Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:25]1([OH:30])[CH2:29][CH2:28][CH:27]=[CH:26]1.C([O-])(=O)C.[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([CH:27]3[CH2:28][CH2:29][C:25](=[O:30])[CH2:26]3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: OC1C=CCC1
Reactant: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: O=C1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 90 °C

Procedure:
A suspension of N-(4-(3-iodopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (493 mg, 1.107 mmol), cyclopent-2-enol (373 mg, 4.43 mmol), potassium acetate (217 mg, 2.214 mmol), tetrabutylammonium chloride (338 mg, 1.218 mmol) and Palladium (II) acetate (24.86 mg, 0.111 mmol) in acetonitrile (3 mL) and water (0.300 mL) was degassed and backfilled with argon. The reaction was heated to 90° C. for 18 h. Palladium (II) acetate (24.86 mg, 0.111 mmol) was added, and the reaction was capped, degassed and filled with argon, and heated to 135° C. in a microwave for 1 h. The crude reaction mixture was diluted with dichloromethane (75 mL) and washed with brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 35-50% EtOAc/hexane), affording a white solid. It was further purified on a prep HPLC system (and free-based by partitioning between dichloromethane and saturated sodium bicarbonate solution), affording the product as a white solid. MS (ESI, pos. ion) m/z: 402.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: CO[C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([S:16]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[C:24]([O:26][CH3:27])=[O:25])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.[CH3:28][C:29]1[O:33][C:32]([CH:34]([NH2:40])[C:35]2([CH3:39])[CH2:38][O:37][CH2:36]2)=[CH:31][CH:30]=1>C(O)C>[CH3:28][C:29]1[O:33][C:32]([CH:34]([NH:40][C:3]2[C:6](=[O:7])[C:5](=[O:8])[C:4]=2[NH:9][C:10]2[CH:11]=[C:12]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[C:24]([O:26][CH3:27])=[O:25])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:35]2([CH3:39])[CH2:36][O:37][CH2:38]2)=[CH:31][CH:30]=1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1
Solvent: CCO
Product: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cccc(Nc2c(NC(c3ccc(C)o3)C3(C)COC3)c(=O)c2=O)c1
Temperature: 60 °C
Yield: 76.7 %

Procedure:
A mixture of 408.4 mg of methyl (R)-1-[3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzenesulfonyl]pyrrolidine-2-carboxylate and 350 mg of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 30 ml of ethanol was heated at 60° C. overnight. The solvent was evaporated off and the residue was taken up with 50 ml of ethyl acetate and washed twice with a 1 M sodium hydrogen phosphate solution. The organic phase was dried over magnesium sulfate and evaporated. 432 mg of methyl (R)-1-[3-(2-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzenesulfonyl]pyrrolidine-2-carboxylate were obtained. Yield=79%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:4]=1)#[CH:2].[F:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]([CH3:21])[CH:15]=1.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2].[Cu]I.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:4]=2)=[C:16]([CH3:21])[CH:15]=1
Reactant: C#Cc1ccnc(NC(N)=O)c1
Reactant: Cc1cc(F)ccc1I
Agent: [Cu]I
Agent: [Pd+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(F)ccc1C#Cc1ccnc(NC(N)=O)c1
Yield: 19.8 %

Procedure:
(4-Ethynyl-pyridin-2-yl)-urea (75 mg, 0.47 mmol), 4-fluoro-1-iodo-2-methyl-benzene (224 mg, 0.931 mmol), triethylamine (5.0 mL), palladium bis(triphenylphosphine)dichloride (16 mg, 0.023 mmol) and Copper (I) iodide (8.8 mg, 0.047 mmol) are mixed in DMF (1.8 mL). The reaction mixture is stirred for 16 hrs at room temperature before saturated NH4Cl solution (5 mL) is added along with water (25 mL). The mixture is extracted with EtOAc (3×20 mL) and the organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 5%) affords 25 mg of the desired product.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=1>C(Cl)(Cl)(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:1])=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Br)ccc1CBr

