Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:19])[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[N-:20]=[N+:21]=[N-:22].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[N:20]([CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:19])[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3)=[N+:21]=[N-:22]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(CBr)O3
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(CN=[N+]=[N-])O3
Temperature: 150 °C
Reaction time: 3 h

Procedure:
The compound obtained in Example 295 (1.49 g, 4.62 mmol) was dissolved in dimethyformamide (20 ml). Sodium azide (1.8 g, 27.69 mmol) was added to the mixture, and stirred at 150° C. for 3 hours. After cooling, ethyl acetate and water were added to the mixture for phase separation. The organic phase was washed with water and saturated aqueous NaCl solution in this order, and dried. The solvent was distilled off under reduced pressure to obtain 1.43 g (assayed quantitatively) of the title compound as crude crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH3:19])[C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])=[O:8])=[O:4].C[SiH](C)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH3:19])[C@@H:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[OH:8])=[O:4]
Reactant: COC(=O)N[C@@H](C)C(=O)c1cc(OC)ccc1OC
Agent: C[SiH](C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@@H](C)[C@H](O)c1cc(OC)ccc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a stirred solution of ketone i.e. (S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanone (20 g, 74.9 mmol) and dimethylphenyl silane (10.7 g, 78.6 mmol) in dry DCM (500 cm3) at 0° C. in an ice bath was added dropwise trithioroacetic acid (TFA) (50 cm3). The solution was stirred at 0° C. for 1 h and then quenched by the addition of sodium hydroxide (500 cm3, 1N). The organic layer was dried and concentrated under reduced pressure to give a yellow oil which solidified on standing. This solid was crystallized from ether/hexane to give the product as a white crystalline solid (15.6 g, 75%). 1H NMR (250 MHz; C2HCl3) 1.03 (3H, d, J7.0, CH3), 3.04 (1H, d, J4.3, OH), 3.68 (3H, s, COCH3), 3.78 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.94-3.99 (1H, m, H-2), 5.05-5.15 (2H, m, H-1 and NH), 6.72-6.85 (2H, m, ArH) 6.97 (1H, d, J 2.0, ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[CH:8]=1)([O-])=O.[BH4-].[Na+].O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[CH2:17][CH2:18]2)[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
10.2 g (43.2 mmol) of nickel II chloride hexahydrate are added to a solution of 7.2 g (21 mmol) of 4nitro-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, Example no. 7, in 60 ml of ethanol, with vigorous stirring. The mixture is cooled in an ice bath and 10.2 g (81 mmol) of sodium borohydride are added slowly. The mixture is left stirring for 1 hour and, after 1 hour at room temperature, water is added, the mixture is evaporated under vacuum, the residue is acidified with concentrated hydrochloric acid and the mixture is filtered, alkalinised with ammonia solution and extracted with ethyl ether. 4.4 g of 4-amino-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are thereby obtained in liquid form.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:21])(/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][OH:10].C([O-])(O)=O.[Na+]>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:7][C:8]([CH3:21])(/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[O:10]
Reactant: CCCCC/C=C\C/C=C\C(C)(C)CO
Agent: [Cr+6]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\C(C)(C)C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.7 %

Procedure:
To a cooled solution of 2.25 g (27 mmoles) of pyridine in 30 ml of dichloromethane was added 1.38 g (13.8 mmoles) of chromium trioxide in portions. A solution of 0.345 g (1.65 mmoles) of (Z,Z)-2,2-dimethyl-3,6-dodecadien-1-ol in 5 ml of dichloromethane was slowly added to the stirred suspension at room temperature. After stirring at room temperature for 12 hours, the mixture was poured into 10% aqueous NaHCO3 solution and the product was extracted with ether. The ether extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with 9:1 hexane-ether afforded 0.195 g (57%) of (Z,Z)-2,2-dimethyl-3,6-dodecadienal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37]C1C=CC=C2C=1OC(C1C=CC=CC=1)=C(I)C2=O>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([Br:37])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(Br)cccc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Yield: 67 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-bromo-3-iodo-2-phenyl-chromen-4-one was reacted to give the title compound (73 mg, 67%). 1H NMR (400 MHz, CDCl3): δ 8.24 (dd, J=7.9 and 1.6 Hz, 1H), 7.94 (dd, J=7.7 and 1.5 Hz, 1H), 7.50 (d, J=7.0 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.36-7.19 (m, 6H), 5.06 (s, 1H), 2.60-2.47 (m, 4H), 2.14-2.01 (m, 1H), 1.91-1.77 (m, 1H), 1.37 (bs, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:15]O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C(O)Cc1cccs1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccs1
Temperature: 25 °C
Yield: 91 %

Procedure:
Thiophene acetic acid (27.3 g, 192 mmol) was treated with a solution of H2SO4 (5.76 mL, 108 mmol) in MeOH (384 mL) at reflux for one hour. The reaction was then cooled to room temperature, concentrated by rotovap, diluted with ether, washed with 5% sodium bicarbonate and brine. The organic phase was then dried with magnesium sulfate and concentrated by rotovap to yield the product as a yellow oil (27.4 g, 176 mmol, 91%), which was used without further purification. The product matches data for commercially available methyl 2-(thiophen-2-yl)acetate (CAS No. 19432-68-9).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH2:22][CH2:23][OH:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@@H:10]([CH2:21][CH2:22][CH2:23][O:24][CH3:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CCCO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Yield: 81.9 %

