thionyl chloride. The reaction mixture is refluxed under nitrogen for one hour until evolution of gas ceases. The mixture is concentrated in vacuo and the residue is taken up into 100 ml of dimethylformamide. To this solution is added 1-(2-pyridyl)piperazine (4.89 g) and sodium bicarbonate (5.0 g) and the mixture is heated at 85° C. for six hours. The solvent is evaporated in vacuo, and the residue is partitioned between dichloromethane and water. The organic layer is dried (magnesium sulfate) and purified by MPLC. The hydrochloride salt is prepared to give (±)-4,5,6,7-tetrahydro-6-[[4-(2-pyridinyl)-1-piperazinyl]methyl]benzothiazole containing 2.85 molecules of hydrochloric acid and 1.1 molecules of water; mp 251°-252° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH:14]=[CH:13][C:12]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](N1CCOCC1)=[O:19].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][C:14]([CH:18]=[O:19])=[CH:13][C:12]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=Cc2cc(Oc3ccccc3)ccc2OC1
Reactant: O=CN1CCOCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=Cc2cc(Oc3ccccc3)ccc2OC1
Temperature: 60 °C

Procedure:
6-Phenoxy-2H-1-benzopyran (3.36 g, 15 mmol) and N-formylmorpholine (10.4 g, 90 mmol) are dissolved in 10.5 ml of methylene chloride and treated with phosphorus oxychloride (13.8 g, 90 mmol) at 0° C. over 15 minutes. The mixture is then heated at 60° C. for 27 hours, cooled and poured slowly into an ice-water mixture. The mixture is then neutralized with aqueous ammonium hydroxide, and extracted twice with methylene chloride. The combined organic extracts are washed with water, dried (MgSO4), and evaporated to give crude 6-phenoxy-2H-1-benzopyran-3-carboxaldehyde, which is used without further purification.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[C:18]#[N:19]>C(Cl)(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([C:18](=[NH:13])[NH2:19])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)c1ccc(F)c(F)c1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 33 %

Procedure:
3.6 mL (7.2 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 10 mL of toluene containing 384 mg (7.17 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 1 g (7.1 mmol) of 3,4-difluorobenzonitrile was added thereto and the resulting mixture was heated to 85° C. for 9 hours. After completion of a reaction, the reaction solution was poured into 100 mL of chloroform containing 200 g of silicagel and filtered off. The residue was washed with 200 mL of methanol and distillation was conducted to give 370 mg (2.36 mmol) of the title compound in a yield of 33%.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:52]([C:51]3[CH:55]=[CH:56][C:48]([Cl:47])=[CH:49][CH:50]=3)=[O:53])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.210 g, 0.35 mmol) in pyridine (2 mL) was added 4-chlorobenzoyl chloride (0.051 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.090 g, 62% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 14.20 (br s, 1H), 13.45 (br s, 1H), 10.54 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.10 (d, 1H), 8.04 (d, 2H), 7.93 (d, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 7.64 (d, 2H), 7.56 (t, 1H); ES-MS (m/z) 415 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)=[C:4]([O:15][CH3:16])[CH:3]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[N:21]=[C:20]([O:25][CH3:26])[N:19]=1>C(N(CC)CC)C>[Cl:17][C:18]1[N:19]=[C:20]([O:25][CH3:26])[N:21]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]3)=[C:4]([O:15][CH3:16])[CH:3]=2)[N:23]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(CO)c1
Solvent: CCN(CC)CC
Product: COc1nc(Cl)nc(Nc2ccc(-n3cnc(CO)c3)c(OC)c2)n1
Yield: 61 %

Procedure:
This compound was prepared in analogy to example 8 from [1-(4-amino-2-methoxy-phenyl)-1H-imidazol-4-yl]-methanol, triethylamine and 2,4-dichloro-6-methoxy-1,3,5-triazine. The title compound was isolated as a brownish solid in 61% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)[CH3:9].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29].C(=O)(O)[O-].[Na+]>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.COCCOC>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:27])=[CH:19][C:20]=2[CH3:25])=[CH:35][CH:34]=1)[CH3:29]
Reactant: Cc1cc(-c2onc(C)c2NC(=O)O[C@H](C)c2ccccc2F)ccc1Br
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2C)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
[5-(4-Bromo-3-methyl-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester (0.350 g, 0.80 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.292 g, 0.96 mmol), and sodium bicarbonate (0.235 g, 2.8 mmol) were combined in 2:1 DME:water (11 mL), and the solution was purged with N2 for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.030 g, 0.04 mmol) was added, and the reaction was stirred at 80° C. for 2 hour. After work-up, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH3:39][N:35]1[C:36](=[O:38])[C:37]2[C:33](=[C:32]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:31]=[CH:30][C:29]=2[NH:28][C:2]2[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:15][CH:14]=3)[N:3]=2)[CH2:34]1
Reactant: CN1Cc2c(N3CCOCC3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-2-methyl-4-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 208A). MS (ES+): m/z 636.24 (100) [MH+]; HPLC: tR=1.05 min (UPLC, purity).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[Cl:24][C:25]1[N:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=1>>[Cl:24][C:25]1[N:30]=[C:29]([C:31]([NH:23][C:22]2[CH:21]=[N:20][N:17]3[CH:18]=[CH:19][C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:9]4[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])=[N:15][C:16]=23)=[O:32])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)c1cccc(Cl)n1
Yield: 31 %