Procedure:
After N-bromosuccinimide (1.49 g, 6.63 mmol) and 2,2′-azobis(isbutyronitrile) (20 mg) were added to a solution of 4-bromo-1-methyl-2-(trifluoromethyl)benzene (2.0 g, 8.4 mmol) in carbon tetrachloride (20 ml), the mixture was heated under reflux for 5 hours. The temperature of the reaction mixture was returned to room temperature and the residue obtained by removing the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane) to give crude 4-bromo-1-bromomethyl-2-(trifluoromethyl)benzene. Potassium cyanide (365 mg, 5.6 mmol) was added to a solution of crude 4-bromo-1-bromomethyl-2-(trifluoromethyl)benzene obtained in the above in a mixture of ethanol-water (3:1, 12 ml), and the mixture was stirred at 70° C. for 3 hours. After the reaction mixture was poured into water and extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1-5/1) to give [4-bromo-2-(trifluoromethyl)phenyl]acetonitrile as a solid (1.14 g, total yield: 52%).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:17][CH:18]=3)[C:13](=O)[C:12]([CH3:28])([CH3:27])[CH2:11]2)=[CH:6][CH:5]=1.O>CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:17][CH:18]=3)[C:13](=[CH2:1])[C:12]([CH3:28])([CH3:27])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: [Li]C
Reactant: CN(C)CCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: O
Product: C=C1c2cc(OCCN(C)C)ccc2C(c2ccc(Cl)cc2)CC1(C)C

