Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C@@H:13]([CH2:16][CH3:17])[CH2:14][OH:15].O>ClCCl.C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:15][CH2:14][C@@H:13]([CH3:12])[CH2:16][CH3:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC[C@H](C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
To a ice-cooled solution of p-toluenesulphonyl chloride (9.53 g, 50 mmol), (S)-2-methylbutan-1-ol (4.41 g, 50 mmol) in absolute dichloromethane (200 ml), triethylamine (84 ml) was dropwise added. After complete addition and stirring for further 6 h at room temperature, the reaction mixture was poured into water (150 ml), the organic layer was separated and the aqueous phase was further extracted with dichloromethane (2×200 ml). The combined organic extracts were washed with HCl 1N (2×200 ml), with saturated NaCl solution (2×200 ml), dried over magnesium sulphate and evaporated under reduced pressure. The obtained slightly yellow oil was chromatographed on silica (diethylether/petroleumether: 1/3) to give (s)-2-methyl-butyl p-toluenesulphonate as a colourless oil (Yield: 10.0 g, 89%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3[CH:20]=[CH:21][C:22]([CH:24](OC)[O:25]C)=[N:23][C:14]2=3)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+]>C1COCC1>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3[CH:20]=[CH:21][C:22]([CH:24]=[O:25])=[N:23][C:14]2=3)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)N2CCCCc3ccc(C=O)nc32)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (0.65 ml) was added to a solution of N-(5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxamide (intermediate 236, 29 mg, 0.079 mmol) in THF (0.9 ml) at room temperature. After stirring for 1 h at room temperature, sat. aq. NaHCO3 was added and the mixture extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was triturated with Et2O to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Cl>CN(C)C=O>[CH2:28]([O:27][C:25]1[CH:24]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:26]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:37][CH:39]1[O:41][CH2:40]1)[CH:15]=2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(O)ccc12
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a well-stirred solution of 3′,5′-dibenzyloxy-7-hydroxy-flavone, 22 (8 g, 17.8 mmol) in dry dimethyl formamide (200 mL) was added 50% sodium hydride (3 g, 125 mmol) at 0-5° C. and after 30 minutes, excess of epichlorohydrin (8.3 mL, 107 mmol) was added and stirred at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with chloroform. The combined organic layers were dried over sodium sulphate, filtered and evaporated to dryness. The crude product was purified by column chromatography to afford 28. Yield 7.1 g (79%); mp 172-173° C.; MS (FAB) 507 (M++1); IR (KBr) 1640; 1H NMR (200 MHz, CDCl3) δ 8.13 (d, J=8.7 Hz, 1H), 7.47-7.34 (m, 10H), 7.11 (d, J=2.2 Hz, 2H), 7.00 (dd, J=10.9 Hz, 2.1 Hz, 1H), 6.97 (d, J=1.9 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.69 (s, 3H), 5.10 (s, 4H), 4.38 (dd, J=11.1 Hz, 2.8 Hz, 1H), 4.04 (dd, J=11.1 Hz, 5.8 Hz, 1H), 3.41-3.40 (m, 1H), 2.95 (t, J=4.5 Hz, 4.5 Hz, 1H), 2.80 (dd, J=4.8 Hz, 2.6 Hz, 1H); 13C NMR δ 177.9, 163.8, 162.9, 160.7, 158.1, 136.7, 133.9, 129.1, 128.6, 127.9, 127.5, 118.2, 115.1, 108.1, 106.0, 105.4, 101.7, 70.8, 69.7, 50.2, 44.9.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([CH3:10])=[N:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:40]=[CH:41][CH:42]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[N:35]=2)[N:32]=1>O1CCCC1.CN(C)C(=O)C.O>[C:37]([NH:36][C:34]1[N:35]=[C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]3[CH:24]=[C:23]([NH:22][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=4)=[O:9])[CH:42]=[CH:41][CH:40]=3)=[N:32][N:31]2[CH:33]=1)(=[O:39])[CH3:38]
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution (4.0 mL) of 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (109 mg, 0.85 mmol) in tetrahydrofuran were added N,N-dimethylformamide (30 μL, 0.39 mmol) and oxalyl chloride (135 μL, 1.55 mmol), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and a solution of the residue in N,N-dimethylacetamide (2.0 mL) was added dropwise to a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (200 mg, 0.71 mmol) in N,N-dimethylacetamide (2.0 mL). After the reaction mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (182 mg, 67%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCl>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][Br:19])[CH:3]=1
Reactant: O=C(Br)CBr
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of methyl 3-aminobenzoate (4.53 g, 30.0 mmol) and triethylamine (3.54 g, 4.88 mL, 35.0 mmol) in dichloromethane (100 mL), at 0° C. while stirring, was added bromoacetyl bromide (6.66 g, 2.9 mL, 33.0 mmol) dropwise. After the addition, the mixture was stirred at room temperature overnight and passed through a short silica pad. The crude product, 3-(2-bromoacetylamino)benzoic acid methyl ester (8.09 g, 99.1%), obtained after the removal of the solvent (>99% by LC/MS, MS (ES+) m/z: 272, 274) was used without further purification.
Reaction SMILES: C([Cl:4])(=O)C.[CH2:5]([C:9]1[S:18][C:17]2[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=[C:12]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[C@@H:25]([CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:24]3)[C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8].CO>C(O)C>[ClH:4].[ClH:4].[CH2:5]([C:9]1[S:18][C:17]2[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=[C:12]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[C@@H:25]([CH2:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:24]3)[C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)Cl
Agent: CCCCc1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2)C1
Solvent: CCO
Solvent: CO
Product: Cl

