Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].S(O[N:13]=[C:14]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:21][CH:20]=1)[C:15]([F:18])([F:17])[F:16])(C1C=CC(C)=CC=1)(=O)=O>CCOCC>[C:30]([Si:27]([CH3:28])([CH3:29])[O:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2([C:15]([F:16])([F:18])[F:17])[NH:13][NH:1]2)=[CH:20][CH:21]=1)([CH3:32])([CH3:33])[CH3:31]
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)ON=C(c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)C(F)(F)F)cc1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C2(C(F)(F)F)NN2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
Liquid ammonia (2 mL) was added a −78° C. to an ether (15 mL) solution of 1-(4-((tert.-butyldimethylsilyloxy)methyl)phenyl)-2,2,2-trifluoroethanone O-tosyl oxime (4.00 g, 8.2 mmol) in a sealed tube. The solution was stirred at rt (16 h). The mixture was carefully cooled at −78° C. and the sealed tube was opened. The ammonia was evaporated and the white precipitate was filtered and washed with ether. The filtrate was concentrated in vacuum to obtain 2.4 g of a colorless oil (87%); NMR (CDCl3): δ 0.10 (s, (CH3)2Si), 0.95 (s, CH3)3C), 2.21 (d, J=8.1 Hz, NH), 2.77 (d, J=8.1 Hz, NH), 4.76 (s, CH2), 7.38 (d, J=8.4 Hz, 2 C6H4), 7.58 (d, J=8.4 Hz, 2 C6H4); 13C NMR (CDCl3): δ −5.3 (CH3Si), 18.4 (C(CH3)3), 25.9 (C(CH3)3), 58.0 (q, J=35.8 Hz, C diaziridine), 64.4 (CH2O), 123.6 (q, J=276.0 Hz, CF3), 126.2 (C6H2), 128.0 (C6H2), 130.2 (C6H2), 143.8 (C6H2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]Br.[OH-].[Na+]>S(=O)(=O)(O)O.O>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1cccc(N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(N)ccc1Br
Temperature: 0 °C
Yield: 55.2 %

Procedure:
32.4 g(0.3 mole) of 6-aminopicoline was dissolved in a mixture of 28 g of conc. sulfuric acid and 120 ml of water and the resulting solution was cooled in ice water. 52.8 g(0.33 mole) of bromine was added dropwise to the solution over 30 minutes at 0° C. The reaction solution was stirred for 20 minutes at room temperature and neutralized with cold aqueous NaOH solution. The resultant was filtered and purified by column chromatography using methylene chloride and ethyl acetate as an eluent to obtain 31 g of the title compound(yield 55%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:34])[C:29]([O:31]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:35].[C-]#N.[Na+]>CO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:34])[C:29]([NH2:35])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reactant: N
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)C(N)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 48 h
Yield: 78 %

Procedure:
A solution of (S)-ethyl 2-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-oxoacetate (245 mg, 0.525 mmol) in a 7 N ammonia solution in MeOH (10 mL) was treated with catalytic amount of sodium cyanide and allowed to stir for 48 h. The reaction mixture was then evaporated, washed with water and air dried to afford a residue then purified by silica gel flash chromatography with 50% then 75% EtOAc/hexanes as eluant to afford the title compound as colorless foam (180 mg, 78%). LC/MS (Method B) 3.31 min, [M+1]+ 438.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]2[CH3:39])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:34]1[N:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:40])[NH:22][C:9]4[CH:10]=[C:11]([C:14]#[C:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:37]=[C:36]([CH3:38])[N:35]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccccc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2cccc(C3=Nc4ccc(C#Cc5ccccc5)cc4NC(=O)C3)c2)c(C)n1