Procedure:
The title compound was prepared according to the procedure described in Example 7, Step C, except using 4-benzyl-1-tert-butoxycarbonyl-2(S)-(3-hydroxy-1-propyl)piperazine (1.02 g, 3.05 mmol), sodium hydride (0.183 g, 60% dispersion in oil, 4.58 mmol), and methyl iodide (0.247 mL, 3.97 mmol) in DMF (6 mL). The crude product was chromatographed on silica gel with 30% ethyl acetate in hexane to obtain the title compound as a clear oil (0.870 g). NMR (CDCl3, 300 MHz) δ 7.3 (5H, m), 4.05 (1H, m), 3.85 (1H, m), 3.46 (2H, AB q, J=12 Hz, D n=42 Hz), 3.39 (1H, m), 3.22 (3H, s), 3.04 (1H, t, J=13 Hz), 2.74 (1H, d, J=12 Hz), 2.66 (1H, d, J=12 Hz), 1.45-2.12 (7H, m), 1.44 (9H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]2[S:8][C:9]3([S:23][C:6]=2[CH:5]=1)[CH2:14][CH2:13][N:12](C(=O)C1C=CC=CC=1)[CH2:11][CH2:10]3)([O-:3])=[O:2].[OH-].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]2[S:8][C:9]3([S:23][C:6]=2[CH:5]=1)[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)N1CCC2(CC1)Sc1ccc([N+](=O)[O-])cc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)SC1(CCNCC1)S2
Temperature: 70 °C

