Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.N1CCOCC1.Br[C:13]1[O:17][CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=1.Cl[Si:21]([CH3:24])([CH3:23])[CH3:22]>CCCCCC.O1CCCC1>[CH3:22][Si:21]([CH3:24])([CH3:23])[C:13]1[O:17][CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=1
Reactant: O=Cc1coc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1COCCN1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C=O)co1
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (a 1.6M solution in hexane; 31.0 ml, 49.7 mmol) was added dropwise to a solution of morpholine (4.33 ml, 49.7 mmol; freshly distilled from barium oxide) in tetrahydrofuran at -78° under argon. After 15 minutes, a solution of 5-bromo-3-furaldehyde (7.5 g, 49.7 mmol) in tetrahydrofuran (THF) was added dropwise. Stirring was continued for 30 min. and n-butyl lithium (a 1.6M solution in hexane; 46.6 ml, 74.5 mmol) was added dropwise. After 1 hour at -78°, chlorotrimethylsilane (18.9 ml, 149 mmol) was added and stirring continued while the cooling bath attained room temperature. The reaction mixture was quenched with 10% hydrochloric acid and the phases were separated. The aqueous phase was stirred, in the presence of ethyl ether (30 ml), with 10% hydrochloric acid at 0° C. for 1/2 hour. The organic phases were combined, washed (brine), dried (magnesium sulfate) and evaporated down. The residue was distilled under vacuum to give the title aldehyde as a colorless oil b.p. 48°-50°/0.25 torr.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:21]=1>>[OH:29][C@@:25]([C:22]1[CH:21]=[C:20]([CH3:19])[O:24][N:23]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: C#C[C@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: Cc1cc([C@@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)no1
Yield: 9 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2S)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (34 mg, 9%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C1C=CN=CC=1)C.ClCCl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2c(c(Br)c(Br)n2Cc2ccccc2)c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a stirring mixture of 1-benzyl-2,3-dibromo-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (492 mg, 1.08 mmol), triethylamine (300 μL, 2.16 mmol), and DMAP (13 mg, 0.11 mmol) in anhydrous dichloromethane (5 mL) was added pivaloyl chloride (160 μL, 1.30 mmol); the mixture was stirred for 1 h at room temperature before diluted with EtOAc, then washed with diluted HCl aqueous solution, saturated NaCl aqueous solution respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, the residue was purified by column to give a foamy brown solid, the desired title compound (495 mg, 85%). The title compound, ESI MS (m/z): 537 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>CC(O)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Solvent: CC(=O)O
Product: CCC(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)c3ccccc3n4CC)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 9-ethyl-9H-carbazole-3-carbaldehyde and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 440.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:35])[C@H:18]([NH:27]C(=O)OC(C)(C)C)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[CH:10][C:4]=23)[CH2:12][CH2:13]1)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
(R)-tert-Butyl 1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.022 g, 0.039 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour and then concentrated. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid (R)-2-amino-1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)propan-1-one (0.016 g, 88% yield) was collected and dried as the dihydrochloride salt. MS ESI (+) m/z 463 detected.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:1]([Si:5]([CH3:6])([CH3:7])[O:8][CH2:9][CH2:10][CH:11]=[CH:12][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCCC[Sn](C=CCCO[Si](C)(C)C(C)(C)C)(CCCC)CCCC
Yield: 95 %

