Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].CO[CH2:22][CH2:23]OC>>[NH:2]1[CH2:23][CH2:22][CH:8]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:3][CH2:1]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Product: N#Cc1cccc(C2CCNCC2)c1

Procedure:
A solution of lithium diisopropylamine (54 mmol) in anhydrous tetrahydrofuran (50 ml) at −78° C. is treated dropwise with a solution of benzyl 4-oxo-1-piperidinecarboxylate (11.4 g, 49 mmol) in anhydrous tetrahydrofuran (50 ml). The reaction mixture is then stirred a further 20 min. at −78° C. and treated with a solution of N-phenyltrifluoromethanesulfonimide (19.26 g, 54 mmol) in anhydrous tetrahydrofuran (55 ml). The resultant orange suspension is warmed to 0° C. and stirred for 2 hours before being concentrated under vacuum. The residue is chromatographed on silica gel (CH2Cl2) to yield benzyl 1,2,3,6-tetrahydro-4-(trifluoromethylsulphonyloxy)-pyridine-1-carboxylate as a yellow oil (11.34 g). A portion of this material (3.65 g, 10 mmol) is dissolved in anhydrous 1,2-dimethoxyethane (30 ml) and treated with 3-cyanophenyl boronic acid (1.47 g, 10 mmol), lithium chloride (1.27 g, 30 mmol), 2.0 M aqueous sodium carbonate (10 ml) and palladium tetrakistriphenylphosphine (0.73 g, 0.6 mmol). The reaction mixture is heated at reflux for 2.5 hours, cooled and concentrated under vacuum. The residue is partitioned between dichloromethane (2×100 ml) and 2.0M aqueous sodium carbonate (100 ml) containing conc ammonium hydroxide (6 ml). The combined organic extracts are dried (magnesium sulfate), concentrated under vacuum and the resultant oil is chromatographed on silica gel (ethyl acetate/pentane 2:5) to yield a yellow oil (2.31 g). This material is dissolved in ethanol (70 ml), treated with 10% palladium on carbon (1.0 g) and stirred at ambient temperature under an atmosphere of hydrogen for 5 hours. The reaction mixture is filtered through a short pad of hyflo and concentrated under vacuum to give the title compound as a colourless oil (1.26 g). 1H NMR (CDCl3, 500 MHz) δ9.78 (br m, 1H), 7.50 (m, 4H), 4.49 (br m, 1H), 3.65 (br m, 1H), 3.00 (m, 2H), 2.82 (m, 1H), 2.21-1.75 (m, 4H). EI MS M++H: 187.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39]>C1COCC1>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[CH2:31][CH:15]1[CH2:16][CH2:17][CH2:18][N:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:21])[CH3:20])[CH2:12][CH2:11]2)[C:14]1=[O:19]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCCC2=O)CC1
Reactant: Fc1cccc(Cl)c1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCC(Cc3c(F)cccc3Cl)C2=O)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Dissolve trans-1-(4-[tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one (0.3 g, 0.96 mmol) in anhydrous THF (6 mL) under nitrogen, cool to −78° C. and add LDA (2M solution in THF) (0.72 mL, 1.44 mmol) dropwise. Stir the reaction mixture for 5 minutes and add 2-bromomethyl-1-chloro-3-fluoro-benzene (0.3 g, 1.44 mmol) in anhydrous THF (2 mL) dropwise. Stir the reaction mixture at −78° C. for 3 hours, slowly warm to room temperature, quench with saturated aqueous NH4Cl (5 mL) and extract with DCM (3×10 mL). Dry the organic layer over Na2SO4, remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 20% EtOAc in hexane) to obtain trans-3-(-2-chloro-6-fluoro-benzyl)-1-(4-[tert-butyl-dimethyl-silanyloxy]-cyclohexyl)-piperidin-2-one as a white solid (0.2 g). Dissolve the trans-3-(-2-chloro-6-fluoro-benzyl)-1-(4-[tert-butyl-dimethyl-silanyloxy]-cyclohexyl)-piperedin-2-one in methanol containing concentrated hydrochloric acid (5% v/v) and heat at 40° C. for 1 hour. Evaporate the solvent, dissolve the residue in DCM (10 mL) and wash with saturated aqueous NaHCO3 (5 mL). Dry the organic layer over anhydrous Na2SO4, remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 50% EtOAc in hexane) to obtain the title compound as a clear oil (110 mg, 34%): MS (ES+) m/z=340 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9]1([CH2:15][SH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.