Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:19][C:18]([C:20]([F:23])([F:22])[F:21])=[N:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:34][Si:35]([CH3:42])([CH3:41])[CH2:36][CH2:37][O:38][CH2:39]Cl>CCCCCC>[CH3:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]([CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:42])([CH3:41])[CH3:34])[C:18]([C:20]([F:22])([F:23])[F:21])=[N:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cccc(-c2[nH]c(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)nc(C(F)(F)F)n2COCC[Si](C)(C)C)c1
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
Sodium hydride (60% in oil, 1.06 mmol, 42 mg) was washed with hexane (ca 2×1 ml), then covered with N,N-dimethyformamide (2.1 ml). 5-(3-Methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-trifluoromethyl-1H-imidazole (Example 59) (0.70 mmol, 268 mg) was added, with stirring. After 15 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (1.06 mmol, 0.19 ml) was added and the mixture was stirred overnight. The reaction was quenched with saturated ammonium chloride (ca. 4 drops), and concentrated in vacuo. The residue was subjected to chromatography (2:1 hexane: ethyl acetate) and concentrated to afford the title compound (284 mg, 79%) as an oil as a mixture of the two possible N alkylated isomers (by NMR).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Br)=[O:4].[NH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][CH:2]1[CH2:6][CH2:7][N:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:3]1=[O:4]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Br)C(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(N2CCC(Br)C2=O)cc1

Procedure:
2,4-Dibromobutyryl bromide (BBBB, 12.13 g, 0.039 mole) was added via an addition funnel to a cold (5° C.), well stirred slurry of 4-aminobenzonitrile (4-ABN, 4.0 g, 0.034 mole), Na3PO4 (3.05 g, 0.019 mole) and acetonitrile (42 mL) while maintaining a temperature below 30° C. during the addition. The addition funnel was rinsed with acetonitrile (2 mL). Upon completion of the coupling (determined by LC), K2CO3 (9.36 g, 0.069 mole) was added via an addition funnel while maintaining the reaction temperature below 30° C. Upon completion of the reaction (determined by LC), the slurry was filtered. The flask and the cake were washed with acetonitrile (40 mL). The filtrate and the wash were combined to afford a solution of 4-(3-bromo-2-oxopyrrolidin-1-yl)benzonitrile in acetonitrile. Qualitative LC analysis showed the product with 96.1 area % purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=1>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=1
Reactant: NC(=O)c1cccc(-c2ccc(CO)cc2Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(-c2ccc(C=O)cc2Cl)c1
Reaction time: 12 h

Procedure:
2′-Chloro-4′-hydroxymethyl-biphenyl-3-carboxylic acid amide (I-6d: 5.0 g) was suspended in 500 mL of ethyl acetate and treated with activated manganese dioxide (5 equivalents). After stirring for 12 hours, the reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure to afford the title compound (I-6e).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[S:16](=[O:26])(=[O:25])[CH2:15][CH2:14]2)[CH:3]=1.CC1(C)[O:32][CH:31]([CH2:33][NH2:34])[CH2:30][O:29]1>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[S:16](=[O:25])(=[O:26])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:34][CH2:33][CH:31]([OH:32])[CH2:30][OH:29]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3C)cc(Cl)c2c1
Reactant: CC1(C)OCC(CN)O1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3C)cc(NCC(O)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 32-1 in Scheme 10 by using 4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and 1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (dd, J=7.96, 1.39 Hz, 1 H), 7.90 (d, J=6.57 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.46 (ddd, J=8.15, 6.63, 1.64 Hz, 2 H), 7.33 (dd, J=8.59, 1.77 Hz, 1 H), 6.15 (s, 1 H), 5.86 (d, J=6.82 Hz, 1 H), 4.64-4.53 (m, 4 H), 3.70 (d, J=8.59 Hz, 1 H), 3.62-3.58 (m, 2 H), 3.57-3.49 (m, 1 H), 2.43 (s, 3 H), 2.00 (d, J=7.07 Hz, 3 H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=O)C1C=CC=CC=1>C(O)C.[Pd].C(OCC)(=O)C>[CH3:20][O:19][CH2:18][CH2:17][O:16][CH2:15][O:14][CH2:13][CH2:12][NH2:11]
Reactant: COCCOCOCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOCOCCN
Reaction time: 8 h

