Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[N:22]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[N:23]1>>[N:22]1([C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:1]3[CH2:2][CH2:3][C:4]4([O:11][C:10]5[C:12]6[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=5[S:8][CH2:7]4)=[CH:16][CH:15]=[CH:14][CH:13]=6)[CH2:5][CH2:6]3)=[O:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[N:23]1
Reactant: O=C(Cl)c1ccc(-n2cccn2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccc(-n4cccn4)cc3)CC1)O2

Procedure:
Compound 44 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-(1H-pyrazol-1-yl)benzoyl chloride and conditions outlined in procedure N. M.p.=299-300° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.06 (d, 1H), 8.0 (s, 1H), 7.64 (m, 4H), 7.65 (t, 1H), 7.50 (m, 3H), 6.52 (s, 1H), 3.42 (m, 2H), 2.96 (s, 2H), 2.22 (m, 2H), 1.92 (m 2H), 1.58 (s, 2H); LCMS: 472 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:16]([O:20][C:21]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][C:22]=1B(O)O)[CH2:17][CH2:18][CH3:19]>>[C:27]([C:26]1[C:21]([O:20][CH2:16][CH2:17][CH2:18][CH3:19])=[C:22]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:3]=2)[CH:23]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Reactant: CCCCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Product: CCCCOc1c(-c2cc(C=CC(=O)O)ccc2O)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 7.2 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 6.2 g (22.8 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 14 g (45.7 mmol) of 2-butyloxy-3,5-di-tert-butylphenylboronic acid obtained above, 700 mg (7%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: COC1(c2cc(F)cc(Cl)c2)CCNC1
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 22. (+)-3-(3-chloro-5-fluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.043 mmol), triethylamine (12.1 μL, 0.086 mmol), tetrahydrofuran (2 ml) and iodoethane (5.2 μL, 0.065 mmol). The crude product analyzed by GCMS. Analysis showed 74% conversion. MS m/z (relative intensity, 70 eV) 257 (M+, 10), 242 (94), 227 (39), 157 (40), 71 (bp).
Reaction SMILES: C(#N)C=CCCCCCCC.[CH2:12]([OH:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH3:26].CCCCCC.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([O:27][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC=CC=CCCCCCCCO
Agent: CCCCCCCC=CC#N
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCCC=CC=CCCCCCCCOC(C)=O

Procedure:
The pentadecadiene (D) (5.9 g) in 200 ml methanol containing eight drops concentrated HCl was refluxed for 15 minutes. After the solution was cooled, 400 ml of water were added, and the mixture was extracted three times with hexane. The hexane extract was dried over sodium sulfate, and the hexane was removed with a rotary evaporator leaving 3.1 g of crude 8,10-pentadecadienol, which was purified by silica gel liquid chromatography. Unwanted side products were eluted with 10% ether/hexane, and the alcohol was eluted with 50% ether/hexane, giving 2.5 g (66% yield based on the decenenitrile (B)). 8,10-Pentadecadienol in 75 ml pyridine and 5 ml acetic anhydride was refluxed 1.5 hours. After the solution was cooled, 200 ml hexane was added, and the mixture was extracted successively with water, 6N hydrochloric acid (twice), and water. The pentane phase was dried over sodium sulfate, filtered, and the pentane was removed by rotary evaporation, leaving crude product, which was purified by silica gel liquid chromatography (elution in 10% ether/hexane); the yield was 2.8 g (94% based on the alcohol). The product was 39% EE and 61% EZ by GC analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][N:31]=1>C(Cl)Cl>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([S:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]3)=[CH:4][CH:3]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CN(Cc2ccc(NS(=O)(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Yield: 66 %