Procedure:
Prepared from (2-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example K60) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (57 mg). MS (EI) 430 (M+); mp 134° C. (dec.).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[C:34]([O-:37])(=[S:36])[CH3:35].[K+]>CN(C)C=O>[CH2:25]([C:23]1([OH:24])[C:13]2[CH:12]=[C:11]3[N:16]([C:15](=[O:19])[C:14]=2[CH2:20][O:21][C:22]1=[O:27])[CH2:17][C:18]1[C:6]([CH2:5][CH2:4][Si:3]([CH2:2][S:36][C:34](=[O:37])[CH3:35])([CH3:33])[CH3:32])=[C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]2=[N:9][C:10]3=1)[CH3:26]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CSC(C)=O
Temperature: 70 °C
Yield: 74 %

Procedure:
A mixture of Compound 3 (300 mg) and potassium thioacetate (400 mg) in N,N-dimethylformamide (2 mL) was heated at 70° C. under argon for 16 hours. The N,N-dimethylformamide was removed under vacuum and the resulting residue was directly eluted on a silica gel using 1% ethanol in dichloromethane to obtain the required product in 74% yield (240 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@:3]([C:9]1[S:13][C:12]([S:14][C:15]2[CH:24]=[C:23]3[C:18]([C:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:20][C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)=[N:11][CH:10]=1)([OH:8])[CH2:4][C:5]([OH:7])=[O:6].[N+](=[CH2:37])=[N-]>C1COCC1>[F:34][C:2]([F:1])([F:33])[C@:3]([C:9]1[S:13][C:12]([S:14][C:15]2[CH:24]=[C:23]3[C:18]([C:19]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)=[CH:20][C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)=[N:11][CH:10]=1)([OH:8])[CH2:4][C:5]([O:7][CH3:37])=[O:6]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C[C@](O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)C[C@](O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F

Procedure:
To a solution of (3R)-4,4,4-trifluoro-3-(2-{[4-(4-fluorophenyl)-2-oxo-2H-chromen-7-yl]thio}-1,3-thiazol-5-yl)-3-hydroxybutanoic acid (see example 12, step 4b) (0.140 g, 0.27 mmol) in THF was added an ethereal solution of diazomethane until the evolution of gas was finished. The solvent was removed to yield 0.120 g of the crude title compound. 1H NMR (400 MHz, acetone-d6): δ 7.96 (s, 1H), 7.77 (m, 2H), 7.58 (m, 2H), 7.48 (d, 1H), 7.39 (t, 2H), 6.53, (s, 1H), 6.42 (s, 1H), 3.63 (s, 3H), 3.40 (d, 1H), 3.25 (d, 1H).
Reaction SMILES: [I:1][C:2]1[S:10][C:9]2[C:8]([C:11]#[N:12])=[CH:7][NH:6][C:5](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:5]1[C:4]2[CH:3]=[C:2]([I:1])[S:10][C:9]=2[C:8]([C:11]#[N:12])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c[nH]c(=O)c2cc(I)sc12
Product: N#Cc1cnc(Cl)c2cc(I)sc12

Procedure:
To 2-iodo-4-oxo-4,5-dihydro-thieno[3,2-c]pyridine-7-carbonitrile 25 (7.75 g, 25.6 mmol) was added POCl3 (90 mL). The reaction was stirred under reflux overnight. POCl3 was removed by rotary evaporation followed by suspension of solids in H2O (500 mL) and filtration. The solids were washed with copious amounts of H2O, saturated bicarbonate solution, and washed further with H2O to provide upon drying 7.52 g of 26. 1H NMR (400 MHz, d6-DMSO) δ 8.82 (s, 1H), 8.06 (s, 1H).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C1C=CC([C:20]#[C:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[S:28][CH:27]([CH3:32])[CH2:26][C:25]3([CH3:34])[CH3:33])=CC=1)C.[OH-].[K+]>>[CH3:32][CH:27]1[CH2:26][C:25]([CH3:34])([CH3:33])[C:24]2[C:29](=[CH:30][CH:31]=[C:22]([C:21]3[CH:4]=[CH:3][C:2]([C:1]([OH:9])=[O:8])=[C:7]([C:6]#[CH:5])[CH:20]=3)[CH:23]=2)[S:28]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)S3)cc1
Reactant: O=C([O-])c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: C#Cc1cc(-c2ccc3c(c2)C(C)(C)CC(C)S3)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 37 mg (0.102 mmol) of ethyl 4(2,4,4-trimethyl-6-thiochromanyl)-ethynyl]benzoate (Compound 56) and 11 ml of ethanolic potassium hydroxide solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was taken up with water and then acidified with IN HCl. The mixture was extracted with three portions of ether. The organic extracts were combined and then washed with water and saturated NaCl solution and dried (MgSO4). The solvent was removed in-vacuo to give the title compound as an orange solid PMR (CDCl3): 1.17 (3H, s), 1.26 (3H, d, J=6.3 Hz), 1.34 (3H, s), 1.58 (1H, t, J=13.1 Hz), 1.92 (1H, dd, J=13.1 Hz, 2.4 Hz), 3.33-3.48 (1H, m), 7.20 (1H, d, J=8.1 Hz), 7.21 (1H, s), 7.45 (1H, d, J=8.1 Hz), 7.62 (2H, d, 8.4 Hz), 7.95 (2H, d, J=8.4 Hz).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](OCC)=[O:12].[O-]CC.[Na+]>C1COCC1.O>[OH:12]/[CH:11]=[C:7](/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)\[C:8]([CH3:9])=[O:10]
Reactant: CC(=O)Cc1ccccc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)/C(=C\O)c1ccccc1