Procedure:
N-Benzyloxycarbonyl-O-(2-methoxyethoxymethyl)ethanolamine (6.25 g, 22.0 mmol) was dissolved in ethanol (10 ml) and placed under a blanket of argon. A slurry of 10% palladium on charcoal (1 g) in ethyl acetate was added and hydrogen gas was bubbled through the suspension for 3 hours and then the mixture was placed under hydrogen atmosphere overnight. TLC indicated that some starting material still remained so a further batch ofcatalyst (1 g) was added and hydrogenation was allowed to continue for a further 6 hours, after which all the starting material had been consumed. The catalyst was removed by filtration and the filtrate was used directly in Example 1 h (product volatile).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[CH2:12]([O:19][N:20]1[C:26](=[O:27])[N:25]2[CH2:28][C@H:21]1[CH2:22][CH2:23][C@H:24]2[C:29](Cl)=[N:30][OH:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CCOC(C)=O>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:1][C:2]1[O:31][N:30]=[C:29]([C@@H:24]2[CH2:23][CH2:22][C@@H:21]3[CH2:28][N:25]2[C:26](=[O:27])[N:20]3[O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Reactant: C#CCNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
tert-Butyl prop-2-yn-1-ylcarbamate (0.37 g, 2.4 mmol) was added to the solution of (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride (˜2.0 mmol) in dry DCM (20 mL), followed by the addition of TEA (0.31 mL, 2.2 mmol) in dry DCM (2.0 mL) over a period of 30 minutes. The reaction mixture was stirred at rt overnight, then the mixture was diluted with EtOAc, washed with water and saturated sodium chloride. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (1:2 petroleum ether/EtOAc) to afford tert-butyl((3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)isoxazol-5-yl)methyl)carbamate (180 mg, 21% for two steps) as a white solid. ESI-MS (EI+, m/z): 429.1 [M+H]+. 1H NMR (500 MHz, CDCl3): δ 7.45-7.35 (m, 5H), 6.24 (s, 1H), 5.09 (d, J=11.5 Hz, 1H), 4.93 (d, J=11.5 Hz, 1H), 4.58 (d, J=7.5 Hz, 1H), 4.43 (m, 2H), 3.32 (s, 1H), 2.86-2.84 (m, 1H), 2.68 (d, J=11.5 Hz, 1H), 2.34-2.30 (m, 1H), 2.23-2.18 (m, 1H), 2.10-2.04 (m, 1H), 1.82-1.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[OH:10])[CH3:2].C1(=O)O[CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([O:10][CH2:14][CH2:13][OH:12])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cc(Br)ccc1OCCO
Temperature: 125 °C
Yield: 82.1 %

Procedure:
To a solution of 2-ethyl-4-bromophenol (3.5 g, 17.4 mmol) and ethylene carbonate (3.22 g, 37 mmol) in NMP (60 mL) was added potassium carbonate (5.17 g, 37.4 mmol). The resulting mixture was heated to 125° C. and maintained for 3 h. The reaction was cooled and poured into water (250 mL) and extracted with EtOAc (2×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10-20% EtOAc in hexanes) to give the product (3.5 g, 82% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 1.19 (t, J=7.6 Hz, 3H), 1.89 (brs, 1H), 2.61 (q, J=7.6 Hz, 2H), 4.05 (m, 4H), 6.70 (d, J=8.7 Hz, 1H), 7.24 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:24]=3[N:25]=2)=[C:15]([Cl:32])[CH:14]=1)(=[O:11])=[O:10].[OH-:33].[K+].Cl>C(O)(C)(C)C>[Cl:19][C:17]1[CH:18]=[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH:14]=[C:15]([Cl:32])[C:16]=1[S:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([C:30]([NH2:31])=[O:33])=[CH:26][C:24]=2[N:25]=1
Reactant: N#Cc1ccc2sc(Sc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)nc2c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc2sc(Sc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)nc2c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
To a solution of 2,4-dichloro-N-[3,5-dichloro-4-(5-cyano -benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide (297) (250 mg, 0.45 mmol) in tert-butanol (10 mL), was added KOH (EM Science Product, 126 mg, 2.25 mmol). The resulting mixture was refluxed for 1 hour. After cooling to room temperature, a 1M aqueous solution of HCl (50 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (20% EtOAc in CH2Cl2, then 10% MeOH in CH2Cl2) to yield 207 mg (80%) of compound 303 as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH:5]([C:7]1[CH:36]=[CH:35][CH:34]=[CH:33][C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:32])[CH2:17][NH:18][C:19]([C:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][N:22]=2)=[O:20])[CH2:12][CH2:11]1)=O.C([O-])(=O)C.[Na+]>CO.O>[CH3:2][O:3][N:4]=[CH:5][C:7]1[CH:36]=[CH:35][CH:34]=[CH:33][C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:32])[CH2:17][NH:18][C:19]([C:21]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:23][N:22]=2)=[O:20])[CH2:12][CH2:11]1
Reactant: CON
Reactant: O=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 4 h
Yield: 31.1 %