Procedure:
D2 (500 mg, 1.64 mmol) and pyridine (1.5 mL) were combined in DCM (5 mL). 2-chloro-pyridine-5-sulfonylchloride (314 mg, 1.48 mmol) in DCM (5 mL) was added dropwise. The solution was stirred over the weekend and the solvent removed. The residue was partitioned between DCM (25 mL) and water (25 mL). The aqueous layer was re-extracted with DCM (25 mL) and the combined organic layers washed with brine (50 mL), dried and concentrated. The crude product was purified by column chromatography. Eluting with 0-50% EtOAc/petroleum ether yielded the product as a yellow foam (470.1 mg), δH (CDCl3, 400 MHz) 1.18 (3H, d), 1.46 (9H, s), 1.97 (1H, m), 2.08 (1H, m), 2.48 (1H, d), 2.68 (1H, d), 3.07 (1H, m), 3.32-3.46 (2H, AB), 3.78 (1H, d), 4.16 (1H, br.s), 7.07 (2H, d), 7.23 (2H, d), 7.39 (1H, d), 7.96 (1H, dd), 8.72 (1H, m). MS (ES+): MH+ 481.2/483.1
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.CN.[NH2:9][C:10]1[C:11]([F:35])=[CH:12][C:13]([F:34])=[C:14]([N:16]2[C:25]3[C:20](=[C:21]([OH:29])[C:22]([F:28])=[C:23](F)[C:24]=3[CH3:26])[C:19](=[O:30])[C:18]([C:31]([OH:33])=[O:32])=[CH:17]2)[CH:15]=1>C(O)(=O)C.C(O)C>[NH2:9][C:10]1[C:11]([F:35])=[CH:12][C:13]([F:34])=[C:14]([N:16]2[C:25]3[C:20](=[C:21]([OH:29])[C:22]([F:28])=[C:23]([NH:1][CH3:2])[C:24]=3[CH3:26])[C:19](=[O:30])[C:18]([C:31]([OH:33])=[O:32])=[CH:17]2)[CH:15]=1
Reactant: Cc1c(F)c(F)c(O)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: c1ccncc1
Agent: CN
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1c(F)c(O)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 30 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
Pyridine (300 mg) and a 40% aqueous solution (300 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-5-hydroxy-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was stirred at 30° C. for 2 days. Acetic acid (1 drop) and ethanol (1 ml) were added to the reaction mixture, and the solvent was distilled off. Methanol was added to the residue, and solids were collected by filtration to obtain the title compound (33 mg) as a brown powder.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:28][C:26]1[O:25][N:24]=[C:23]([CH:21]2[CH2:22][N:19]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]3[CH:7]=[C:6]4[C:11](=[N:10][CH:9]=3)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]4)[CH2:20]2)[N:27]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Cc1nc(C2CNC2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C2CN(C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)C2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-azetidin-3-yl-5-methyl-1,2,4-oxadiazole hydrochloride (25 mg, 0.14 mmol; which may be prepared as described in Step 5), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a white solid. This solid was triturated in acetone and diethyl ether, filtered, washed with acetone and diethyl ether then dried to give the title compound (23 mg, 56%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([OH:18])([C:14](F)(F)F)=[O:13]>>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:14][C:12]([OH:18])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: Brc1cccc2cccnc12
Reactant: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cccc2cccnc12