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>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([S:16][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccncc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1ccncc1SCc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
To a solution of 3-bromo-4-methylpyridine (1.0 g) in toluene (12 mL) were added phenylmethanethiol (794 mg), N,N-diisopropylethylamine (1.65 g), tris(dibenzylideneacetone)dipalladium(0) (213 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (269 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 1.5 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:1→1:1) to give the title compound as a yellow oil (yield 740 mg, 59%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3.[Br:26][CH2:27][CH2:28][CH2:29]Br.[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[Br:26][CH2:27][CH2:28][CH2:29][O:25][C:18]1[CH:19]=[CH:20][C:21]2[C@@H:22]3[C@H:13]([C@H:10]4[C@@:8]([CH2:24][CH2:23]3)([CH3:9])[CH:7]([O:6][CH2:5][O:4][CH3:3])[CH2:12][CH2:11]4)[CH2:14][CH2:15][C:16]=2[CH:17]=1
Reactant: BrCCCBr
Reactant: COCOC1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCOC1CC[C@H]2[C@@H]3CCc4cc(OCCCBr)ccc4[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A suspension of a 60 % sodium hydride (0.531 g) in tetrahydrofuran (100 ml) is cooled to 0° C., and 17-(methoxymethoxy)-estra-1,3,5(10)-trien-3-ol (3.5 g) is slowly added thereto. After addition of dimethylformamide (50 ml), the mixture is stirred at room temperature for 2 hours. To the resulting solution is added 1,3-dibromo-propane (2.68 g), and the mixture is stirred at room temperature overnight. The reaction mixture is poured into an aqueous ammonium chloride, followed by extraction with ethyl acetate. The solvent is removed under reduced pressure and the residue thus obtained is purified over column chromatography (n-hexane:ethyl acetate=2:1) to give 3-[(3-bromopropyl)oxy]- 17-(methoxymethoxy)-estra-1,3,5(10)-triene (3.0 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:22]=[C:21]([C:31]([NH:33][CH3:34])=O)[CH:20]=2)[CH:15]=[CH:16][CH:17]=1.[OH-].[Na+]>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:22]=[C:21]([CH2:31][NH:33][CH3:34])[CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CNC(=O)c1cc(Sc2cccc(Br)c2)n(-c2ccccc2Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCc1cc(Sc2cccc(Br)c2)n(-c2ccccc2Cl)n1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a suspension of aluminum chloride (763 mg) in tetrahydrofuran (8 mL) was slowly added lithium aluminum hydride (217 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min. To the obtained suspension was added dropwise a solution of 5-[(3-bromophenyl)thio]-1-(2-chlorophenyl)-N-methyl-1H-pyrazole-3-carboxamide (595 mg) in tetrahydrofuran (2 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. A 8 mol/L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 522 mg, 