Procedure:
A solution of Example 31A (1.08 g, 5687 mmol), tri-(n-butyl)tin hydride (1.43 mL, 5.31 mmol), and AIBN (cat.) in benzene (10 mL) was stirred at 80° C. for 3 hours. Volatiles were removed under reduced pressure to provide the title compound as a colorless oil (>95% E-isomer). 1H NMR (300 MHz, CDCl3): δ 0.05 (s, 6H), 0.80-0.98 (m, 15H), 0.90 (s, 9H), 1.23-1.38 (m, 6H), 1.42-1.53 (m, 6H), 2.34-2.40 (m, 2H), 3.66 (d, J=6 Hz, 2H), 5.94-5.98 (m, 2H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:14]1([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[CH:14]1([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:31])([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Reactant: C#Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(C#Cc1ccccc1)(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.4 ml of phenylacetylene (3.6 mmol in 10 ml of THF at −78° C. was added 1.9 ml (4.75 mmol) of a 2.5 M solution of n-butyllithium in hexanes. The color of the solution turned dark blue and the reaction mixture was stirred at −78° C. for 30 min. After this time, a solution of 450 mg of 1-(4-cyclopentylamino-phenyl)-2,2,2-trifluoro-ethanone (1.75 mmol) in 2 ml of THF was added and the resultant mixture stirred at −78° C. for 1.5 h before being allowed to warn to room temperature and stirred for a further 14 h. After this time, the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica (hexanes:EtOAc, 3:1) to give the title compound. 1H-NMR (CDCl3) δ 1.48–1.56 (m, 2H), 1.68–1.76 (m, 4H), 2.03–2.14 (m, 2H), 3.76–3.85 (m, 1H), 6.65 (d, J=8.6 Hz, 2H), 7.36–7.82 (m, 10H). Mass Spectrum (CI+) m/e=360.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH:9](S(Cl)(=O)=O)[CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[Br-:23]>CC(C)=O>[Br:23][CH:9]1[CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10]1
Reactant: [Br-]
Reactant: O=S(=O)(Cl)C1CC(c2ccccc2)=C(c2ccccc2)C1
Agent: [Li+]
Solvent: CC(C)=O
Product: BrC1CC(c2ccccc2)=C(c2ccccc2)C1
Yield: 82.6 %

Procedure:
To a mixture of 3,4-diphenyl-3-cyclopentene-1-sulfonyl chloride (4 g) and 3 g of LiBr was added 70 mnL of acetone. Reaction mixture was stirred under reflux for 2.5 hr. Solvent was removed under reduced pressure and the residue was extracted with 60 mL of methylene chloride. Solution was filtered and solvent was removed under reduced pressure giving 3.1 g of product as brown-yellow solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([O:22][CH3:23])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)=[C:15]([O:22][CH3:23])[CH:14]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(F)ccc1-c1n[nH]c2ncnc(N)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 35.3 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g, 3.83 mmoles) in DMF (14 ml), ethanol (7 ml) and water (7 ml), 4-fluoro-2-methoxyphenyl boronic acid (0.846 g, 4.979 mmoles) and sodium carbonate (2.06 g, 19.15 mmoles) were added and the system is degassed for 30 min Tetrakis triphenylphosphine Palladium (0.754 g, 0.652 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.350 g, 35% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.46(s, 1H), 8.14(s, 1H), 7.40(t, J=8.4Hz, 1H), 7.09(dd, J=11.5,2.9Hz, 1H),6.91(dt, J=8.4,2.4Hz 1H),3.78(s,3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:12]3[O:13][CH:11]3[C:10]([CH3:15])([CH3:14])[O:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].Cl.[NH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C@@H:12]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@H:11]([OH:13])[C:10]([CH3:15])([CH3:14])[O:9][C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCN
Reactant: CC1(C)Oc2cc([N+](=O)[O-])ccc2C2OC21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCCN[C@@H]1c2ccc([N+](=O)[O-])cc2OC(C)(C)[C@H]1O

Procedure:
7-Nitro-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran (0.48 g, the preparation of which is described in Example 3 of U.K. Pat. No. 1,548,221), ethyl 4-aminobutyrate hydrochloride (0.34 g) and sodium hydroxide pellets (0.08 g) were refluxed in ethanol (50 ml) for 12 hours. Filtration and evaporation and chromatography on a chromatotron (2 mm silica gel HF254, gradient elution with pentane-ethyl acetate) gave recovered epoxide (0.20 g) and trans-4-(3-carbethoxypropylamino)-7-nitro-2,2-dimethyl-2H-benzo[b]pyran-3-ol (0.21 g) as a gum, which was used as such in Example 10.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]1([C:67]2[CH:68]=[C:69]([C:72](O)=[O:73])[S:70][CH:71]=2)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:72]([C:69]1[S:70][CH:71]=[C:67]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:68]=1)=[O:73]
Reactant: O=C(O)c1cc(-c2ccccc2)cs1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 34.9 %