Procedure:
An ethereal solution of methyllithium (50 ml, 1.9 M) was added over 45 min. to a stirred solution of 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-tetralone (18.5 g) in dry ether (150 ml) and the mixture heated under reflux for 30 min. After cooling, excess methyllithium was decomposed with water, the ether layer was separated, dried (MgSO4) and treated with a solution of hydrogen chloride in ether. The hydrochloride salt of 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-methylidene tetralin precipitated as a white solid (15.6 g, 77%). A portion was recrystallized from ethanol-ether, m.p. 233°-235°.
Reaction SMILES: CS(Cl)(=O)=O.[N:6]1([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([C:20]3[S:24][C:23]4[C:25]([C:29]5[CH:34]=[C:33]([F:35])[N:32]=[CH:31][C:30]=5[CH:36](O)[CH3:37])=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)[C:17]([F:39])=[CH:16][N:15]=2)[CH:10]=[CH:9][N:8]=[N:7]1.C(N(CC)CC)C.[CH:47]1([NH2:50])[CH2:49][CH2:48]1>C(Cl)Cl>[N:6]1([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([C:20]3[S:24][C:23]4[C:25]([C:29]5[C:30]([CH:36]([NH:50][CH:47]6[CH2:49][CH2:48]6)[CH3:37])=[CH:31][N:32]=[C:33]([F:35])[CH:34]=5)=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)[C:17]([F:39])=[CH:16][N:15]=2)[CH:10]=[CH:9][N:8]=[N:7]1
Reactant: NC1CC1
Reactant: CC(O)c1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC1CC1)c1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 45 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
Slowly add methanesulfonyl chloride (0.04 mL, 0.55 mmol) to a solution of newly synthesized 1-(4-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)-6-fluoropyridin-3-yl)ethanol (240 mg, 0.50 mmol) and triethylamine (0.14 mL, 1.0 mmol) in methylene chloride (5 mL) at −78° C. After stirring the mixture at the same temperature for another 60 min, add cyclopropylamine (0.040 mL, 0.55 mmol) and leave it overnight at RT. Heat it to 45° C. for 5 h, cool to RT, and remove the solvent. Purify by column chromatography (10% methanol in DCM) to afford the title compound (42 mg 17%). MS (ES) m/z 519 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[N:13]1([CH2:18][C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:17]=[CH:16][N:15]=[CH:14]1.CCOC(C)=O>O1CCOCC1>[N:13]1([CH2:18][C:19]2[CH:20]=[C:21]([NH:22][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Nc1cccc(Cn2ccnc2)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1cnn2ccc(Nc3cccc(Cn4ccnc4)c3)nc12
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.221 mmol) in dioxane was added 3-((1H-imidazol-1-yl)methyl)aniline (115 mg, 0.663 mmol). The mixture was heated in microwave for 120 minutes at 120° C. EtOAc was added to the mixture, and washed with water. The organic layer was then dried over Na2SO4 and solvent was removed under reduced pressure to yield 5-(3-((1H-imidazol-1-yl)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. The resulting solid was used in the next step without further purification. LCMS (M+1=319)
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([C:17]([F:20])([F:19])[F:18])([C:13]([F:16])([F:15])[F:14])[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([C:13]([F:14])([F:15])[F:16])([C:17]([F:20])([F:19])[F:18])[C:8]([OH:10])=[O:9])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (14.6 g.), 4.5 N-aqueous potassium hydroxide (19.2 ml.) and methanol (35 ml.) is stirred at ambient temperature for 21/4 hours. The resulting solution is diluted with water and washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid, and extracted with ether. The extract is washed with water, dried with sodium sulphate and evaporated. The residue is sublimed twice at 100° C. and 0.3 mm. pressure, and the sublimate is washed with light petroleum (b.p. 30°-40° C.) to give (2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 81°-83° C. (5.1 g.). The acid may be further purified by crystallisation (prisms) from light petroleum (b.p. 60°-80° C.) followed by sublimation, which yields material of m.p. 82°-83° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=O.Cl.[NH2:16]O.O.C(=O)([O-])O.[Na+]>C(O)=O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:16]
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: COC(=O)c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution (20 ml) of methyl 4-formyl-3-methoxybenzoate (870 mg, 4.48 mmol) in formic acid was added hydroxylamine hydrochloride (405 mg, 5.82 mmol), and the mixture was stirred at room temperature for 1 hr. The temperature was raised to 50° C., and the mixture was further stirred for 24 hrs. Water was added to the reaction mixture, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (780 mg, 91%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:44])[CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1.[ClH:45]>CO>[ClH:45].[F:44][C:42]1[CH:41]=[C:4]([CH:3]=[C:2]([F:1])[CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: CO
Product: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCNCC4)cc3)cc12
Yield: 63.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.167 mmol) was deprotected in methanol (5 ml), HCl in 1,4-dioaxane (5 ml). This afforded 100 mg (63.3% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 8.56 (s, 1H), 7.858-7.853 (d, 1H), 7.54-7.51 (d, 2H), 7.03-7.01 (d, 2H), 6.69-6.67 (m, 2H), 5.29 (s, 2H), 3.65-3.59 (t, 4H), 3.21-3.19 (t, 4H), 2.26 (s, 3H), 2.15 (s, 3H), 1.49 (s, 9H). MS: m/z=599.2 (M+1).
Reaction SMILES: C[C@@H]1O[C@@H:6]([O:8][C@@H:9]2[C:14]3[C:15]([OH:43])=[C:16]4[C:27](=[O:28])[C:26]5[C:21](=[C:22]6[O:35][C@@H:34]7[O:36][C@@:30]([CH3:42])([C@H:31]([OH:41])[C@@H:32]([N:38]([CH3:40])[CH3:39])[C@@H:33]7[OH:37])[C:23]6=[CH:24][C:25]=5[OH:29])[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH2:12][C@:11]([OH:45])([CH3:44])[CH2:10]2)[C@H](OC)[C@@](OC)(C)[C@H]1OC.FC(F)(F)C(O)=O.C[O-].[Na+].O>CO.C(Cl)(Cl)Cl>[CH3:44][C@@:11]1([OH:45])[CH2:12][C:13]2[CH:18]=[C:17]3[C:19](=[O:20])[C:21]4[C:26](=[C:25]([OH:29])[CH:24]=[C:23]5[C:30]6([CH3:42])[O:36][CH:34]([C@@H:33]([OH:37])[C@H:32]([N:38]([CH3:39])[CH3:40])[C@H:31]6[OH:41])[O:35][C:22]5=4)[C:27](=[O:28])[C:16]3=[C:15]([OH:43])[C:14]=2[C@@H:9]([O:8][CH3:6])[CH2:10]1
Reactant: CO[C@H]1[C@H](O[C@H]2C[C@](C)(O)Cc3cc4c(c(O)c32)C(=O)c2c(O)cc3c(c2C4=O)O[C@@H]2O[C@@]3(C)[C@H](O)[C@@H](N(C)C)[C@@H]2O)O[C@@H](C)[C@H](OC)[C@@]1(C)OC
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CO[C@H]1C[C@](C)(O)Cc2cc3c(c(O)c21)C(=O)c1c(O)cc2c(c1C3=O)OC1OC2(C)[C@H](O)[C@@H](N(C)C)[C@@H]1O
Reaction time: 5 h