91%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:15]([CH2:19][NH:20][C:21](OCC)=O)[CH2:16][CH2:17][OH:18])[CH:11]=[CH:12][C:13]=1[F:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:15]([CH2:19][NH:20][CH3:21])[CH2:16][CH2:17][OH:18])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CCOC(=O)NCC(CCO)c1ccc(F)c(F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCC(CCO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a stirred cooled (−10° C.) mixture of lithium aluminum hydride (2.46 g, 65 mmol) and dry THF (50 mL) was added dropwise a solution of 3-(3,4-difluorophenyl)4-(ethoxycarbonylamino)-1-butanol (8.85 g, 32.4 mmol) in THF (40 mL). The solution was heated under reflux for 1.25 h, cooled (ice bath) and saturated sodium sulfate (150 mL) solution was added dropwise. The mixture was stirred at room temperature for 1 hr, filtered through diatomaceous earth, washed with THF and the solvent removed in vacuo. The residue was dissolved in DCM, washed with water, dried (Na2SO4), filtered and the solvent removed in vacuo. Purification by chromatography (2-5% and 10% methanol in DCM) provided the title compound (5.20 g, 75%) as a pale green oil. 1H-NMR (CDCl3) δ 1.85-1.96 (m, 2H, CH) 2.45 (s, 3H, CH3) 2.74-2.85 (m, 3H, CH) 3.37 (br s, 2H, NH, OH) 3.50-3.58 (m, 1H, CH) 3.66-3.73, m, 1H, CH), 6.87-7.35 (m, 3H, ArH). MS m/z 216 (M+H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(#N)C>CC(O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC#N
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in propan-2-ol (15 ml). The mixture was stirred at about 70° C. for 2 h, after which time the starting material was no longer detectable by HPLC. Then, acetonitrile (40 ml) was dripped into the mixture. The mixture was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (50 ml) and dried at 50□C in a vacuum oven for 24 h to obtain 1.54 g (75.5%) of fluvastatin sodium Form XIV.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[N:4]([CH2:15][C:16](=[O:18])[CH3:17])[C:3]1=[O:19].[CH2:20]([N:22]([CH2:25][C:26]#[CH:27])[CH2:23][CH3:24])[CH3:21].C(O)(=O)/C=C/C(O)=O>>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:25][C:26]#[C:27][C:16]([OH:18])([CH3:17])[CH2:15][N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:19])[CH3:21]
Reactant: CCCn1cnc2c1c(=O)n(CC(C)=O)c(=O)n2C
Reactant: C#CCN(CC)CC
Agent: O=C(O)/C=C/C(=O)O
Product: CCCn1cnc2c1c(=O)n(CC(C)(O)C#CCN(CC)CC)c(=O)n2C
Yield: 48 %

Procedure:
1-(5-Diethylamino-2-hydroxy-2-methyl-3-pentynyl)-3-methyl-7-propylxanthine was prepared as oily substance in 48% yield using 3-methyl-1-(2-oxopropyl)-7-propylxanthine and N,N-diethyl-2-propynylamine as in Example 6C1). Salt formation with fumaric acid as in Example 7F2) took place in 98% yield. Melting point: 109° C. C23H33N5O7 (MW=491.56 g/mol), base C19H29N5O3 (MW=375.48 g/mol)
Reaction SMILES: [CH:1]([C:3]1[C:11]2[N:7]([CH:8]=[CH:9][CH:10]=2)[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)=O.[NH2:17][OH:18].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:18]/[N:17]=[CH:1]/[C:3]1[C:11]2[N:7]([CH:8]=[CH:9][CH:10]=2)[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: NO
Reactant: CCOC(=O)c1ccc(C=O)c2cccn12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C=N/O)c2cccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 8-formylindolizine-5-carboxylate (100 mg, 0.46 mmol) and NH2OH.HCl (48 mg, 0.69 mmol) in THF (10 mL) and H2O (3 mL) at rt was added NaOAc (75 mg, 0.92 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was extracted with EA (2×20 mL). The organic layers was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was used in next step without further purification.