Procedure:
Phenylacetone (Aldrich Chem. Co. 13,538-0; Beilstein 7, 303), XXVIa (101 g, 0.75 mol) was combined with 100 g (1.35 mol) of ethyl formate and added all at once to a suspension of 50 g (0.75 mol) of sodium ethoxide in 500 ml of THF. After 3 hours at room temperature the brown solution was diluted with 400 ml of H2O. Following extraction with benzene to remove unreacted starting material, the aqueous phase was acidified with dilute HCl. The product was extracted with benzene, washed with H2O, dried over MgSO4, and concentrated to give an oil. Distillation gave 39 g (0.24 mol) of (Z)-1-hydroxymethylene-1-phenylacetone, XXVIIa, as a colorless oil, bp 65°-69° C (0.3 mm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:32]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:16]2[CH2:17][CH2:18][C@H:19]([N:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH3:32])[CH2:20][CH2:21]2)[CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (3 g, 6.41 mmol, see, e.g., WO2012142504) in THF (30 mL), NaH (0.184 g, 7.69 mmol) was added at 0° C. and stirred it at same temperature for 20 min. Then methyl iodide (9.10 g, 64.10 mmol) was added at 0° C. and reaction was stirred for overnight at room temperature. On completion, reaction was quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the crude title compound that was used without further purification (3 g, 97.4% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]4)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Product: CS(=O)(=O)N1CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cncc(F)c4)nc23)CC1
Yield: 100 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and 1-(methylsulfonyl)piperidin-4-amine to yield the title compound as a white solid (44 mg, 100% yield). MS (apci) m/z=488.1 (M+H).
Reaction SMILES: C(Cl)Cl.CCCCCCCCCCCCCCC[C:19]1[C:24](=[O:25])[N:23]([CH3:26])[C:21](=[O:22])[C:20]=1[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1.[C:37](Cl)(=[O:44])C1C=CC=CC=1.[OH-].[Na+]>O>[CH3:36][N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:20]2[C:21](=[O:22])[N:23]([CH3:26])[C:24](=[O:25])[C:19]=2[O:44][CH3:37])=[CH:28]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCC1=C(c2cn(C)c3ccccc23)C(=O)N(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC1=C(c2cn(C)c3ccccc23)C(=O)N(C)C1=O
Reaction time: 4 h
Yield: 15.5 %

Procedure:
Into a methylene chloride (500 ml)/a triethylamine (11 g, 1.1 mol) was dissolved IM-7 (124.6 g, 1 mol). Benzoyl chloride (140.6 g, 1 mol) was added dropwise at room temperature. After the mixture was stirred for four hours, water (100 ml) and an aqueous 5% NaOH solution (50 ml) were added, then, the mixture was separated. After a methylene chloride layer was dried with magnesium sulfate, it was concentrated, then, distillated under a reduced pressure (150 to 160° C., 6 mmHg) to obtain 42 g of IM-8.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:18][CH3:19])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:2]
Reactant: Cc1cc(C=O)ccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C=O)cc1C
Temperature: 80 °C
Yield: 80 %

