Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:6]=[C:5]([OH:20])[C:4]=1[OH:21].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[Cl:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=3)[CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:6]=[C:5]([OH:20])[C:4]=1[OH:21]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Oc1cc2c(c(Cl)c1O)CCNCC2c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCc2c(cc(O)c(O)c2Cl)C(c2ccccc2)C1

Procedure:
A solution of 0.74 g (0.002 mole) of 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 0.55 g (0.0025 mole) of p-trifluoromethyl benzoylchloride, 0.17 g (0.002 mole) of sodium bicarbonate and 40 ml of 1:1 acetone-water solution was stirred overnight under nitrogen. The mixture was evaporated to dryness. The residue was extracted with ethylacetate. The extracted material was purified over a silica gel column using methanol-ethyl acetate to give 6-chloro-7,8-dihydroxy-1-phenyl-3-(p-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 243°-245° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[CH2:26]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:27]#[CH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:28]#[C:27][CH2:26][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: C#CCN1CCCC1
Reactant: O=C1Cc2cnc(Nc3cccc(I)c3)nc2-c2ccc(Cl)cc2N1
Product: O=C1Cc2cnc(Nc3cccc(C#CCN4CCCC4)c3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(3-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (v-j) and 1-(prop-2-ynyl)pyrrolidine were converted to I-89 (46%): MS (AA) Rt=1.32 min, m/z=444 (M+H).
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20](O)[CH:21]=[CH:22][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:17]([F:26])([F:25])[F:16])[CH:23]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)N1CCC(CCC(=O)Oc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.1 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 2.75 g of m-trifluoromethylphenol was suspended in 27 ml of dry pyridine. To the suspension was added 3.5 g of dicyclohexylcarbodiimide, and the resulting mixture was stirred at room temperature for 6 hours. After removal of any insoluble materials, the solvent was removed. The residue was washed with ether, dissolved in chloroform and then stirred. After removal of any insoluble materials, the filtrate was washed twice with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 4.0 g (yield: 62.0%) of m-trifluoromethylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 97° to 100° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4]1.C[O:10][C:11]([C:13]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([F:33])[CH:26]=2)[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1)=O>>[CH3:2][N:3]1[N:7]=[C:6]([NH:8][C:11]([C:13]2[CH:23]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([F:33])[CH:26]=3)[C:16]3[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=3[CH:14]=2)=[O:10])[CH:5]=[N:4]1
Reactant: COC(=O)c1cc(Oc2ccc(C#N)c(F)c2)c2c(c1)OC(C)(C)C2
Reactant: Cn1ncc(N)n1
Agent: Cl
Product: Cn1ncc(NC(=O)c2cc(Oc3ccc(C#N)c(F)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 2-methyl-2H-1,2,3-triazol-4-amine hydrochloride (662 mg, 4.92 mmol) and 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (183a) (168 mg, 0.49 mmol) to give a white solid (154 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1 H) 8.06 (s, 1 H) 7.57 (dd, J=8.59, 7.33 Hz, 1 H) 7.06-7.15 (m, 2 H) 6.67-6.88 (m, 2 H) 4.10 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H18FN5O3 m/z 408.00 and 409.00 (M+H+).
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)/[CH:3]=1.[F:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])/[C:9]/2=[C:4]1/[O:5][C:6]([CH3:8])([CH3:7])[C:2]([C:24]2[CH:25]=[N:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:3]/1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Reactant: OB(O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1c1ccc(F)nc1
Temperature: 65 °C
Yield: 47 %

Procedure:
To a mixture or 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (3.24 g, 10.0 mmol), 6-fluoropyridin-3-ylboronic acid (1.8 g, 12 mmol) in THF (150 mL), was added a solution of potassium carbonate (13.8 g, 100 mmol) in water (20 mL). The resulting mixture was deoxygenated by bubbling nitrogen through the reaction mixture for 3 minutes and palladium(0)tetrakis(triphenylphosphine) (578 mg, 5 mol %) was then added. The reaction mixture was heated at 65° C. for 18 hours. The reaction was cooled to room temperature and ethyl acetate (500 mL) added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated to give the crude product, which was purified first by silica gel column chromatography (5% CH3OH/CH2Cl2 elution) and then by titration with ethyl acetate. The resulting product was isolated by filtration and dried under vacuum to provide 5-fluoro-3-[4-(6-fluoro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (1.6 g, yield 48%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:15])[CH:9]=1.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:10]([F:15])[CH:9]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc(Br)ccc1OCCN1CCCCC1
Temperature: 25 °C

