Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1.[CH2:39](O)[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[O:44]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:39][O:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: OCc1ccco1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccco3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A toluene solution (1.74 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (873 mg), furfuryl alcohol (0.216 ml), triphenyl phosphine (984 mg), and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred overnight at room temperature, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(2-furylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (624 mg, yield: 58%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C(=O)C)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:13].C(N)C1C=CC=CC=1>C(O)C.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:13]
Reactant: CCC(CC)COC(=O)c1ccc(OC(C)=O)cc1F
Solvent: CCO
Solvent: NCc1ccccc1
Solvent: CCOCC
Product: CCC(CC)COC(=O)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
9.3 Grams (0.036 mol) of the compound prepared in the above (1) was dissolved in 250 ml of ethanol, and 7.7 g (0.0772 mol) of benzylamine was dropwise added. Further, the mixture was stirred at room temperature for 1 day, then diluted with 300 ml of ether, consecutively washed with diluted hydrochloric acid and with water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified for isolation with a silica gel column chromatograph to give an end product in the yield of 95%.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][CH3:24])[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][N:14]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:8][C:9]1[C:10]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[S:32]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[CH2:19][CH2:20]2)=[N:11][CH:12]=[CH:13][N:14]=1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
Add triethylamine (0.426 mL, 3.058 mmol) to a stirring solution of [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine (0.200 g, 0.612 mmol) in dichloromethane (5 mL). Add pyridine-3-sulfonyl chloride hydrochloride salt (0.157 g, 0.734 mmol) at room temperature. Stir at room temperature for 20 min. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate and extract the aqueous fraction with dichloromethane. Combine the organic fractions, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 4:1 to afford the title preparation (0.220 g, 91% yield). MS ES: m/z=397 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[N:13][OH:14])=[CH:7][CH:6]=1.O1CCCC1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=3)[O:14][N:13]=2)=[CH:7][CH:6]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2F)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4F)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.9 %

Procedure:
To a mixture of (6-(2-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (28 mg) described in Manufacturing Example 74-1-4 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2,6-diamine (10 mg, 0.075 mmol) described in Manufacturing Example 13-1-3 and triethylamine (21 μL, 0.15 mmol), which was stirred for 5 hours at room temperature. Water was added to the reaction mixture at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate alone) to obtain the title compound (13 mg, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C:16]2([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C:16]2([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1([C@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CC[C@H](C2(C(=O)O)CC2)C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A 5.26 g (16.6 mmol) portion of ethyl 1-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)cyclopropanecarboxylate was dissolved in 300 ml of ethanol, and the solution was cooled in an ice bath, mixed with 16.6 ml of 10N sodium hydroxide aqueous solution and then stirred at room temperature for 5 days. After completion of the reaction, ethanol was evaporated, and the remaining water layer was then acidified with hydrochloric acid and extracted with diethyl ether (50 ml×4). The organic layers were combined and dried over magnesium sulfate and then the solvent was evaporated to yield 4.95 g of the title compound quantitatively as an oily substance.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)(=[O:3])[NH2:2].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37]>O1CCOCC1.C(OCC)(=O)C.[Ag-]=O>[C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[C:8]([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=2[O:36][CH3:37])=[CH:7]1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: NC(=O)CCn1ccc2cc(C(=O)NCC3CCCC3)ccc21
Agent: O=[Ag-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2cn(CCC(N)=O)c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 38.8 %