Procedure:
Add a solution of acetyl chloride (0.15 mL, 2.1 mmol) in absolute ethanol at ambient temperature to (S)-2-Butyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.19 g, 0.41 mmol) in absolute ethanol, with added drops of methanol to solubilize the freebase, and concentrate under reduced pressure gives the title compound (0.18 g). Mass spectrum (APCI+, m/e): 460 (M+1−2HCl); exact mass spectrum (ES+, m/e, C27H33N5S.2HCl): calc. 460.2535 (M+1−2HCl), found 460.2556.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][CH2:8]1)=[O:6]>C1COCC1.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]2)(=[O:14])=[O:15])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
Lithium hydroxide (1.45 g, 60.9 mmol) was added in one portion to a stirred solution of 1-(4-nitro-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (10.0 g, 30.4 mmol) in THF/H2O (1:1,100 ml) and the reaction mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was partitioned between ethyl acetate (100 ml) and HCl (2M, 20 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to afford the title compound (5.1 g, 54% yield) as a colourless oil. δH (250 MHz, DMSO) 12.33 (1H, br s), 8.42 (2H, d), 7.99 (2H, d), 3.56-3.44 (2H, m), 2.51 (2H, obscured), 2.32-2.20 (1H, m), 1.90-1.81 (2H, m), 1.62-1.45 (2H, m). Tr=1.71 min m/z (ES+) (M+H+) 315.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][C:18]1=[O:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@H]1(N)CCCC[C@@H]1N>O1CCOCC1.[Cu]I>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:3][C:4]2[CH2:5][CH2:6][CH2:7][NH:8][C:9]=2[N:10]=1
Reactant: O=C1COCCN1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(OC)c1nc2c(cc1N1CCOCC1=O)CCCN2
Temperature: 120 °C

Procedure:
A suspension of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 1 g, 3.48 mmol), morpholin-3-one (0.423 g, 4.18 mmol), K3PO4 (1.552 g, 7.31 mmol), CuI (0.066 g, 0.348 mmol) and (1S,2S)-cyclohexane-1,2-diamin (0.063 mL, 0.522 mmol) in dioxane (7 ml) was heated to 120° C. for 4 days. Solvents were concentrated and the crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-3%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as an orange resin. (UPLC-MS 3) tR 0.43 min; ESI-MS 308.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:12]([CH3:14])[CH3:13]>CN(C)C=O>[CH:12]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 250 mg, 2.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.5 mL) and a 60% dispersion of sodium hydride in mineral oil (97 mg, 2.43 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 25 min, the reaction was chilled to 0° C. and 2-bromo-propane (324 mg, 2.64 mmol) was added. The reaction continued to stir under nitrogen at 0° C. for 20 min. The ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with ethyl acetate (100 mL), washed with water (2×50 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to give an oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 1-isopropyl-3-nitro-1H-pyrazole (146 mg, 43%) as a white waxy solid: H1-NMR (400 MHz, CDCl3) δ 1.58 (6H, d, J=6.8 Hz), 4.59 (1H, septet, J=6.4 Hz), 6.88 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=2.0 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][N:41]([CH3:43])[CH3:42])[CH:35]=4)=[N:30][N:29](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:42][N:41]([CH2:40][C:36]1[CH:35]=[C:34](/[CH:33]=[CH:32]/[C:31]2[C:17]3[C:18](=[N:19][C:20]([C:22]4[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=4)=[CH:21][C:16]=3[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[NH:29][N:30]=2)[CH:39]=[CH:38][CH:37]=1)[CH3:43]
Reactant: CN(C)Cc1cccc(/C=C/c2nn(C3CCCCO3)c3nc(-c4ccc(O)cc4)cc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c23)c1
Agent: Cl
Solvent: CO
Product: CN(C)Cc1cccc(/C=C/c2n[nH]c3nc(-c4ccc(O)cc4)cc(C(=O)N4CCNCC4)c23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.6 %