Procedure:
Potasium carbonate (1.7 g, 12 mmol) was added to a solution of 4-bromo-2-fluorophenol (1.00 g, 5.24 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.965 g, 5.24 mmol) in acetonitrile (25 mL). The reaction mixture was heated at reflux for 2 days and then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. Purification via column chromatography on silica gel (gradient elution with 20-100% ethyl acetate-hexane) afforded 1-(2-(4-bromo-2-fluorophenoxy)ethyl)piperidine 200 as a brown oil. MS (MH+) 302; Calculated 301 for C13H17BrFNO.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:27][C:28]1[CH:47]=[CH:46][C:31]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.Cl>CN(C)C=O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:13]([CH2:27][C:28]3[CH:47]=[CH:46][C:31]([CH2:32][O:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(/C=C/c3ccccc3)[nH]n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3/C=C/c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture of 5-[(E)-2-phenylvinyl]-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole (330 mg, 1.05 mmol), sodium hydride (60% in oil, 40 mg, 1.00 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg, 1.00 mmol) was added to the reaction mixture at room temperature, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:1) to give the title compound (343 mg, yield 57%) as a yellow oil. MS: m/z 597 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([NH:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([C@H:34]3[CH2:39][CH2:38][CH2:37][CH2:36][N:35]3C(OC(C)(C)C)=O)=[O:33])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[F:25])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([NH:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:27][CH2:28][N:29]([C:32]([C@H:34]3[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]3)=[O:33])[CH2:30][CH2:31]2)[CH:22]=[CH:23][C:24]=1[F:25])[CH3:17]
Reactant: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)CC2)ccc1F)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1F)c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a solution (R)-t-butyl 2-(4-(3-((R)-1-(2,4-dichlorophenyl)ethylamino)-4-fluorophenyl)piperazine-1-carbonyl)piperidine-1-carboxylate (0.080 g, 0.14 mmol) in dichloromethane (5 mL) at room temperature, and the solution was stirred for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane. The organic layer was neutralized with aqueous saturated sodium bicarbonate solution, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a white solid (0.042 g, 0.088 mmol, 64%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.60-8.55 (m, 1H), 7.56 (dd, J=8.4, 8.4 Hz, 2H), 7.38 (dd, J=2.4, 8.4 Hz, 1H), 6.92 (dd, J=9.2, 11.2 Hz, 1H), 6.26-6.09 (m, 3H), 4.83 (dd, J=6.4, 13.6 Hz, 1H), 4.37 (t, J=11.2 Hz, 1H), 3.76-3.48 (m, 4H), 3.21 (d, J=11.2 Hz, 1H), 3.09-3.05 (m, 2H), 2.90-2.84 (m, 2H), 1.95 (d, J=13.6 Hz, 1H), 1.73-1.60 (m, 3H), 1.45 (d, J=6.8 Hz, 3H); MS: (ES) m/z calculated for C24H30Cl2FN4O [M+H]+479.2. found 479.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:19]=[O:20])[S:10][C:3]=12
Reactant: CN(C)C=O
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nccc(Cl)c2s1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2 (200 mg, 1.18 mmol) in dry THF (10 mL) at −78° C. was added n-BuLi (0.57 mL, 1.42 mmol, 2.5 M solution in hexanes) and the resultant suspension was stirred for 20 min. Dry DMF (0.5 mL, excess) was added and the reaction mixture was stirred for an additional 2 hrs. The reaction mixture was quenched with methanol at −78° C. and water was added. The mixture was extracted with EtOAc and the organic extracts were combined, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the resultant yellow solid was triturated with hexane to afford 14 (250 mg, 100% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.2 (s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.61 (s, 1H), 7.78 (d, J=5.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1.[C-:16]#[N:17].[Na+]>C(Cl)(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:16]([C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1)#[N:17]
Reactant: [C-]#N
Reactant: O=c1cc(Cl)sn1CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1cc(=O)n(CCc2ccccc2)s1