Procedure:
A Solution of 1 g. of nogamycin in 20 ml. of trifluoroacetic acid is cooled in an ice bath and stirred for 5 hours. Stirring is continued while a solution of sodium methoxide in methanol is added dropwise until the reaction mixture turns purple. One hundred ml. of water is added, the pH is adjusted to 7.0 with additional sodium methoxide, and the mixture is extracted with three 100-ml. portions of methylene chloride. The combined extracts are evaporated to dryness under reduced pressure, wt. 1.004 g. A mixture of 0.5 g. of residue, 15 ml. of 0.1 M glucuronic acid, 10 ml. water, and 10 ml. of methanol is stirred for 15 minutes and filtered. The filtrate is neutralized (pH 7.0) with 1 N sodium hydroxide and stirred while maintaining at pH 7. After about 30 minutes the precipitate is collected by filtration, yield 211 mg. of con 7-0-methylnogarol. TLC in chloroform-methanol-water (78:20:2) indicates the material is homogeneous and identical with the same material prepared by methanolysis: [α]D 897° (c 0.1525, CHCl3); 13C NMR identical with that of previously prepared material; mass spectrum m/e 541.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[N:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=2[NH:17][C:18]2[C:27]3[C:22](=[N:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(C#N)cc3)ccnc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(CN)cc3)ccnc2n1

Procedure:
The product of Example 167c (88 mg, 0.175 mmol) was reacted with lithium aluminum hydride (13.3 mg, 0.351 mmol) in THF (5 mL) at 60° C. for 15 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (15 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 11.04 (s, 1 H) 8.92 (d, J=8.82 Hz, 1 H) 8.54 (d, J=6.99 Hz, 1 H) 8.18 (s, 2 H) 7.72-7.80 (m, 2 H) 7.59 (dd, J=9.01, 2.76 Hz, 1 H) 7.40 (d, J=8.82 Hz, 2 H) 6.99-7.12 (m, 3 H) 6.74 (d, J=6.99 Hz, 1 H) 3.97 (q, J=5.52 Hz, 2 H) 2.74 (s, 3 H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[NH:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH2:35][CH3:36]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:14]([CH2:34][CH2:35][CH3:36])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: O=C(N[C@@H]1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 17.5 g (ca. 46 mM) of 8α-benzyloxycarbonylaminoergoline obtained from step (c), 13.5 g potassium carbonate and 6 ml (62 mM) n-propyl iodide in 300 ml dimethylformamide is stirred for 18 hours at room temperature. The mixture is filtered and concentrated in a rotary evaporator. The residue is treated with methylene chloride and shaken with water. The organic phase is dried over sodium sulphate, filtered and concentrated to give the crude heading compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:28][CH:27]([NH2:29])[CH2:26]1>>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:29][CH:27]2[CH2:26][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH2:28]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: NC1CN(c2ccccn2)C1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)N1C(=O)C(NC2CN(c3ccccn3)C2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-pyridine-2-ylazetidin-3-amine in a similar manner as described for Example 118. 1H NMR (500 MHz CDCl3): δ 1.57 (d, 6H), 3.71-3.75 (m, 2H), 3.84 (t, 2H), 4.04-4.10 (m, 1H), 4.37-4.45 (m, 1H), 5.71-5.76 (m, 1H), 6.19 (d, 1H), 6.60-6.64 (m, 1H), 7.40-7.44 (m, 1H), 7.46-7.52 (m, 5H), 8.10-8.12 (m, 1H); 13C NMR (125 MHz CDCl3): δ 20.36, 44.88, 48.00, 58.15, 106.25, 109.08, 113.90, 124.58, 129.24, 130.35, 131.46, 134.60, 137.46, 148.39, 158.35, 160.10; Mass Spectrum: M+H+ 399.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Cl)[N:25]=1.[CH3:32][NH2:33].O.C(OCC)(=O)C>O1CCOCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:33][CH3:32])[N:25]=1
Reactant: CN
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc(Cl)n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 0.100 g (0.180 mmol) of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-6-chloropicoline amide in 5 ml of 1,4-dioxane were added 0.00600 g (0.0360 mmol) of copper sulfate and 0.140 g (1.80 mmol) of a 40% aqueous methylamine solution, followed by stirring at an oil bath temperature 80° C. for 3 hours under an enclosed condition. The reaction liquid was returned to room temperature and opened, and water and ethyl acetate were added thereto. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=2:1) to prepare 0.0700 g (yield 69%) of a target compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc(Oc3c(F)cccc3F)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Temperature: 90 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained in an inert atmosphere of nitrogen, was placed a solution of tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in 1,4-dioxane/water (60/15 mL), 2-[4-(2,6-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 0.87 mmol, 1.3 equiv), sodium carbonate (180 mg, 1.68 mmol, 2.5 equiv), and tetrakis(triphenylphosphane)palladium (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90° C. in an oil bath and then concentrated under vacuum. The resulting solution was diluted with 50 mL of dichloromethane, washed with water and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 280 mg (79%) of tert-butyl (2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a white solid.