Reaction SMILES: Cl.C(N(CC)CC)C.[C:9]([C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[CH2:14][CH2:15][O:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])#[N:10].[N-:29]=[N+:30]=[N-:31].[Na+].Cl>O.C(O)(C)(C)C>[N:10]1[NH:29][N:30]=[N:31][C:9]=1[C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[CH2:14][CH2:15][O:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20]
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(C#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCOCCc1cccc(-c2nn[nH]n2)c1
Temperature: 140 °C

Procedure:
Triethylamine hydrochloride (2.09 g) was added in one portion to a mixture of tert-butyl 3-(3-cyanophenethoxy)propanoate [Example 7, Step i)] (1.74 g), sodium azide (0.99 g) and tert-butanol (12.64 mL), and sealed into a microwave tube. The reaction was heated to 140° C., over a period of 2 h in the microwave reactor. The reaction mixture was diluted with water and acidified with 2M hydrochloric acid (5 mL). The mixture was extracted with DCM and the organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane, then elution gradient 0-10% methanol in DCM to afford the subtitled compound (1.77 g). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 3.79 (t, J=5.3 Hz, 2H), 3.75 (t, J=5.6 Hz, 2H), 2.96 (t, J=5.2 Hz, 2H), 2.63 (t, J=5.3 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C[Si]([C:15]#[C:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23])(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([C:15]#[C:16][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1ccc(I)cc1Cl
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Product: COc1ccc(C#Cc2cncc(C#N)c2)cc1Cl
Yield: 174.4 %

Procedure:
Prepare according to the general procedure outlined in EXAMPLE 72 using 2-chloro-4-iodo-1-methoxybenzene (520 mg, 19 mmol) and 5-trimethylsilanylethynyl-nicotinonitrile (350 mg, 1.75 mmol), (prepared as described in PREPARATION 3), to give the title compound (820 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[N:4][C:3]=1Cl.C(=O)([O-])[O-].[K+].[K+].[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32].C1OCCOCCOCCOCCOCCOC1.[F-].[Cs+]>C(#N)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[N:4][C:3]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1O
Reactant: Cc1ccccc1Sc1nnc(Cl)c(Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1nc(Sc2ccccc2C)nnc1Cl
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 28 %

Procedure:
To a stirred solution of the dichloro-(2-methylphenylthio)-1,2,4-triazine formed in the reaction above (0.35 g) in dry acetonitrile (10 ml) was added dry potassium carbonate (0.18 g), followed by a solution of (E)-methyl 2-(2-hydroxyphenyl)-3-methoxypropenoate (0.27 g) in dry acetonitrile (2 ml), in one portion, at room temperature. A catalytic amount of 18-crown-6 and dry caesium fluoride (0.20 g) were then added. After stirring at room temperature for 11.5 hours, the mixture was diluted with acetonitrile (25 ml) and filtered through Hyflo Supercel filter aid. The filtrate was concentrated under reduced pressure and the residue was chromatographed twice using first ether-n-hexane (1:1) and then n-hexane-dichloromethane-acetonitrile (16:4:1) as eluent to afford (E)-methyl 2-[2-(6-chloro-3-[2-methylphenylthio]-1,2,4-triazin-5-yloxy)-phenyl]-3-methoxypropenoate as a pale yellow gum (0.16 g, 28%); IR max (nujol mull): 1710, 1630 cm-1 ; 1H NMR δ2.27(3H,s), 3.64(3H,s), 3.75(3H,s), 6.90-6.97(1H,m), 7.09-7.39(6H,m), 7.45-7.53(1H,m), 7.49(1H,s) ppm.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH2:28][CH2:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([N:9]1[CH2:10][CH2:11][N:6]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH2:28][CH2:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:37])[F:38])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCN4CCNCC4)cc3)CC1)CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.4 %

Procedure:
A solution of methanesulfonyl chloride (0.029 mL, 0.38 mmol) in DCM (0.5 mL) was is added dropwise to 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 5.1, preparation of starting materials) (150 mg, 0.31 mmol) and triethylamine (0.088 mL, 0.63 mmol) in DCM (1 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stirred for a further 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge and then the organic layer was evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-(4-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}phenyl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (92 mg, 52.7%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=O)=[CH:12][CH:11]=1.B.C1COCC1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([NH:16][CH2:17][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:12][CH:11]=1
Reactant: CSc1ccc(-c2ccc(NC(=O)C3CCN(C(=O)OC(C)C)CC3)cn2)c(F)c1
Agent: B
Solvent: C1CCOC1
Product: CSc1ccc(-c2ccc(NCC3CCN(C(=O)OC(C)C)CC3)cn2)c(F)c1
Yield: 49.2 %

Procedure:
1-Methylethyl 4-[({6-[2-fluoro-4-(methylthio)phenyl]-3-pyridinyl}amino)methyl]-1-piperidinecarboxylate (195 mg, 49%) was prepared as a yellow solid from 1-methylethyl 4-[({6-[2-fluoro-4-(methylthio)phenyl]-3-pyridinyl}amino)carbonyl]-1-piperidinecarboxylate (410 mg, 0.95 mmol), 1M BH3-THF (2.85 mL, 2.85 mmol) and THF (5 mL) in a manner similar to Example 172, Step 3, except that no 1.8M BH3-THF was used. 1H NMR (400 MHz, CDCl3): δ 8.45 (bs, 1H), 7.70 (d, 1H, J=9.0 Hz), 7.64-7.56 (m, 1H), 7.35 (d, 1H, J=9.1 Hz), 7.11 (d, 1H, J=8.2 Hz), 7.01 (d, 1H, J=11.8 Hz), 4.95-4.82 (m, 1H), 4.24-4.08 (m, 2H), 3.08 (d, 2H, J=5.1 Hz), 2.80-2.60 (m, 2H), 2.50 (d, 3H, J=2.1 Hz), 1.85-1.70 (m, 2H), 1.32-1.09 (m, 8H); LRMS (ESI), m/z 418 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([I:11])[N:3]=1.C1C(=O)NC(=O)N([C@@H:20]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@@H:21]2[OH:28])C=1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[C@@H:20]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH2:1])=[N:3][C:4]=3[I:11])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@@H:21]1[OH:28]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: Nc1nc(I)c2[nH]cnc2n1
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Product: Nc1nc(I)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1
Temperature: 37 °C
Yield: 11 %

Procedure:
2-Amino-6-iodopurine (Sigma Chemicals, St. Louis. Mo.) (25.5 mmoles, 6.75 g) and uracil arabinoside (61.9 mmoles, 15.1 g) were combined in 0.31 liters of 10 mM potassium phosphate pH 6.9 with 0.02% potassium azide. Purified purine nucleoside phosphorylase (17000 units) and uridine phosphorylase (2000 units) were added and the solution stirred at 37° C. After 18 days an additional 5700 units of uridine phosphorylase were added. Fifty-seven days later the reaction was filtered and the filtrate chromatographed on a column containing XAD-2 resin (8×11 cm). The product was eluted with a step gradient of ethanol/water (v/v) as follows: 0.35 liter 10%; 1 liter 20%; 1 liter 50%; 0.2 liter 95%. Product-containing fractions were combined and the ethanol removed under vacuum. The residue was dissolved in 30% n-propanol/water (v/v) and chromatographed on a 7.5×90 cm column containing BioRad P-2 resin. This procedure yielded 1.1 g of 9-β-D-arabinofuranosyl-2-amino-6-iodo-9H-purine as a 0.5 hydrate. NMR and mass spectrometry were consistent with the structure. Anal. Calcd. for C10H12IN5O4.05H2O: Calcd: C, 29.87; H, 3.26; N, 17.41. Found: C, 29.86; H, 3.29; N, 17.39.
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:53]2[N:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[C:30]([CH:52]=1)[C:31]([N:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([CH3:39])[C@H:34]1[CH2:40][N:41]1C(=O)C2C(=CC=CC=2)C1=O)=[O:32]>>[NH2:41][CH2:40][C@@H:34]1[C@H:35]([CH3:39])[CH2:36][CH2:37][CH2:38][N:33]1[C:31]([C:30]1[CH:52]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=1[C:53]1[N:54]=[CH:55][CH:56]=[CH:57][N:58]=1)=[O:32]
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-(((2S,3R)-1-(5-chloro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione. MS (ESI) 345 (M+H).