Procedure:
To a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol) in ethyl alcohol (EtOH; 30 mL) was added sulfuric acid (H2SO4, x M; 2 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10].Br[CH2:16][CH2:17][OH:18]>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:11]=[C:8]([CH:7]=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH2:16][CH2:17][OH:18])[CH:9]=[O:10]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(Cl)c1OCCO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.8 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.24 g, 6.00 mmol) in DMF (8 mL) was added a solution of 5-chlorovanillin (0.746 g, 4.00 mmol) in DMF (2 mL). The reaction mixture was stirred at RT for 20 minutes and 2-bromoethanol (0.42 mL, 5.93 mmol) added. The reaction mixture was heated at 50° C. for 90 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine (×2), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0-50% ethyl acetate in iso-hexane to afford the title compound (0.413 g, 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([N:18]1[CH2:22][CH2:21][CH:20](O)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O>C1COCC1>[CH2:11]([N:18]1[CH2:22][CH2:21][CH:20]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)C2)cc1
Reaction time: 0.75 h
Yield: 86 %

Procedure:
A chilled solution of 4-nitrophenol (3.9 g, 28 mmol) and 1-benzyl-3-pyrrolidinol (7.5 g, 42 mmol) in THF was treated with diisopropyl azodicarboxylate (8.3 mL, 42 mmol), stirred at ambient temperatures, under nitrogen, for 45 minutes, poured into excess water and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was twice purified by flash chromatography with 40% ethyl acetate in hexane to give 1-benzyl-3-(4-nitro-phenoxy)-pyrrolidine as a dark yellow gum, 7.2 g (86% yield), Mass spectrum (+APPI, [M+H]+) m/z 299. 1HNMR (500 MHz, DMSO-d6): δ8.11-8.15 (m, 2H), 7.23-7.29 (m, 4H), 7.17-7.21 (m, 1H), 7.02-7.07 (m, 2H), 4.97-5.02 (m, 1H), 3.56 (s, 1H), 2.80-2.84 (m, 1H), 2.61-2.71 (m, 2H), 2.28-2.41 (m, 2H), 1.73-1.79 ppm (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=1>N1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:30]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:31])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg, 0.47 mmol) in pyridine (2 mL) was added pyridine-3-sulfonyl chloride (100 mg) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by HPLC to give pyridine-3-sulfonic acid [2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 462.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][CH3:12])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][CH3:12])[N:7]=[C:8]([NH:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH:9]=1)=[O:4]
Reactant: CCn1nc(N)cc1C(=O)OC
Reactant: O=Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(=O)OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 5-amino-2-ethyl-2H-pyrazole-3-carboxylic acid methyl ester (527, 1.00 g, 5.91 mmol) in acetonitrile (27.5 mL) were added 4-fluorobenzaldehyde (528, 0.660 mL, 6.26 mmol), triethylsilane (4.77 mL, 0.0298 mol) and trifluoroacetic acid (2.38 mL, 0.0310 mol). The reaction was stirred at 80° C. for 4 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (529, 1.00 g, 61%).