Procedure:
Silver(I) oxide (0.17 g) was added to a solution of 1-(2-carbamoylethyl)-5-(N-cyclopentylmethylcarbamoyl)indole (0.70 g) and methyl 4-bromomethyl-3-methoxybenzoate (B)(0.19 g) in 1,4-dioxane (10 ml). The mixture was protected from light and stirred at 80° C. under an atmosphere of nitrogen for 12 hours. The mixture was then diluted with 1:1 v/v ethyl acetate:ether (50 ml) and filtered. The filtrate was washed sequentially with water and brine, dried (MgSO4), and evaporated. The residual yellow gum was purified by flash chromatography on silica gel (500 ml), eluting with 5:95 v/v methanol:chloroform to give the title compound (0.14 g, 39%) as a white solid; mp 189°-191° C. (d); NMR (250 MHz, DMSO-d6): 1.2-1.8(broad m, 8H, cyclopentyl), 2.2(sep, 1H, cyclopentylmethine), 3.2(t, 2H, CH2NH), 7.2(m, 2H), 7.3(broad s, 1H, CONH2), 7.5 (m, 3H), 7.7(d, 1H, H6 -indole), 8.0(s, 1H, H4 -indole), 8.3(t, 1H, NHCO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[I:11]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[C:6]([I:11])[CH:7]=1
Reactant: COc1cc(Cl)ccc1N
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1cc(Cl)cc(I)c1N
Temperature: 50 °C
Reaction time: 4 h
Yield: 14.8 %

Procedure:
To a solution of 4-chloro-2-methoxy-phenylamine (600 mg, 3.81 mmol) in ethanol (12 ml) at 50° C. was added a solution of silver sulphate (2.14 g, 6.85 mmol) and iodine (967 mg, 3.81 mmol) in ethanol (8 ml). The resulting reaction mixture was stirred at 50° C. for 4 h. After cooling at 25° C., reaction mixture was filtered through a bed of celite and the filtrate was diluted with EtOAc (30 ml). The organic phase was washed with aqueous Na2S2O3 solution (2×15 ml), and brine (10 ml), dried over anhydrous Na2SO4, filtered, and evaporated off in vacuo. The crude residue was purified by flash column chromatography (2% EtOAc in hexane) to afford 4-chloro-2-iodo-6-methoxy-phenylamine (160 mg, 15%) as brown sticky liquid. GC-MS: 283 (M).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][NH:12][C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1.Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: ClCc1ccncc1
Reactant: O=C1NCc2cccnc2N1c1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N(Cc2ccncc2)Cc2cccnc2N1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17 %

Procedure:
Sodium hydride (50% dispersion in oil) (364 mg, 7.6 mmole), previously washed in hexanes, was added to a solution of 1-(3-chlorophenyl)pyrido[2,3-d]pyrimidine-2(1H,3H)-one (500 mg, 1.9 mmole) in tetrahydrofuran (100 ml). The suspension was stirred for 5 minutes at room temperature and 4-chloromethylpyridine hydrochloride was added. The suspension was refluxed for 18 hours. The solvents were removed and H2O was added to the residue. The residue was extracted twice with ethyl acetate (2×25 ml). The organic phases were combined and the solvents removed. The residue was purified with preparative thin-layer chromatography (ethyl acetate as the eluent) yielding 116 mg (0.33 mmole, 17% yield) of 1-(3-chlorophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2(1H,3H)-one (mp 132°-134° C.), as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=O)[CH2:15][C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[S:50])[CH2:15][C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=S)Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Temperature: 50 °C

Procedure:
(S)-N-[1-(tert-Butoxycarbonyl)pyrrolidin-3-yl]-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]acetamide, as described above in Step C, (1.27 g, 2.37 mmol) was dissolved in toluene (20 mL), Lawesson's Reagent (478 mg, 1.18 mmol) was added and the reaction mixture was heated to 50° C. for 5 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2—1% to 5% MeOH—0.1% to 0.5% NH4OH, to yield the above-titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14]([CH3:25])([CH3:24])[C:11]=3[NH:12][N:13]=2)[C:5]([F:26])=[CH:4][N:3]=1.[CH3:27][C:28]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[F:26][C:5]1[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14]([CH3:25])([CH3:24])[C:11]=3[NH:12][N:13]=2)=[N:7][C:2]([CH:27]=[CH2:28])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1Cc2c(Nc3nc(Cl)ncc3F)n[nH]c2C1(C)C
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: C=Cc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)OC(C)(C)C)C3(C)C)n1
Reaction time: 16 h

