Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH:19]=O.[C:25]([C@@H:28]([C@H:30]([C:32]([O-:34])=[O:33])[OH:31])[OH:29])([O-:27])=[O:26]>>[C:25]([C@@H:28]([C@H:30]([C:32]([OH:34])=[O:33])[OH:31])[OH:29])([OH:27])=[O:26].[CH3:25][CH:28]([N:1]([CH2:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1)[CH2:19][C:18]1[CH:17]=[C:16]([Cl:15])[CH:23]=[C:22]([Cl:24])[CH:21]=1)[CH3:30]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Product: CC(C)N(Cc1cc(Cl)cc(Cl)c1)C[C@@H]1CCNC1
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
The title compound is prepared starting from (S)-3-(aminomethyl)-1-N-tert-butyloxycarbonylpyrrolidine following the procedures described in Example 11, except 3,5-dichlorobenzaldehyde replaces 2,4-dichlorobenzaldehyde in step (i). The L-tartrate salt is obtainable by freeze-drying from water-acetonitrile. 1H NMR (300 MHz, DMSO) δH: 7.45 (1H, s), 7.34 (2H, s), 3.88 (2H, s), 3.55 (2H, s), 3.22-3.01 (3H, m), 2.83-2.72 (2H, m), 2.37 (3H, brs), 1.98-1.91 (1H, m), 1.60-1.45 (1H, m), 0.97 (6H, m). LCMS: Rt=3.17 (12 min method) [M+H]=301/3.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:8]([NH:9][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCc1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
To a stirred solution of 2-phenylethylamine (2 g, 16.5 mmol) in 105 ml DMF at room temperature was added Et3N (2.75 ml, 19.8 mmol). This mixture was stirred for 5 min, and then benzenesulfonyl chloride (2.3 ml, 18.1 mmol) was added at this temperature. The reaction was stirred for 2.5 h, and then, the mixture was evaporated to dryness and the crude was chromatographically purified over SiO2 using Hexane/AcOEt 60/40 as the eluant, yielding 3.12 g (72%) of the desired product.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1O[C:6](=O)[C@H:5](O)[C@@H:4](O)[C@@H:3]1O.C([SiH]([CH2:18][CH3:19])CC)C.B(F)(F)F.CCOCC.[F-].[CH2:30]([N+](CCCC)(CCCC)CCCC)[CH2:31][CH2:32]C>>[C:2]1([CH2:1][OH:12])[C:19]2[C:6](=[CH:30][CH:31]=[CH:32][CH:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC[SiH](CC)CC
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: FB(F)F
Agent: [F-]
Solvent: CCOCC
Product: OCc1cccc2ccccc12

Procedure:
As in Reaction Scheme 2, lithium-halogen exchange of compound (76), followed by addition of the resulting nascent lithiated aromatic to perbenzylated gluconolactone (2), produces a mixture of the corresponding lactols, which is reduced using triethylsilane and boron trifluoride etherate. Subsequent desilylation using tetrabutylammonium fluoride (TBAF) affords 1-naphthalenemethanol (77) in a reasonable yield for the three steps.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:29][CH3:30])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23](C(=O)C)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1.CC#N.CC1N=C(NC)SC=1C1C=CN=C(NC2C=C(C=CC=2)CNC(=O)C)N=1.[N+]([O-])(O)=O.N(C1C=C(C=CC=1)CNC(=O)C)C(N)=N>Cl>[CH3:1][C:2]1[N:3]=[C:4]([NH:29][CH3:30])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[N:8]=1
Reactant: CNc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)n2)s1
Agent: CC(=O)NCc1cccc(NC(=N)N)c1
Agent: CNc1nc(C)c(-c2ccnc(Nc3cccc(CNC(C)=O)c3)n2)s1
Agent: Cl
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: CNc1nc(C)c(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)s1

Procedure:
By hydrolysis of 1-(4-{4-[4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone in 2 M aq HCl. Yellow solid. Anal. RP-HPLC: tR=8.8 min (10-70% MeCN, purity >95%). 