Procedure:
DIPEA (76 mg, 0.59 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (100 mg, 0.24 mmol) in DMF (1 mL). HOBT (32 mg, 0.24 mmol) and EDCI.HCl (45 mg, 0.24 mmol) were then added at room temperature. After 2 minutes, 4-phenyl-thiophene-2-carboxylic acid (40 mg, 0.20 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 35 mg (35.7% yield) of 4-phenyl-thiophene-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity %: 99.1%, 1H NMR (DMSO-d6): δ 8.7 (t, 1H), 8.3 (s, 1H), 8.1 (s, 1H), 7.9-7.6 (m, 5H), 7.6-7.5 (m, 1H), 7.5-7.4 (t, 2H), 7.4-7.3 (m, 1H), 4.2 (m, 2H), 3.7-3.5 (m, 4H), 3.4 (m, 4H), 3.2-3.1 (m, 2H).
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])/[CH2:3][OH:4].[CH3:19][O:20][CH:21]([O:30][CH3:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:31][O:30][CH:21]([O:20][CH3:19])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:4][CH2:3]/[C:2](/[CH3:1])=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=2[CH3:18])=[CH:27][CH:28]=1
Reactant: CC1=C(CCCC/C=C(\C)CO)C(C)(C)CCC1
Reactant: COC(Cc1ccc(O)cc1)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(Cc1ccc(OC/C(C)=C/CCCCC2=C(C)CCCC2(C)C)cc1)OC
Temperature: 25 °C
Yield: 91.4 %

Procedure:
(2E)-2-Methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-heptenol (1.5 g), 4-((2,2-dimethoxy)ethyl)phenol (1.1 g) and triphenylphosphine (1.59 g) are dissolved in THF (10 ml) and the solution cooled to 0°. Diethyl azodicarboxylate (1.05 ml, in 9 ml THF) is added dropwise with stirring, and the mixture is allowed to warm to room temperature and stirred overnight. The reaction mixture is concentrated and the residue is chromatographed with dichloromethane to provide 4-((2,2-dimethoxy)ethyl)-1-((2E)-2-methyl-7-(2,6,6-trimethyl- 1-cyclohexen-1-yl)-2-heptenyloxy)benzene as a pale yellow oil (2.27 g). This material is reacted with glyoxylic acid and morpholine hydrochloride by the method of Example 2 above, purified by chromatography with 7% ether in dichloromethane, and recrystallized from hexane-dichloromethane to provide the title compound as a white solid, mp 119°-121° (1.0 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>ClCCl>[CH3:14][C:13]([Si:10]([CH3:12])([CH3:11])[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCN1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN1CCNCC1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To 1-(2-hydroxyethyl)-piperazine (3.36 g, 25.8 mmol) in dichloromethane (25 mL) was added tert-butyldimethylsilylchloride (3.89 g, 25.8 mmol). The reaction mixture was stirred at room temperature. The reaction mixture was stirred overnight, then diluted 1× with CH2Cl2 and extracted against 0.5 N NaOH (100 mL). The aqueous was extracted further with 10% methanol in CH2Cl2 (3×100 mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 100% B (7% methanol in DCM+1% NH4OH additive) against A (3% methanol in DCM+0.175% NH4OH additive) afforded compound 246 (4.71 g, 74.7% yield). 1H NMR (500 MHz, CDCl3) δ 0.06 (s, 6 H) 0.90 (s, 9 H) 2.36-2.59 (m, 6 H) 2.89 (t, J=4.77 Hz, 4 H) 3.76 (t, J=6.48 Hz, 2 H) ppm.
Reaction SMILES: [C:1]12C[CH:5]([C:6]1(C)C)[CH2:4][CH:3]([C:10]1([CH:20]3CC4CC(C4(C)C)=C3C)[CH2:15]C3CC(C3(C)C)=[C:11]1C)[C:2]=2C.C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:33])C>C(Cl)(Cl)(Cl)Cl>[C:10]([CH:3]1[CH2:4][CH2:5][C:6](=[O:33])[CH2:1][CH2:2]1)([CH3:20])([CH3:15])[CH3:11]
Reactant: CC1=C2CC(CC1C1(C3CC4CC(=C3C)C4(C)C)CC3CC(=C1C)C3(C)C)C2(C)C
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C1CCC(=O)CC1
Reaction time: 0.5 h