Procedure:
O-Methyl-hydroxylamine hydrochloride (23 mg, 0.27 mmol) was added to a stirred cold (0° C.) mixture of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-formyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (100 mg, 0.23 mmol) and sodium acetate (56 mg, 0.7 mmol) in MeOH (10 mL) and stirring was continued at ambient temperature for 4 hrs. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 33 mg (31.13% yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid (2-{4-[2-(methoxyimino-methyl)-phenoxy]-piperidin-1-yl}-2-oxo-ethyl)-amide. LC/MS [M+H]+: 462.2, 96.3%. 1H NMR (300 MHz, DMSO-d6): δ13.7 (s, 1H), 8.4 (s, 1H), 8.1 (t, 1H), 7.8 (t, 2H), 7.7 (d, 1H), 7.5-7.34 (m, 4H), 7.2 (d, 1H), 7.1 (s, 1H), 7.0 (t, 1H), 4.8 (bs, 1H), 4.2 (b, 2H), 3.9 (s, 3H), 3.8-3.6 (bs, 2H), 3.5 (b, 2H), 2.1-1.9 (b, 2H), 1.8-1.6 (b, 2H).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[CH2:11][C:12]#[N:13]>CN(C=O)C>[Si:5]([O:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[CH2:11][C:12]#[N:13])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CCC(O)c1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CC#N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
TBDMS-Cl (2.7 g, 18.24 mmol) was added at 0° C. to a stirred solution of aniline 11 (3 g, 15.62 mmol) and TEA (1.73 g, 17.18 mmoles) in DMF and the reaction mixture was stirred at RT for 4 h. The reaction mixture was partitioned between EtOAc and water. Organic layer was washed with water 2×, dried over sodium sulfate and concentrated under reduced pressure to give 3-(tert-butyldimethylsilyloxy)-3-(3-nitrophenyl)propanenitrile as colorless liquid. Yield (4.0 g, 83%); 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.18 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 5.33 (t, J=5.6 Hz, 1H), 3.01-2.92 (m, 2H), 0.88 (s, 9H), 0.13 (s, 3H), −0.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1N1CCCCC1C)C(=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[NH:11][CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1c(I)ccnc1Cl
Product: CNc1cnccc1-c1ccnc(Cl)c1F

Procedure:
The title compound was prepared in analogy to example 55, intermediate, from 2-chloro-3-fluoro-4-iodo-pyridine (CAS RN 148639-07-0) and (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b). Brown sticky solid (86%). MS (ESI): m/z=238.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)N)=[CH:4][CH:3]=1.O=[C:19]([CH3:32])[CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].Cl>O1CCOCC1>[Br:15][C:12]1[CH:11]=[C:10]2[C:9](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=1)[C:19]([CH3:32])=[C:20]2[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: NN(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1CCC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(Br)cc12
Temperature: 70 °C
Yield: 39.3 %

Procedure:
To a room temperature solution of N-(4-bromobenzyl)-N-(4-bromophenyl)hydrazine (335 mg, 0.941 mmol) and methyl 2-(3-oxobutyl)benzoate (202 mg, 0.98 mmol) in 6 mL dioxane was added 1.5 mL of 4N HCl solution in dioxane. Heated to 70° C. for 16 h, then concentrated, the residue was partitioned between EtOAc and water, then washed with 1M HCl and brine. Dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (40% CH2Cl2 /Hexanes) provided 195 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35](O)[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:41]2)=[CH:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35]([O:11][C:10](=[O:12])[C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:16][CH:15]=2)([CH3:13])[CH3:14])[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:49])[CH3:50])[CH2:41]2)=[CH:28]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)(OCc1ccc(C(F)(F)F)cc1)C(=O)O
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)OCc3ccc(C(F)(F)F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 80.6 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 786 mg of 2-(4-trifluoromethylbenzyloxy)-2-methylpropionic acid and 1.10 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.28 g of the title compound as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2-].[Li+].CS[C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=2[N:17]=1.O>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[N:13]=[CH:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=3[N:17]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Agent: [Li+]
Agent: [NH2-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Temperature: 50 °C
Yield: 93.6 %