1H-NMR (DMSO-d6) δ: 2.45 (3, 3H, CH3), 2.83 (t, 4H, J=5.9 Hz, CH2), 2.85 (d, 3H, J=4.9 Hz, CH2), 2.95 (t, 4H, J=4.9 Hz, CH2), 6.81 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.85 (d, 2H, J=9.3 Hz, Ph-H), 7.58 (d, 2H, J=8.8 Hz, Ph-H), 7.99 (m, 1H, NH), 8.26 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.14 (brs, 1H). N-{3-[4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino]-benzyl}-acetamide [63]. By condensation of 3-dimethylamino-1-(2-methylamino-4-methyl-thiazol-5-yl)-propenone and N-(3-guanidino-benzyl)-acetamide nitrate. Yellow solid. Mp 253-255° C. Anal. RP-HPLC: tR=11.3 min (10-70% MeCN, purity >95%): 1H NMR (DMSO): δ 1.86 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.85 (s, 2H, CH2), 3.09 (s, 3H, CH3), 6.82 (d, 1H, J=8.0 Hz, ph-H), 6.88 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.2 (t, 1H, J=8.0 Hz, Ph-H), 7.60 (d, 1H, J=8.0 Hz, Ph-H), 7.73 (s, 1H, Ph-H), and 8.32 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 391.55 [M+Na] (C18H20N6OSNa requires 391.46).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>N.CCO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][NH2:23])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ccccc3C#N)CC2C1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccccc3CN)CC2C1
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
To a solution of 5-(2-cyano-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (150 mg, 0.48 mmol) in NH3/EtOH (2M, 10 mL) was added Raney Nickel (3 mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 2.5 h. After this time the mixture was filtered through celite and concentrated to yield the title compound (140 mg). m/z (M+1) 318.29.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)=[CH:26][C:11]=1[C:12]([NH:14][CH2:15][C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:13]>CS(C)=O>[Cl:9][C:10]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:32][CH2:33][C:34]3([O:37][CH2:4]3)[CH2:35][CH2:36]2)=[CH:26][C:11]=1[C:12]([NH:14][CH2:15][C:16]12[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][CH:20]([CH2:21]3)[CH2:25]1)[CH2:17]2)=[O:13]
Reactant: O=C1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CN2CCC3(CC2)CO3)ccc1Cl
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To dimethylsulfoxide (2 ml) was added sodium hydride (0.033 g, 60 % in oil) at room temperature. The mixture was stirred for 5min. at this temperature and a solution of trimethylsulfoxonium iodide (0.178 g) in dimethylsulfoxide (2 ml) was added. After 30 min., 2-chloro-5-[(4-oxo-1-piperidinyl)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.28 g, Example 83a) in dimethylsulfoxide (2 ml) was added and the reaction stirred at room temperature for 3 h before being quenched with ice/water (20 ml). The mixture was extracted three times with ethyl acetate, the combined organic layers washed with brine and dried over magnesium sulfate. The crude material was purified on silica gel, eluting with ethyl acetate to afford the subtitle compound as a white foam (0.25 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]=1[O:10]C)([CH3:3])[CH3:2].B(Br)(Br)Br>ClCCl>[CH:1]([C:4]1[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]=1[OH:10])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cc(C(C)C)c(OC)c(C(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
To a solution of methyl 3,5-diisopropyl-4-methoxyphenylacetate (100 mg) in dichloromethane (12 mL) at −78° C. was added a solution of boron tribromide (0.57 mL) in dichloromethane. The reaction mixture was stirred at −78° C. for 1 hour and at 0° C. for 1 hour, quenched by water, and extracted with dichloromethane. The combined organics were washed (brine), dried (MgSO4), filtered, and concentrated. Purification by preparative thin layer chromatography, with ethyl acetate:hexane:acetic acid (90:9:1) gave the title compound (24 mg); 1H-NMR (CDCl3) δ=1.25 (d, 12H, CH(CH3)2), 3.15 (m, 2H, CCH(CH3)2), 3.55 (S, 2H, CH2), 3.70 (S, 3H, OCH3), 6.98 (S, 2H, ArH)
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:36][CH2:37][CH3:38])=[C:30]([O:33][CH2:34][CH3:35])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH2:34]([O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:36][CH2:37][CH3:38])[N:26]=[CH:25][N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1)[CH3:35]
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: CCOc1cc2ncnc(Cl)c2cc1OCC
Agent: Br