Procedure:
A mixture of 4.8 g. (0.02 mole) of 5-chloro-2-phenethyl-4-isothiazolin-3-one in 25 ml of CHCl3, 1.0 g. (0.02 mole) of sodium cyanide in 5 ml of water and 0.015 g of tetrabutyl ammonium bromide was heated under reflux for 1 hour, while stirring. The mixture was then washed with water, dried, and concentrated to give a gummy brown residue, which was recrystallized from 300 ml of ethanol to give 0.15 g. of the named product, mp 228°-230 (softened at 210°).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:42][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[CH3:38])=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: Cc1ccccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2ccccc2C)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 2-methylbenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 1.31 (t, 3H) 2.28-2.34 (m, 3H) 4.38-4.55 (m, 4H) 7.05-7.10 (m, 1H) 7.11-7.21 (m, 4H) 8.92-8.99 (m, 1H). MS (ESI) positive ion 311 (M+H)+; negative ion 309 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH3:3])=[CH:13]2
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1

Procedure:
3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) (0.72 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (344 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the product, 8-chloro-2-phenyl-3((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one (Compound 10), as a white solid (60% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCOc2ccc(C3=NNC(=O)CC3)cc21
Reactant: CCCCCBr
Product: CCCCCN1N=C(c2ccc3c(c2)N(S(C)(=O)=O)CCO3)CCC1=O

Procedure:
6-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one was reacted with pentyl bromide in place of methyl iodide following the procedure of Example 9. The title compound was recovered, yield 1.46 g, mp 138°-139° C.
Reaction SMILES: C([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)C.C([C:11]([CH2:24][CH3:25])(P(=O)([O-])[O-])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])C.C[O-].[Na+]>CN(C)C=O>[S:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:24]([CH3:25])=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19]
Reactant: CCC(CC)(c1ccccc1C#N)P(=O)([O-])[O-]
Reactant: CC(=O)c1cccs1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=Cc1ccccc1C#N)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material may be produced as follows: (a) A solution of 10.0 g of 2-acetylthiophene and 21.0 g of diethyl-o-cyanobenzylphosphonate in 70 cc of anhydrous dimethyl formamide is added dropwise at 20°-30° in an atmosphere of nitrogen to a suspension of 4.5 g of pulverized sodium methylate in 100 cc of anhydrous dimethyl formamide, the reaction mixture is stirred at 40° for 2 hours, and at 100° for a further 2 hours, is cooled to room temperature and diluted with 600 cc of ice water. The condensation product is extracted with ether, the extract is washed with water until neutral, is dried over potassium carbonate and concentrated by evaporation. The evaporation residue is chromatographed through 110 g of silica gel with a mixture of benzene/petroleum ether (1:4). The 2-[2-(2-thienyl)-1-propenyl]benzonitrile (nD20 =1.6460, B.P. 165°-175°/0.1 mm Hg), isolated as main fraction, is used for the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]1[CH2:26][O:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]3[CH2:26][O:25][CH2:24]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Reactant: BrC1COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1COC1

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in acetonitrile and K2CO3 (1.5 equiv.) and 3-bromooxetane (2 equiv.) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH3:5].[CH3:7][C:8](=[CH:11][CH2:12][CH3:13])[CH:9]=[O:10]>CCOCC>[CH3:7][C:8]([CH:9]([OH:10])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH2:12][CH3:13]
Reactant: CCC=C(C)C=O
Reactant: CCCCBr
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)CCCC

Procedure:
A Grignard reagent [29.1 g (1.2 g atoms) of magnesium in 300 ml of ether and 164 g (1.2 mol) of butyl bromide in 500 ml of ether] is reacted with 98.15 g (1 mol) of 2-methyl-2-pentenal in 200 ml of ether in a manner analogous to Example 5. Fractional distillation of the crude product (195.2 g) over a 20 cm Widmer column gives 124.2 g (79.5%) of olfactorily good 4-methyl-3-nonen-5-ol of boiling point 89°-90° C./12 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(Br)c(OCC2CC2)n1
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 32 a, using 2-[(5-bromo-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester (Example 265) and pyrrolidine (CAN 123-75-1) as starting materials. MS (EI): m/e=404.4 [M+H]+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[O:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C(O)(=O)C>[Cl:4][C:23]1[C:19]([O:18][C:8]2[C:7]([Cl:6])=[CH:12][C:11]([C:13]([F:16])([F:14])[F:15])=[CH:10][C:9]=2[Cl:17])=[N:20][NH:21][C:22]=1[CH3:24]
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1[nH]nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
Sulfuryl chloride (0.48 g, 3.6 mmol) was added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.93 g, 3.0 mmol) in acetic acid (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of 4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.57 g, yield: 55.0%). mp: 156-158° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.28 (s, 3H), 7.65 (s, 2H), 8.75-9.15 (br s, 1H).