Procedure:
To a septum capped sealed tube was added tert-butyl 3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (2.00 g, 5.22 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2 dioxaborolane (2.41 g, 15.7 mmol), Na2CO3 (1.66 g, 15.7 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (850 mg, 1.04 mmol) followed by DME (50 mL) and water (12 mL). The reaction mixture was purged with argon for 2 min. then placed in a preheated 100° C. oil bath and stirred for 16 h. The crude reaction was concentrated then taken up in EtOAc (100 mL) and washed with water (50 mL). The EtOAc solution was dried (MgSO4), filtered and concentrated. Purification was performed by silica gel column chromatography using 1-10% 7N NH3/MeOH in CH2Cl2 to provided the desired compound E1(i) as an orange solid (1.8 g, 91%). 1H NMR (300 MHz, CDCl3) δ ppm 1.45-1.58 (m, 9H), 1.65-1.78 (m, 6H), 4.45-4.71 (m, 2H), 5.58-5.71 (m, 1H), 6.34-6.46 (m, 1H), 6.68-6.82 (m, 1H), 7.99 (s, 1H), 8.12-8.32 (m, 1H). Mass spectrum: Calcd for C18H24FN6O2 (M+H): 375. Found 375.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:10][C:9]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:7]=[CH:6][C:5]=2[C:4](=[O:21])[CH2:3]1.[Br:23]N1C(=O)CCC1=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>C1COCC1.O>[Br:23][C:6]1[C:5]2[C:4](=[O:21])[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:10][C:9]=2[NH:8][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c1CC(C)(C)CC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(=O)c2c(Br)c[nH]c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A solution of 6,6-dimethyl-1-(triisopropylsilyl)-4,5,6,7-tetrahydroindol-4-one (410 mg, 1.28 mmol) in THF (20 mL) was cooled to −70° C. and N-bromosuccinimide (228 mg, 1.28 mmol) was added. Stirring was continued at −70° C. for 1 h then warmed to room temperature. After attaining room temperature, tetrabutylammonium fluoride (1.28 mL of a 1.0 M solution in THF, 1.28 mmol) was added and stirring continued for 5 min. Ether (20 mL) was added, followed by water, and the organic layer separated. The aqueous phase was extracted with ether and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified on silica gel, eluting with DCM, to give the title compound (210 mg, 68%) as a colourless solid. 1H NMR (360 MHz, d6-DMSO) δ 1.02 (6H,s), 2.22 (2H,s), 2.64 (2H,s), 6.89 (1H,d, J=2.4 Hz), 11.58 (1H,br s). MS (ES+) 242/244 (M+1).
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1[S:21][CH2:22][C:23]([OH:25])=[O:24].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](/[N:36]=[C:37]2\[CH:38]=[C:39](Cl)[C:40](=[O:47])[C:41]3[C:46]\2=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]([OH:47])=[C:39]([S:21][CH2:22][C:23]([OH:25])=[O:24])[CH:38]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)cc2)c2ccccc21
Product: O=C(O)CSc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c2ccccc2c1O

Procedure:
5.2.58 2-(4-(4-chlorophenylsulfonamido)-1-hydroxynaphthalen-2-ylthio)acetic acid (14p) was prepared according to the procedure of procedure B for 10a except using (E)-4-chloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)-benzene sulfonamide (12e), which afforded the title compound 57.7 mg (68.4%) as a white solid, m.p.: 158-160° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH4+].[OH-].N>CCO.[Ni]>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][CH2:16][CH2:17][NH2:18])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: N#CCCc1c2ccccc2cc2ccccc12
Agent: [Ni]
Agent: N
Agent: [NH4+]
Solvent: CCO
Product: NCCCc1c2ccccc2cc2ccccc12
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 3-anthracen-9-yl-propionitrile (3.0 g, 13 mmol) in EtOH (140 mL) was added concentrated NH4OH (14 mL) and Raney nickel (14 g), and ammonia gas was bubbled through the mixture at 0° C. for 10 minutes. The suspension was hydrogenated at room temperature for 24 hours. Air was bubbled through the solution and Raney nickel was removed by filtration. The filtrate was concentrated, and the oily residue was dissolved in CH2Cl2, washed with an aqueous solution of Na2CO3 (10%), dried over MgSO4 and concentrated to give 3-anthracen-9-yl-propylamine as a brown oil (2.60 g, 85% yield). 1H NMR (CDCl3) δ 8.35 (1H, s), 8.30 (2H, d), 8.02 (2H, d), 7.54-7.46 (4H, m), 3.68 (2H, t), 2.95 (2H, t), 2.01-1.95 (2H, m) 1.32 (2H, br-s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([N:15]5[CH2:16][CH2:17][O:18][CH2:19][CH2:20]5)[CH:10]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 75.6 %