Product: CCOc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Yield: 24 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 354.0 mg (1.00 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4 -dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6,7-diethoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 116.8 mg (yield: 24%) of Compound 98 was obtained as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([O:11][C:12](=[O:16])[C:13]#[C:14][CH3:15])[CH3:10].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:9]([O:11][C:12](=[O:16])/[CH:13]=[C:14](/[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])\[CH3:15])[CH3:10]
Reactant: Cc1ccccc1O
Reactant: CC#CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1C

Procedure:
To a stirred mixture of 2-methyl-phenol (4.90 g, 0.045 mol) and ethyl-2-butynoate (10.1 g, 0.09 mol) in tetrahydrofuran (15 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.80 g, 0.045 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product, (E)-3-o-tolyloxy-but-2-enoic acid ethyl ester, was obtained as a brown oil (6.45 g, 65%) and used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([C:12]([Cl:21])=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc2c1S(=O)(=O)CCC2(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)ccc2c1S(=O)(=O)CCC2(C)C

Procedure:
20.0 g (0.075 mol) of 4,4,8-trimethyl-1,1-dioxothiochroman-7-carboxylic acid were dissolved in 200 ml of toluene and three drops of dimethylformamide and 10.7 g (0.09 mol) of thionyl chloride were added. After three hours of heating under reflux, the solvent was removed and the colorless oil that remained (yield 21.3 g) was directly used further.
Reaction SMILES: [Si](O[C@:9]([C@@H:21]([CH:23]([O:25][Si](C(C)(C)C)(C)C)O)[OH:22])([OH:20])[C:10]([F:19])([F:18])[C:11]([O:13]S(C)(=O)=O)=O)(C(C)(C)C)(C)C.[F:33][C:34]1[C:35]([O:45][Si](C)(C)C)=[N:36][C:37]([O:40][Si](C)(C)C)=[N:38][CH:39]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(Cl)Cl>CO>[F:33][C:34]1[C:35](=[O:45])[NH:36][C:37](=[O:40])[N:38]([C:11]([C:10]([F:18])([F:19])[C@@H:9]([C@@H:21]([CH2:23][OH:25])[OH:22])[OH:20])=[O:13])[CH:39]=1
Reactant: C[Si](C)(C)Oc1ncc(F)c(O[Si](C)(C)C)n1
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)OS(C)(=O)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(n1cc(F)c(=O)[nH]c1=O)C(F)(F)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.1 g. of 3,5-bis(t-butyldimethylsilyloxy)-1-methanesulfonyloxy-2-desoxy-2,2difluororibose, 0.83 g. of 5-fluoro-2,4-bis(trimethylsilyloxy)pyrimidine, and 0.655 g. of trifluoromethanesulfonyloxytrimethylsilane in 20 ml. of methylene chloride was refluxed for approximately 17 hours under nitrogen. The reaction mixture was cooled to room temperature and 3 ml. of methanol was added thereto. The resulting solution was stirred for approximately 30 minutes at room temperature and the precipitated solid was collected by filtration. The filtrate was evaporated to dryness under vacuum at 50° and the residue was dissolved in 15 ml. of methylene chloride saturated with anhydrous hydrogen bromide. The resulting suspension was stirred for approximately 30 minutes and the volatiles were removed in vacuo at 45° . The residue was dissolved in 15 ml. of water and the aqueous solution was extracted one time with 10 ml. of ethyl acetate. The aqueous layer was neutralized with sodium carbonate to a pH of approximately 7 and the solution was evaporated to dryness in vacuo at 50°. The residue was dissolved in about 6 ml. of water and the resulting solution was chromatographed in 2 ml. portions on a Whatman ODS-3 50 cm reverse-phase column using water as the eluent to provide 30 mg. of 1-(5-fluoro-2,4-dioxo-1H,3H-pyrimidin-1-yl)-2-desoxy-2,2-difluorori (CD3OD, 90 MHz) δ 3.63-4.6 (m, 4H), 4.79 (s, 3H), 6.04 (t, J=7 Hz, 1H), 8.07 (d, J=6 Hz, 1H); mass spec. m/e=282 =p.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([Zn]CC)[CH3:13].O.Cl>O1CCOCC1>[CH2:12]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:13]