Reaction SMILES: CCC/C=C/C=[CH:7]/[C:8]([O:10][C@@H:11]1[C@@:49]2([OH:51])[O:50][C@H:19]([CH2:20][CH:21]([C@H:62]([OH:64])[CH3:63])[O:22][C:23]([CH2:25][C@H:26]([OH:61])[CH2:27][C@H:28]3[O:33][C@@:32]([OH:54])([CH2:34][C@H:35]4[O:45][C@@H:44]([CH:46]=[CH:47][C:48]2([CH3:53])[CH3:52])[CH2:43]/[C:37](=[CH:38]\[C:39]([O:41][CH3:42])=[O:40])/[CH2:36]4)[C:31]([CH3:56])([CH3:55])[C@@H:30]([O:57][C:58]([CH3:60])=[O:59])[CH2:29]3)=[O:24])[CH2:18]/[C:12]/1=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[O:9].[CH3:65][CH2:66][CH2:67]CCC.CC(C)=O>C(OCC)(=O)C>[CH3:63][C@@H:62]([OH:64])[C@@H:21]1[O:22][C:23](=[O:24])[CH2:25][C@H:26]([OH:61])[CH2:27][C@H:28]2[O:33][C@:32]([OH:54])([C:31]([CH3:55])([CH3:56])[C@@H:30]([O:57][C:58]([CH2:60][CH:66]([CH3:67])[CH3:65])=[O:59])[CH2:29]2)[CH2:34][C@H:35]2[O:45][C@H:44]([CH2:43]/[C:37](/[CH2:36]2)=[CH:38]\[C:39]([O:41][CH3:42])=[O:40])[CH:46]=[CH:47][C:48]([CH3:52])([CH3:53])[C@:49]2([OH:51])[O:50][C@H:19]([CH2:18]/[C:12](/[C@@H:11]2[O:10][C:8]([CH3:7])=[O:9])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])[CH2:20]1
Reactant: CCC/C=C/C=C/C(=O)O[C@H]1/C(=C/C(=O)OC)C[C@H]2CC([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H]3C[C@H](OC(C)=O)C(C)(C)[C@](O)(C[C@@H]4C/C(=C/C(=O)OC)C[C@H](C=CC(C)(C)[C@]1(O)O2)O4)O3
Reactant: CCCCCC
Agent: CCC/C=C/C=C/C(=O)O[C@H]1/C(=C/C(=O)OC)C[C@H]2CC([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H]3C[C@H](OC(C)=O)C(C)(C)[C@](O)(C[C@@H]4C/C(=C/C(=O)OC)C[C@H](/C=C/C(C)(C)[C@]1(O)O2)O4)O3
Agent: COC(=O)/C=C1/C[C@H]2C[C@]3(O)O[C@H](C[C@@H](O)CC(=O)O[C@@H]([C@@H](C)O)C[C@H]4C/C(=C\C(=O)OC)[C@H](OC(C)=O)[C@@](O)(O4)C(C)(C)/C=C/[C@@H](C1)O2)C[C@H](OC(=O)CC(C)C)C3(C)C
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C1/C[C@H]2C[C@]3(O)O[C@H](C[C@@H](O)CC(=O)O[C@@H]([C@@H](C)O)C[C@H]4C/C(=C\C(=O)OC)[C@H](OC(C)=O)[C@@](O)(O4)C(C)(C)C=C[C@@H](C1)O2)C[C@H](OC(=O)CC(C)C)C3(C)C

Procedure:
From a succession of silica gel column chromatographies and gel permeation (Sephadex LH-20) chromatography, an active fraction (0.38 g) was isolated as a white amorphous powder with PS ED50 =1.6×10-3 μg/ml and which contained bryostatins 4-7 by TLC (7:3 n-hexane:acetone and 2:3 n-hexane:ethyl acetate). By using dry column (2×60 cm) silica gel chromatographic methods with n-hexane:acetone (5:1→1:1) and n-hexane:ethyl acetate (2:1→1:2), six fractions were selected for further purification. The first fraction contained bryostatin 4. The second, third and fifth fractions were subjected to HPLC using Partisil-10M-9-ODS-2 (C-18 reversed phase) with a 1:1→9:1 methanol:water gradient (flow rate of 2 ml/min). The second fraction (15 mg) yielded pure bryostatin 5 (14.1 mg), melting at 169°-172° C. (needles from CH2Cl2 --CH3OH); FAB MS m/z 866 for C44H66O17 :[α]27D+106.92 (c=0.028, CH3OH); uv (CH3OH) λmax 226 nm (ε 36,300); and ir (KBr) 3465, 2980-2935, 1740, 1725, 1660-1640, 1440, 1385, 1370, 1290, 1230, 1165, 1100, 1080, 1060, and 1000 cm-1.