Procedure:
Using 1.18 g of t-butyl N-{2-amino-5-[3-(morpholin-4-yl)phenoxy]phenyl}-N-methylcarbamate, 0.92 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.53 g of diethyl cyanophosphonate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to Example (2-1), whereby 1.48 g of the desired compound were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.Br[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[CH3:17][O:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3][CH:2]2[O:1][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:13][CH:12]=1)=[O:15]
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: BrCc1ccc2ccccc2c1
Product: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-methoxycarbonyl-phenyl)-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-methoxycarbonyl-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate as a colourless oil; MS: 476 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[CH:22](=[O:24])[CH3:23]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:22]([OH:24])[CH3:23])=[CH:8][C:6]=2[N:7]=1
Reactant: CC=O
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 in THF (General Procedure D-1, 10 mL) at −78° C. was added n-butyllithium (0.94 mL of a 2.5 M solution in hexanes). After stirring for 1 h at −78° C., acetaldehyde (0.33 mL) was added and the mixture was allowed to warm to room temperature over 16 h. The reaction was then quenched with water and extracted into dichloromethane. The combined organics were washed with brine, dried (MgSO4) and reduced in vacuo to yield 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol (540 mg).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]3[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]3[CH2:6]2)[CH2:2]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[N:19]=[C:20]([Cl:22])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>ClCCl.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1CCOCC1>[Cl:22][C:20]1[CH:21]=[C:16]([NH:14][C:12]2[CH:13]=[C:7]3[CH2:6][N:5]([CH:3]4[CH2:4][O:1][CH2:2]4)[CH2:10][CH2:9][N:8]3[N:11]=2)[C:17](=[O:24])[N:18]([CH3:23])[N:19]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: Nc1cc2n(n1)CCN(C1COC1)C2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(Cl)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 90 °C
Yield: 69.5 %

Procedure:
In a 250 mL round-bottomed flask, 5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (555 mg, 2.86 mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (638 mg, 2.86 mmol, Eq: 1.00) cesium carbonate (3.26 g, 10.0 mmol, Eq: 3.50) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (248 mg, 429 μmol, Eq: 0.15) were combined with dioxane (40 ml) and the reaction mixture was vacuum flushed 3× with argon. Bis(dibenzylideneacetone)palladium (123 mg, 214 μmol, Eq: 0.075) was added and the reaction was heated at 90° C. for 18 hr. After cooling to room temperature it was diluted with 50 mL dichloromethane and water. The aqueous layer was back-extracted with DCM (2×25 mL).The combined organic layers were dried over MgSO4 and concentrated in vacuo to near dryness. The resulting solid was collected by filtration and washed with ethyl ether. A second crop of solid that formed in the filtrate and washes was collected by filtration and washed with ethyl ether. The combined solids were dried under vacuum to afford the desired product (669 mg) as a solid. (M+H)+=337 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.01 (t, J=5.18 Hz, 2 H) 3.73 (s, 2 H) 3.81 (s, 3 H) 3.92 (t, J=6.44 Hz, 1 H) 4.26 (t, J=5.43 Hz, 2 H) 4.79 (d, J=6.57 Hz, 4 H) 5.77 (s, 1 H) 7.60 (s, 1 H) 7.88 (s, 1 H).