Reactant: CC[Zn]CC
Reactant: COC(=O)c1ccncc1Br
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCc1cnccc1C(=O)OC
Temperature: 70 °C
Yield: 21.2 %

Procedure:
Methyl 3-bromopyridine-4-carboxylate (5 g, 23.1 mmol) was dissolved in anhydrous dioxane (150 mL). A solution of diethyl zinc (18.9 mL, 20.8 mmol, 1.1 M in toluene) was added dropwise and then was added catalyst ((1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (254 mg, 347 μmol). The mixture was heated at 70° C. for 3.5 hours and then water followed with 1 N HCl was added. The mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-20% hexane/ethyl acetate to afford methyl 3-ethylpyridine-4-carboxylate (730 mg, 19% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Cu][C:23]#[N:24].[CH3:25][N:26](C=O)C>>[CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18]([C:23]#[N:24])=[CH:17][CH:16]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:25]#[N:26])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: Cc1cnc(-c2ccc(Br)cc2)nc1-c1ccc(Br)cc1
Reactant: CN(C)C=O
Product: Cc1cnc(-c2ccc(C#N)cc2)nc1-c1ccc(C#N)cc1
Reaction time: 2.5 h
Yield: 48 %

Procedure:
A mixture of 5-methyl-2,4-bis(4-bromophenyl)pyrimidine (8.08 g, 0.02 mole) and copper(I) cyanide (4.45 g, 0.05 mole) in 35 mL dry DMF is refluxed under nitrogen for 40 hr (TLC monitored), the excess DMF is distilled under vacuum using a water aspirator. The residual mass is diluted with water and poured into 200 mL 10% NaCN solution, stirred for 2-3 hr, filtered, washed thoroughly with water, dried and subjected to soxlet extraction using acetone. The acetone is distilled and the residue dissolved into 75 mL CHCl3 and chromatographed over an aluminumoxide column, eluted with ether to 80:20 CHCl3 :ether to yield a white crystalline solid (2.8 g, 48%), mp 194°-195° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)O1.[CH2:24]([OH:27])[CH2:25][CH3:26]>>[Cl:1][C:2]1[N:7]=[C:6]([O:27][CH2:24][CH2:25][CH3:26])[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:4][N:3]=1
Reactant: CCCO
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Reactant: Clc1ncc(I)c(Cl)n1
Product: CCCOc1nc(Cl)ncc1-c1cccs1

Procedure:
Preparation according to procedures 4a and 3 with the use of 2,4-dichloro-5-iodopyrimidine, n-propanol and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][C@H:6]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[CH2:22]([Mg]Br)[CH2:23][CH3:24].C1COCC1>>[OH:11][C@@:10]1([CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:6]1[CH3:5]
Reactant: CCC[Mg]Br
Reactant: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC[C@]1(O)CCN(C(=O)OCc2ccccc2)[C@H]1C

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (12.9 g), 2 mol/L propylmagnesium bromide—THF solution (20 mL) and benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (3.5 g), the title compound was obtained as pale-yellow oil (yield: 2.32 g, yield: 56%).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:10]3[C:14]=2[CH2:13][N:12]([CH3:15])[C:11]3=[O:16])[CH2:5][CH:4]=[CH:3][CH2:2]1.C[N+]1([O-])CC[O:29]CC1.[OH2:33]>CC(O)(C)C.CCOC(C)=O>[OH:33][CH:4]1[CH:3]([OH:29])[CH2:2][CH:1]([C:6]2[CH:7]=[CH:8][C:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[C:10]3[C:14]=2[CH2:13][N:12]([CH3:15])[C:11]3=[O:16])[CH2:5]1
Reactant: CN1Cc2c(C3CC=CC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CN1Cc2c(C3CC(O)C(O)C3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of tert-butyl [7-(cyclopent-3-en-1-yl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 243C: 33 mg, 0.10 mmol) in t-BuOH (1 mL) and H2O (1 mL) were added N-methylmorpholine N-oxide (14 mg, 0.12 mmol) and potassium osmate dihydrate (0.37 mg, 0.0010 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure to give the title compound as a white solid, 36 mg, 99% yield. 