Procedure:
Prepared by the method as described in Example 68, substituting (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine with (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B), and substituting picolinic acid with 6-chloropicolinic acid, to provide the final product as a yellowish solid (9.1 mg, 31% yield). MS (apci) m/z=455.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])[O:3]1.[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])[O:5]1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1

Procedure:
The title compound was prepared using methods analogous to those described in Step A of Example 490 using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and ethanesulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.82-7.74 (m, 1H), 7.64 (d, J=8.3, 1H), 7.49-7.41 (m, 1H), 7.14-7.06 (m, 1H), 3.12 (q, J=7.4, 2H), 1.37 (s, 12H), 1.32 (t, J=7.4, 3H).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:33][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]1.CC(O)=O>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:31][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)C1CNC1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (30 mg, 0.066 mmol) and tert-butyl azetidine-3-carboxylate, AcOH (21.52 mg, 0.099 mmol) in DMSO (2 mL) was added TEA (0.028 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 30-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions were obtained with the correct mass were freeze-dried overnight to yield 10 mg of Preparation 1D. MS (m+1)=531. HPLC Peak RT=3.67 minutes (Analytical Method A). Purity=92%.
Reaction SMILES: C([CH:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])C=C.[NH:29]1[C:37]2[C:32](=[CH:33][C:34](B(O)O)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[CH:33][C:34]([C:11]3[N:12]=[C:13]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[C:8]4[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:4][C:9]=4[N:10]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: C=CCC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2CCN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: C[C@H]1COCCN1c1nc(-c2ccc3[nH]ccc3c2)nc2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
Compound fm was prepared according to the procedure described in Example 2 step 2 by reacting tert-butyl 8-allyl-2-chloro-4-((S)-3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate with 1H-indol-5-ylboronic acid. LC-MS: m/z=+450 (M+H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[Cl:24])=[CH:10]2)=[O:4].N1C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:16]1[C:17]([Cl:24])=[CH:18][C:19]([NH:23][S:39]([C:33]3[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=3[Cl:31])(=[O:41])=[O:40])=[CH:20][C:21]=1[Cl:22])=[CH:10]2)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cccc2cc(Oc3c(Cl)cc(N)cc3Cl)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
To a solution of 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-8-carboxylic acid methyl ester (315) (1.26 mmol) in Pyridine (0.15 ml, 1.80 mmol) and CH2Cl2 (5 ml), was added 2,4-Dichlorobenzenesulfonyl chloride (381 mg, 1.55 mmol). The mixture was stirred at room temperature for 12 hr. Sat NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by Brine, dried over MgSO4, and concentrated. The crude residue was purified by column chromatography (Hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 182 (506 mg, 70%) as a white solid.
Reaction SMILES: Cl[C:2]1[NH:3][S:4](=[O:13])(=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CO>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[NH:3][S:4](=[O:13])(=[O:12])[C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:17][CH2:16]1
Reactant: O=S1(=O)NC(Cl)=Nc2ccccc21
Reactant: CN1CCNCC1
Solvent: CO
Product: CN1CCN(C2=Nc3ccccc3S(=O)(=O)N2)CC1
Yield: 72.2 %

Procedure:
To a stirred suspension of 10.7 g of 3-chloro-2H-1,2,4-benzothiadiazine 1,1-dioxide in 100 ml of methanol is added 9.9 g of 1-methylpiperazine and the mixture is heated under reflux for 2 hours. After cooling, the crystalline precipitate is collected by suction filtration and recrystallized from a mixture of dimethylformamide and water to give 10.0 g of the desired product, m.p. 265°-267° C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]1([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C(c1ccccc1)c1ccccc1

Procedure:
Crude DPE (Aldrich or from reaction of phenylmagnesium bromide with acetophenone, acetylation with acetic anhydride and thermal elimination of acetic acid) is distilled through a column having at least 50 theoretical plates (spinning-band column; a Sulzer packed column for larger amounts) to a purity of 99.8%. The usually slightly yellow distillate is filtered through a 20 cm Alox column (Woelm alumina for chromatography, anhydrous), titrated with 1.5N sec-butyllithium to a deep red color and distilled off over a simple still head under reduced pressure (1 mbar). The resulting product is completely colorless and can be used directly in the anionic polymerization.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:22])[CH2:3]1.Cl.Cl.[NH:26]1[C:30]2=[N:31][CH:32]=[CH:33][C:34]([CH2:35][NH2:36])=[C:29]2[CH:28]=[CH:27]1>>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3[NH:36][CH2:35][C:34]3[CH:33]=[CH:32][N:31]=[C:30]4[NH:26][CH:27]=[CH:28][C:29]=34)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:22])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc(NC(=O)c3cccnc3F)ccc21
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Product: CC1(C)CC(=O)Nc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21

Procedure:
The titled compound was prepared from N-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 441 (M+H). Calc'd. for C25H24N6O2—440.51.