Procedure:
To a cold solution (0° C.) of 4-[3-[(E)-2-(3-dimethylaminomethyl-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.25 g, 0.37 mmol) in dry methanol (5 ml) was added dropwise a solution of aqueous 6N HCl (0.7 ml, 3.8 mmol). The reaction mixture was allowed to warm to room temperature and stirring was pursued for 2 hours before being concentrated under reduced pressure. Aqueous 6N HCl (0.7 ml, 3.8 mmol) was added to the crude mixture and stirring was pursued for another hour. Solvents were evaporated under vacuum, methanol and diethyl ether were added, the resulting precipitate was filtered and dried to give a chlorhydrate salt of the title compound as an orange solid (0.21 g; 95%).
Reaction SMILES: [Br:1]Br.[CH2:3]([N:10]1[C:14]2=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:16]=[N:17][CH:18]=[C:13]2[CH:12]=[C:11]1[CH3:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>ClCCl>[CH2:3]([N:10]1[C:14]2=[C:15]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]=[N:17][CH:18]=[C:13]2[C:12]([Br:1])=[C:11]1[CH3:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1c(Br)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A solution of 180 μl (3.5 mmol) of bromine in 7 ml of anhydrous dichloromethane is added dropwise at 0° C. to a solution of 910 mg (2.6 mmol) of 1-benzyl-7-(4-fluorobenzyloxy)-2-methylpyrrolo[2,3-d]pyridazine in 15 ml of anhydrous dichloromethane in the course of 30 min. The solution is kept at 0° C. for a further 1 h, then treated with 50 ml of ice-water and extracted. The organic phase is separated off, washed with 3×25 ml of water, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (eluent: ethyl acetate). The fractions of Rf=0.6 are concentrated and crystallized from diisopropyl ether/cyclohexane. 880 mg (79%) of the title compound are isolated. M.p.: 128°-130° C.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[N:15]=1.Cl>O.O1CCOCC1>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:24])=[O:5])[S:12][CH:13]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2OC)cs1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1csc(CCCCC(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
Add a solution of LiOH.H2O (2.62 g, 62.5 mmol) in water (60 mL) to a rapidly stirred solution of 5-[4-(2-methoxy-phenyl)-thiazol-2-yl]-pentanoic acid methyl ester (3.82 g, 12.5 mmol) in dioxane (120 mL), stir at room temperature. After 1 hour, acidify to pH 1 with 5N HCl solution and concentrate to remove the majority of the dioxane. Partition residue between 20% i-PrOH/CHCl3 and 1N HCl solution, separate layers. Backextract from aqueous layer with 20% i-PrOH/CHCl3 and dry combined organic layers over MgSO4, and concentrate to get 3 grams of a pink oil. Recrystallize from EtOAc to afford the title compound (2.52 g, 69%). MS (IS) 292 (M+1)+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CO.C(OCC)(=O)C>[C:6]([C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1csc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C#Cc1csc(C=O)c1
Yield: 69 %

Procedure:
To a solution of 4-[(trimethylsilyl)ethynyl]thiophene-2-carboxaldehyde (3.3 g, 16 mmol) that was obtained in Example 9 (9a) in methanol (160 ml) was added potassium carbonate (4.3 g, 31 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, insoluble materials were removed by filtration, and the filtrate was evaporated in vacuo. The residue thus obtained was diluted with ethyl acetate, poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:1 to 1:19) as the eluent to afford the title compound (1.5 g) in a yield of 69% as a brown solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:17][CH:16]=3)=[CH:11][CH:10]=2)O1.Cl[C:34]1[N:39]=[CH:38][C:37]([C:40]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:43]([C@@H:53]3[CH2:57][CH2:56][CH2:55][N:54]3[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:42][CH:41]=2)=[CH:36][N:35]=1.C([O-])(O)=O.[Na+].COCCOC>C(OCC)(=O)C.O>[C:61]([O:60][C:58]([N:54]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:43]1[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:40]([C:37]2[CH:36]=[N:35][C:34]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[NH:19][C:18]([C@@H:20]5[CH2:24][CH2:23][CH2:22][N:21]5[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:17][CH:16]=4)=[CH:13][CH:14]=3)=[N:39][CH:38]=2)=[CH:41][N:42]=1)=[O:59])([CH3:64])([CH3:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)n1COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)n4COCC[Si](C)(C)C)cn3)cc2)[nH]1
Temperature: 80 °C
Yield: 98.3 %