1H NMR (CDCl3): 1.52 (s, 9H), 1.90-1.94 (m, 2H), 2.14-2.19 (m, 2H), 2.34 (br s, 2H), 3.17 (s, 3H), 3.56 (m, 1H), 4.33 (s, 2H), 4.39 (m, 2H), 7.26 (d, J=8.6 Hz, 1H), 8.14 (d, J=8.6 Hz, 1H), 9.50 (br s, 1H). MS (ES+): m/z=363.16 [MH+]. HPLC: tR=3.44 min (ZQ3, polar—5 min).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12](=[O:19])[N:11]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][N:26]=[C:25]([C:28]4[CH:33]=[C:32]([O:34][CH:35]([CH3:43])[C:36]([O:38]C(C)(C)C)=[O:37])[CH:31]=[CH:30][C:29]=4[CH3:44])[C:24]=3[CH:45]=2)[C:10]1=[O:46]>C(Cl)Cl>[CH3:8][N:9]1[C:14]([C:15]([F:17])([F:18])[F:16])=[CH:13][C:12](=[O:19])[N:11]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][N:26]=[C:25]([C:28]4[CH:33]=[C:32]([O:34][CH:35]([CH3:43])[C:36]([OH:38])=[O:37])[CH:31]=[CH:30][C:29]=4[CH3:44])[C:24]=3[CH:45]=2)[C:10]1=[O:46]
Reactant: Cc1ccc(OC(C)C(=O)OC(C)(C)C)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(OC(C)C(=O)O)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (75 mL) is added to a solution of tert-butyl 2-{{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1 (2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}propionate (12.0 g, 21.4 mmol) in methylene chloride. The reaction mixture is stirred at room temperature for 24 hours and concentrated in vacuo to give the title product as a yellow foam which is identified by NMR spectral analyses.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[C:4]([I:16])[N:3]=1.C([Li])CCC.O.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[I:16][C:4]1[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:7]([O:8][CH3:9])=[CH:2][N:3]=1
Reactant: COCCCOc1cc(I)nc(I)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCCOc1cc(I)ncc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2 mmol of 2,6-diiodo-3-methoxy-4-(3-methoxy-propoxy)-pyridine are added to a solution of 4 mmol n-butyllithium in 1.6 ml hexane and 10 ml tetrahydrofuran at −78° C. under an argon atmosphere. The reaction mixture is stirred at −78° C. for 15 minutes. 2 mmol of water are introduced and the reaction mixture is allowed to reach room temperature. 10% Aqueous ammonium chloride solution is added to the mixture followed by extraction with tert-butyl methyl ether (3×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and identified based on its Rf value.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13].[N+]([O-])([O-])=O.[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1nccc2ccccc12
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1cccc2c(Cl)nccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-chloroisoquinoline (6.0 g, 0.037 mol) in conc. H2SO4 (35 mL) was treated with a solution of fuming HNO3 (10 mL) and potassium nitrate (4.0 g, 0.040 mol) in conc. H2SO4 (35 mL) at 0-5° C. The mixture was stirred at 0° C. for a further 90 min, and poured into ice. The precipitate was collected, washed and dried to give the product as a yellow solid. LC-MS: 3.68 min, 209.2 & 211.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16]2[N:17]=[N:18][C:19]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:21]=2)[C@H:10]([OH:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:42]I.O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16]2[N:17]=[N:18][C:19]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:26][CH:27]=3)[CH:21]=2)[C@H:10]([O:39][CH3:42])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a stirred solution of (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.46 mmol, 0.25 g) in anhydrous DMF (1.5 mL) was added sodium hydride (60% dispersion in mineral oil) (0.92 mmol, 0.037 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added methyl iodide (0.57 mmol, 0.035 mL) and the reaction was stirred for 12 hours coming to room temperature. The reaction was poured into a mixture of water (5 mL) and ethyl acetate (5 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 24 g SiO2 cartridge using a gradient of ethyl acetate/hexanes to give (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.20 g).