Procedure:
The title compound (278 mg) was prepared from 8-bromoquinoline (3.0 g, 14.5 mmol) according to protocol P above. LCMS (0.05% TFA): [M+1]+ 188.1. 1H-NMR (CD3OD, 400 MHz): δ 9.01 (d, 1H, J=3.6 Hz), 8.72 (d, 1H, J=6.4 Hz), 8.06 (d, 1H, J=6.8 Hz), 7.87 (d, 1H, J=5.6 Hz), 7.77 (m, 2H), 4.31 (s, 2H).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[CH:13][C:14]=1[Cl:15].Cl[C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]>O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:16][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
Sodium hydride dispersion, 60% by weight (2.54 grams, 63.47 mmol) is placed into a 125 ml round bottom flask equipped with a stir bar and condenser under nitrogen and is charged with 32 ml of dimethyl formamide. 3,4-Dichlorophenol (5.17 grams, 31.73 mmol) is added portionwise over five minutes. During this addition, an exotherm and vigorous gas evolution are observed. The reaction is allowed to stir for five minutes. 2-Chloronicotinic acid (5.00 grams, 31.73 mmol) is then added portionwise over five minutes. When gas evolution subsides, the reaction is heated to reflux for 21 hours. It is then cooled to room temperature and 300 ml of water added. The aqueous layer is extracted with diethyl ether (3×200 ml), then pH adjusted to acidic with glacial acetic acid and stirred. After 2 hours, the precipitate which has formed is filtered and washed with (3×100 ml) water then (3×100 ml) pentane to yield 1.78 grams (19.8%) of product as a tan crystalline solid.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:34][C:35]1[C:36]2[O:44][CH:43]=[CH:42][C:37]=2[C:38](=[O:41])[NH:39][CH:40]=1.[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][C:46]=1[CH2:55][CH2:56]O>C1COCC1>[Br:34][C:35]1[C:36]2[O:44][CH:43]=[CH:42][C:37]=2[C:38](=[O:41])[N:39]([CH2:56][CH2:55][C:46]2[CH:47]=[CH:48][C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:45]=2)[CH:40]=1
Reactant: O=c1[nH]cc(Br)c2occc12
Reactant: OCCc1ccc2ccccc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2ccoc2c(Br)cn1CCc1ccc2ccccc2n1
Reaction time: 0.5 h
Yield: 23 %

Procedure:
DIAD (4.91 mmol, 992 mg) was added dropwise to PPh3 (753 mg, 2.80 mmol) in 20 mL of THF. The mixture was stirred for 30 min. Then 7-bromofuro[3,2-c]pyridine-4(5H)-one (300 mg, 1.402 mmol) was added followed by the addition of 2-(quinolin-2-yl)ethanol (243 mg, 1.402 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with water/ethyl acetate. The organic phase was extracted with 1N HCl. The acidic aqueous phase was basified with 1N NaOH and extracted with DCM. The organic phase was extracted with water, dried over MgSO4, filtered, concentrated and purified by chromatography to give the title compound as white solid (119 mg, 23%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:18]=[CH:17][S:16][C:15]=1[S:19]([N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1)(=[O:21])=[O:20]>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:18]=[CH:17][S:16][C:15]=3[S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(=O)(c1sccc1Br)n1cccc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=S(=O)(c1sccc1-c1ccc2c(c1)OCO2)n1cccc1
Yield: 90 %

Procedure:
N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 13C using 3,4-methylenedioxyphenylboronic acid and N-(3-bromothiophene-2-sulfonyl)pyrrole. The crude product was purified by flash column chromatography on silica gel using 2% EtOAc in hexane as the eluent resulting in N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole in a 90% yield.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[C:11](Cl)(=O)[CH3:12]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8][CH:11]2[CH3:12])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CC(=O)Cl
Product: CC1NCCc2ccc(F)cc21

Procedure:
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using 4-fluorophenethylamine and acetyl chloride, 7-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 69%) The product was used in the subsequent step without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][N:21]1[C:26]2[CH:27]=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[CH:27][C:26]5[N:21]([CH3:20])[CH2:22][CH2:23][O:24][C:25]=5[CH:30]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1CCOc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CN1CCOc2cc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)ccc21

Procedure:
(1-Methyl-cyclohexyl)-[2-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-methyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[1,4]oxazine following general procedures as described in these Examples. MP 243-244° C., M+H=391.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:10]=[C:9]1[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.CN(C)C=O>ClCCl.C(=O)(O)[O-].[Na+]>[N:32]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCOS(C)(=O)=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCN2CCCC2)CC1
Temperature: 50 °C
Yield: 93 %

Procedure:
Combine tert-butyl 4-(1-(2-(methylsulfonyloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.02 g, 4.42 mmol), pyrrolidine (1.1 mL, 3.0 eq), and dimethylformamide (19 mL). Heat the reaction mixture to 50° C. overnight. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate the layers. Wash the organics with water. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to ethyl acetate to 10% methanol in dichloromethane, to give the title compound as a yellow oil (1.79 g, 93%). MS (ES) m/z=433 [M]+.
Reaction SMILES: O[CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].P(Br)(Br)[Br:17]>>[Br:17][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4]
Reactant: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: BrP(Br)Br
Product: C[C@H](CBr)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 142.8 %