Procedure:
To a 4-t-butylcyclohexane-1,1-dihydroperoxide and terpinene (trapping reagent) in a stirred room temperature solution of carbon tetrachloride was added, over a period of five to ten minutes, a solution of bisacetoxyiodobenzene (BAIB) in carbon tetrachloride. Rapid bubbling commenced upon addition of the BAIB solution and ceased within a few minutes after addition was completed. Stirring was continued for 0.5 h, after which the solution was filtered through a plug of silica, which was washed with CH2Cl2. The residue obtained upon concentration was purified by column chromatography on silica gel to give 4-t-butyl cyclohexanone and the trapping product ascaridole (endoperoxide of terpinene).
Reaction SMILES: [CH3:1][N:2](C(=O)C)[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10].[OH-].[K+]>C(O)C.O>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1ccsc1N(C)C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=O)c1ccsc1NC
Temperature: 95 °C

Procedure:
To a solution of 1.255 g of N-methyl-2-acetylamino-3-propionylthiophene in 25 ml of ethanol, is added 0.45 g of potassium hydroxide in 10 ml of water. The mixture is heated at 95°C for 1 hour, evaporated under reduced pressure to a residue. Water is added to the residue and extracted with dichloromethane. The dichloromethane extracts are washed with water, dried over sodium sulfate, then evaporated under reduced pressure to give an oil. The residual oil is chromatographed on silica gel, using chloroform as an eluent to give 2-methylamino-3-propionylthiophene as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: CNc1ccccc1C
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), methyl-o-tolyl-amine (44 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-o-tolyl-amide: MS m/z: (M+H) 518.0.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:24][CH2:23]1)=[O:21])[C:9]([O:11]CC1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[CH2:1]([C@H:8]([CH2:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]([F:32])([F:30])[F:31])[CH2:26][CH2:27]1)=[O:21])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCN(CC(F)(F)F)CC1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@H](CC(=O)N1CCN(CC(F)(F)F)CC1)Cc1ccccc1
Yield: 96.4 %

Procedure:
The resultant compound from Example 24 (610 mg), and 10% palladium on carbon (300 mg) in methanol were stirred under an H2 atmosphere for 2 h. Filtration and solvent evaporation afforded 470 mg (96%) of a solid, m.p. 96°-98° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([O:20]CC)=[O:19])[CH:9]=1.Cl>C(O)C>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=1
Reactant: CCOC(=O)c1cc(CCCOC)c2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCc1cc(C(=O)O)cc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
5N Aqueous solution of sodium hydroxide (3.4 ml) was added to a solution of ethyl 4-(3-methoxypropyl)-2-naphthoate (2.41 g) in ethanol and the mixture was stirred at room temperature for 3 hours. The reaction solution was acidified by adding 10% hydrochloric acid under ice-cooling and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was triturated in n-hexane to give 4-(3-methoxypropyl)-2-naphthoic acid (2.09 g) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11].[N+]([O-])(O)=O>O>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH:10]([O:11][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])[CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(C)=CCOC(C=C(C)C)OCC=C(C)C
Reaction time: 4.5 h

Procedure:
690 g (8.2 moles) of 3-methyl-but-2-en-1-al, 1730 g (20 moles) of 3-methyl-but-2-en-1-ol and 23 mg of 65% strength nitric acid (corresponding to 0.62 × 10-4 % by weight of 100% strength HNO3, based on 2,420 g of starting compounds) are boiled under 60 mm Hg in a 4 liter flask surmounted by a packed column (filled with 5 mm Raschig rings). The bottom temperature assumes a value of 76-88° C. The packed column has a diameter of 45 mm and has 30 theoretical plates. The water formed in the reaction is taken off at the top of the column and the organic material which separates from the water is returned continuously into the top of the column. With a reflux of 600 g/hour, quantitative conversion of the aldehyde is achieved after 4.5 hours. 1,1-Bis-(3-methyl-but-2-en-1-yl-oxy)-3-methyl-but-2-ene is obtained about 99% pure after distilling off the excess alcohol, the yield being 98.6% based on 3-methyl-but-2-en-1-al and 98.2% based on 3-methyl-but-2-en-1-ol.