Procedure:
To a 100-mL, three-neck, round bottom flask were added 294.0 mg (3.124 mM) of 4-aminopyridine, 238.8 mg (10.40 mM) of lithium amide, and 15 mL of tetrahydrofuran. The reaction mixture was heated to 50° C. for 1 hour. A solution of 998 mg (2.792 mM) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one in 25 mL of tetrahydrofuran was added in one portion. The reaction mixture was heated at reflux for 24 hours. The reaction mixture was cooled to 50° C. and diluted by dropwise addition of 25 mL of water. The solid precipitate was collected by filtration and dried in a vacuum oven at 45° C. for 12 hours to provide 93.6% yield of the filtered compound, mp 305-307° C. Mass Spec (APCI) 403.9 m/z. HPLC established the product was 98.5% pure.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[C:5]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])\[CH3:13])=[C:4]([OH:20])[C:3]=1[CH:21]=[O:22].[H][H]>[Pd].C(O)C>[Cl:8][C:7]1[C:2]([CH3:1])=[C:3]([C:4]([OH:20])=[C:5]([CH2:10][CH2:11][CH:12]([CH3:13])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=1[OH:9])[CH:21]=[O:22]
Reactant: [H][H]
Reactant: CC(C)=CCC/C(C)=C/Cc1c(O)c(Cl)c(C)c(C=O)c1O
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cl)c(O)c(CCC(C)CCCC(C)C)c(O)c1C=O
Yield: 21.9 %

Procedure:
An ethanol solution (24.5 ml) of colletochlorin B (991 mg, 3.07 mmol) described in H. Saimoto et al., Bull. Chem. Soc. Jpn., 67, 1178 (1994) was stirred in the presence of 5% Pd/C (496 mg) at 0° C. in a hydrogen atmosphere for 4.5 hours. After the catalyst was separated by filtration with the use of Celite, the filtrate was concentrated to obtain a crude product (963 mg). This product was purified by silica gel column chromatography (hexane:diethyl ether=30:1) to obtain 3-chloro-4,6-dihydroxy-5-(3,7-dimethyloctyl)-2-methylbenzaldehyde (pale yellow solid 220 mg, yield 22%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:15])[C@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=[O:5].CS(C)=O.F[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:24]#[N:25].C(=O)(O)[O-].[Na+]>C([O-])([O-])=O.[Na+].[Na+]>[C:11]([O:10][C:8]([NH:7][C@@H:3]([C@@H:2]([NH:1][C:21]1[CH:22]=[C:23]([C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[CH3:15])[C:4]([OH:6])=[O:5])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: C[C@H](N)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](Nc1cc(C#N)ccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 108.6 %

Procedure:
A mixture of (2S,3S)-3-amino-2-(tert-butoxycarbonylamino)butanoic acid (3.14 g, 14.4 mmol), dimethylsulfoxide (40 ml), 3-fluoro-4-nitrobenzonitrile (2.63 g, 15.8 mmol), and sodium bicarbonate (4.83 g, 57.5 mmol) was stirred at 55° C. for 3 h. Additional NaHCO3 (0.9 g) was added and the mixture was stirred at 60° C. for 1 hour, then cooled to RT, diluted with cold sat. Na2CO3, and washed with MTBE. The aqueous phase was carefully acidified to pH ˜4 with solid citric acid and extracted with EtOAc (three times). The combined organic layers were washed with H2O twice and brine, dried over Na2SO4, filtered, and concentrated to provide (2S,3S)-2-(tert-butoxycarbonylamino)-3-(5-cyano-2-nitrophenylamino)butanoic acid (5.7 g, quant.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:48])[CH2:44][CH2:45][CH2:46][CH3:47]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:48][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCCCCN
Product: CCCCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and pentylamine (15.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-pentylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (39.6 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[OH2:5]>>[CH:1]([OH:5])=[CH:2][CH:3]=[CH:4][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C=CC=C
Reactant: O
Product: CCCCC=CC=CO

Procedure:
U.S. Pat. Nos. 4,356,333 and 4,417,079 and EP-A 436 226 describe a two-phase system for the telomerization of butadiene with water to give octadienol. The reaction is carried out in a water/sulfolane mixture from which the octadienols formed precipitate. The palladium catalyst is retained in the sulfolane phase by means of monosulfonated triphenylphosphine (TPPMS).