Procedure:
(R)-2-(1-hydroxypropan-2-yl)isoindoline-1,3-dione (8.75 g, 43 mmol) and phosphorus tribromide (2.73 ml. 29 mmol) were heated at 175° C. for 50 min. To cooled reaction mixture was added ice (50 ml). Thus formed precipitate was filtered, washed with water and dried under vacuum to obtain 11.1 g (97%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 3.85 (m, 1H), 4.01 (m, 1H), 4.49 (m, 1H), 7.88 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.6 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (98 mg, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[BH4-].[Na+].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:17])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(Br)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: FC(F)(F)c1cc(Br)ccc1CBr
Yield: 73.4 %

Procedure:
Treat a mixture of 4-bromo-2-(trifluoromethyl)benzaldehyde (6.52 g, 25.8 mmol) and methanol (250 mL) in a 500 mL flask with sodium borohydride (778 mg, 20.6 mmol). Stir the reaction at room temperature for 1 hour then dilute with ethyl acetate (300 mL). Wash with water (2×200 mL) and saturated sodium chloride solution (1×200 mL), then dry over anhydrous magnesium sulfate. After filtering, concentrate the solution under vacuum to dryness. Add dimethylformamide (250 mL) to the residue and cool in an ice bath before treating with carbon tetrabromide (12.78 g, 38.5 mmol) and triphenylphosphine (10.11 g, 38.5 mmol) for 3 hours. Add ethyl acetate (300 mL) and wash with water (2×200 mL) then saturated sodium chloride solution (1×200 mL). Dry over anhydrous magnesium sulfate and concentrate under vacuum. Purify the crude product via silica gel chromatography eluting with hexanes to afford 6.02 g (74%) of the product as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.78 (d, 1H, J=1.9 Hz), 7.68 (dd, 1H, J=1.9 Hz, J=8.3 Hz), 7.47 (d, 1H, J=8.3 Hz), 4.57 (s, 2H).
Reaction SMILES: NCC(N)C.[CH3:6][CH:7]([CH3:13])[CH2:8][C@H:9]([NH2:12])[CH2:10][NH2:11].[C:14]([NH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:8]([CH:9]1[CH2:10][NH:11][C:26]([C:25]2[CH:29]=[CH:30][N:31]=[C:23]([NH:22][C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=2)=[N:12]1)[CH:7]([CH3:13])[CH3:6]
Reactant: CC(C)C[C@H](N)CN
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: CC(N)CN
Product: CC(C)CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Yield: 23 %

Procedure:
Following the procedure as described in Example 9, making variations as required to replace 1,2-diaminopropane with (S)-4-methylpentane-1,2-diamine to react with 2-benzamidoisonicotinic acid, N-(4-(4-isobutyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained in 23% yield: MS (ES+) m/z 323.2 (M+1).
Reaction SMILES: [BrH:1].C(O)(=O)C.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=2[F:6])[N:18]=1
Reactant: N#CSCC(=O)c1cccc(F)c1F
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Fc1cccc(-c2csc(Br)n2)c1F
Temperature: 130 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A 25% hydrogen bromide/acetic acid (40 ml) solution was added to a solution of 2-(2,3-difluorophenyl)-2-oxoethyl thiocyanate (5.67 g, 26.6 mmol) in acetic acid (40 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 6.74 g (91.8%) of the desired product as a solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]([CH3:42])[CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:39](=[O:40])[CH2:38][N:37]([CH3:42])[C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.054 g, 0.00014 mol), 2-[(tert-butoxycarbonyl)(methyl)amino]acetic acid (0.0033 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-oxoethyl)-N-methylcarbamate. The solid was dissolved in dichloromethane (2 mL) and 25% trifluoroaceticacid in dichloromethane (4 mL) was slowly added into the reaction at 0° C. The reaction mixture was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure. To the residue a 5 N aqueous solution of sodium hydroxide was addded to pH 11 at 0° C. The water phase was extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-(methylamino)-1-ethanone acetate (0.010 g, 0.00002 mol).