Procedure:
Pd(Ph3)4 (0.12 g, 0.103 mmol) was added in one portion to a stirred suspension of (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1c, 1.00 g, 2.27 mmol), (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152c-1, 0.99 g, 2.06 mmol) and NaHCO3 (0.87 g, 10.3 mmol) in a solution of DME (20 mL) and H2O (6 mL) at room temperature under N2. The vessel was sealed and the mixture was placed into a preheated (80° C.) oil bath and stirred at 80° C. for 16 h before additional catalyst (0.12 g) was added. After heating the mixture for an additional 12 h at 80° C., the mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with sat'd NaHCO3 soln and brine prior to drying over anhydrous sodium sulfate and solvent concentration. Purification of the residue by Biotage™ flash chromatography on silica gel using a 40M column (preequilibrated with 40% B followed by step gradient elution with 40% B to 40% B for 150 mL, 40% B to 100% B for 1500 mL, 100% B to 100% B for 1000 mL where B=ethyl acetate and A=hexanes) furnished the title compound as a yellow foam (1.533 g, 98%). A small amount of the yellow foam was further purified for characterization purposes by pHPLC (Phenomenex GEMINI, 30×100 mm, S10, 10 to 100% B over 13 minutes, 3 minute hold time, 40 mL/min, A=95% water, 5% acetonitrile, 10 mM NH4OAc, B=10% water, 90% acetonitrile, 10 mM NH4OAc) to yield 95% pure title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16]([S:18][CH3:19])[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH2:27][CH2:28][CH3:29]>CC(C)=O>[CH2:26]([N:15]1[C:16]([S:18][CH3:19])=[CH:17][C:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])=[N:14]1)[CH2:27][CH2:28][CH3:29]
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC
Yield: 32 %

Procedure:
A solution of 0.8 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-5-(methylsulfenyl)pyrazole (compound 16), 0.7 g of anhydrous potassium carbonate and 0.4 g of n-butyl bromide in 25 ml of acetone were refluxed for 4 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (eluent: ether/hexane=1/20) to obtain 0.3 g of the desired product in the form of a light brown oil (yield 69.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH:15]([NH:20]C(=O)OC(C)(C)C)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>O1CCOCC1>[NH2:20][CH:15]1[CH:16]([CH3:19])[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:14]1
Reactant: CC1CCN(C(=O)CNc2cc(Cl)cc(Cl)c2)CC1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCN(C(=O)CNc2cc(Cl)cc(Cl)c2)CC1N
Yield: 87.8 %

Procedure:
Tert-butyl 1-(2-(3,5-dichlorophenylamino)acetyl)-4-methylpiperidin-3-ylcarbamate (150 mg, 0.36 mmol) was treated with dioxane.HCl (5 mL) at rt for 2 h. The solvent was concentrated in vacuo, the resulting residue was dissolved in water (10 mL) and treated with solid NaHCO3. The aqueous solution was extracted with EtOAc (3×25 mL) and the combined organic layers were dried over Na2SO4, concentrated in vacuo to yield the titled intermediate (100 mg, 87%), which was used next without further purification. LC-MS: m/z [M+1]=316.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:20]C=C)[CH2:17][CH:18]=[CH2:19])=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:23]([NH2:26])(=[O:25])=[O:24]>C(Cl)(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH:18]=[CH:19][CH2:20]3)=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:23]([NH2:26])(=[O:24])=[O:25]
Reactant: C=CCN(CC=C)c1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1cc(C(O)c2ccc(N3CC=CC3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 100 mg of 2-chloro-5-((4-diallylamino-phenyl)-hydroxy-methyl)-benzenesulfonamide (0.25 mmol, 1 equivalent) in 5 mL of chloroform is degassed with argon for 5 minutes, then 5 mg of Grubb's catalyst (0.005 mmol, 2% mmol) is added. The reaction mixture is stirred at room temperature for 1 h, then diluted with dichloromethane, filtered through Celite, and a pad of silica gel, then concentrated in vacuo to give 70 mg of the title compound which is carried forward without further purification.