Procedure:
1.20 grams of the nitro dithioacetal from Step B in 46 mL of ethanol was treated with 18 mL of 40% aqueous NaOH and heated to 70° C. for 8 hours. The solution was diluted with water and extracted with CH2Cl2. The organics were combined, washed with water, saturated aqueous sodium carbonate, brine, dried (Na2SO4) and concentrated to an oil. The oil was filtered through silica gel eluting with 10% CH3OH in CH2Cl2 to give the product as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: Cl
Product: CCOC(=O)[C@@H](NCc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(C)C
Yield: 97 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and (S)-ethyl 2-amino-3-methylbutanoate hydrochloride. Yield 97%, colorless liquid. MS 352 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[S:31]([NH:34]C(=O)OC(C)(C)C)(=[O:33])=[O:32])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[N:3]=1.Cl>O1CCOCC1>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[S:31]([NH2:34])(=[O:33])=[O:32])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(N)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
A mixture of crude tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonyl carbamate 1c and 4N HCl in dioxane (3 mL) was stirred at RT for 2 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried and concentrated and the residue was purified by prep. HPLC (Method Y) to provide 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide 1 as a white solid (45 mg, 16% yield). 1H NMR (300 MHz, DMSO) δ 8.05 (m, 1H), 7.63 (m, 3H), 7.39-7.15 (m, 9H), 5.61 (m, 2H), 4.60 (m, 1H), 4.38 (m, 1H), 3.43-3.04 (m, 5H), 2.54 (s, 3H), 2.35-2.17 (m, 4H), 2.13-1.40 (m, 12H). ES-LCMS m/z 612.25 (M+H). Analytical HPLC (Method W) Rt 7.59 (95.89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH:21]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1)(=[O:25])=[O:24])=[CH2:22]>C(Cl)Cl.N1C=CC=CC=1>[CH:21]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:33])=[O:34])[CH:31]=1)(=[O:24])=[O:25])=[CH2:22]
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (10 mmol, prepared as in Example 1) in DCM (20 mL) and pyridine (20 mL), 5-ethenesulfonyl-2-methoxybenzenesulfonyl chloride (11 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (100 mL). The organic phase was washed with 10% aqueous HCl (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain benzo[b]thiophene-2-sulfonic acid [2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl] amide (2.8 g). LC: Tr 1.15 min; MS: 565.9 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.17 (s, 3H), 6.03 (d, 1H), 6.42 (d, 1H), 6.56 (dd, 1H), 6.81 (dd, 1H), 6.97 (t, 1H), 7.13 (t, 1H), 7.18 (d, 1H), 7.32 (d, 1H), 7.42-7.52 (m, 2H), 7.62 (s, 1H), 7.80 (d, 1H), 7.83 (d, 1H), 8.04 (dd, 1H), 8.19 (d, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[C:10]1([NH:16][C:17]([NH2:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[OH:5][C:4]([CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:19][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18])=[O:6]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(=O)Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCC(C(=O)O)C(F)(F)F)Nc1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and phenylurea (776 mg; 5.7 mmoles) in DMF (5 ml) was heated at 90° C. with stirring for 8 hours. DMF was evaporated under reduced pressure, and the residue was purified by a column chromatography on silica gel (ethyl acetate) to give 1.09 g (yield: 79%) of 1-(2-hydroxycarbonyl-3,3,3-trifluoropropyl)-3-phenylurea. m.p.: 180.5°-181° C.
Reaction SMILES: CC[C@@H]1OC(=O)C[C@@H]2C(=C[C@@H]3[C@H]2C=C[C@H]2[C@H]3C[C@H](O[C@@H]3O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]3OC)C2)C(=O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](N(C)C)CC2)CCC1.[CH3:52][CH2:53][C@@H:54]1[O:77][C:75](=[O:76])[CH2:74][C@@H:73]2[C:62](=[CH:63][C@@H:64]3[C@@H:72]2[CH:71]=[C:70]([CH3:78])[C@@H:69]2[C@@H:65]3[CH2:66][C@@H:67]([O:79][C@@H:80]3[O:85][C@@H:84]([CH3:86])[C@H:83]([O:87][CH3:88])[C@@H:82]([OH:89])[C@H:81]3[O:90][CH3:91])[CH2:68]2)[C:60](=[O:61])[C@H:59]([CH3:92])[C@@H:58]([O:93][C@@H:94]2[O:99][C@H:98]([CH3:100])[C@@H:97]([N:101](C)[CH3:102])[CH2:96][CH2:95]2)[CH2:57][CH2:56][CH2:55]1.CC[C@@H]1OC(=O)C[C@@H]2C(=C[C@@H]3[C@H]2C=C[C@H]2[C@H]3C[C@H](O[C@@H]3O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]3OC)C2)C(=O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](NC)CC2)CCC1>>[CH3:52][CH2:53][C@@H:54]1[O:77][C:75](=[O:76])[CH2:74][C@@H:73]2[C:62](=[CH:63][C@@H:64]3[C@H:72]2[CH:71]=[C:70]([CH3:78])[C@H:69]2[C@H:65]3[CH2:66][C@@H:67]([O:79][C@@H:80]3[O:85][C@@H:84]([CH3:86])[C@H:83]([O:87][CH3:88])[C@@H:82]([OH:89])[C@H:81]3[O:90][CH3:91])[CH2:68]2)[C:60](=[O:61])[C@H:59]([CH3:92])[C@@H:58]([O:93][C@@H:94]2[O:99][C@H:98]([CH3:100])[C@@H:97]([NH:101][CH3:102])[CH2:96][CH2:95]2)[CH2:57][CH2:56][CH2:55]1
Reactant: CC[C@H]1CCC[C@H](O[C@H]2CC[C@H](N(C)C)[C@@H](C)O2)[C@@H](C)C(=O)C2=C[C@@H]3[C@H](C=C(C)[C@H]4C[C@H](O[C@@H]5O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]5OC)C[C@H]34)[C@@H]2CC(=O)O1
Agent: CC[C@H]1CCC[C@H](O[C@H]2CC[C@H](N(C)C)[C@@H](C)O2)[C@@H](C)C(=O)C2=C[C@@H]3[C@@H](C=C[C@@H]4C[C@@H](O[C@@H]5O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]5OC)C[C@@H]34)[C@@H]2CC(=O)O1
Agent: CC[C@H]1CCC[C@H](O[C@H]2CC[C@H](NC)[C@@H](C)O2)[C@@H](C)C(=O)C2=C[C@@H]3[C@@H](C=C[C@@H]4C[C@@H](O[C@@H]5O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]5OC)C[C@@H]34)[C@@H]2CC(=O)O1
Product: CC[C@H]1CCC[C@H](O[C@H]2CC[C@H](NC)[C@@H](C)O2)[C@@H](C)C(=O)C2=C[C@@H]3[C@@H](C=C(C)[C@@H]4C[C@H](O[C@@H]5O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]5OC)C[C@@H]34)[C@@H]2CC(=O)O1

Procedure:
The following tables illustrate the amount of Spinosyn J, Spinosyn L, Spinosyn M, and Spinosyn N that were produced by culture NRRL 18719
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C([O:29][B:30](OCC)[O:31]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:14][C:13]=1[B:30]([OH:31])[OH:29]
Reactant: COc1ccc(-c2ccncc2)cc1Br
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccncc2)cc1B(O)O
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium in hexane (1.7 mL of 2.5 M, 4.25 mmol) is added to a stirred solution of 4-(3-bromo-4-methoxyphenyl)pyridine (Example 1b; 1.06 g, 4 mmol) and triethylborate (0.62 g, 4.2 mmol) in dry tetrahydrofuran (20 mL) at −85° C. under an argon atmosphere. The mixture is stirred for 15 min at −80° C., then treated with a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give 2-methoxy-5-(pyridin-4-yl)phenylboronic acid as a beige crystalline solid, m.p. 194-200° C. and having the following physical characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:30]1[CH2:34][C@@H:33]([CH3:35])[C:32](=[O:36])[O:31]1)[CH2:10][C@@H:11]([CH:27]([CH3:29])[CH3:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1>>[OH:46][CH:43]1[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][NH:37][C:32](=[O:36])[C@H:33]([CH3:35])[CH2:34][C@H:30]([OH:31])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:10][C@@H:11]([CH:27]([CH3:29])[CH3:28])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:14]=2)[CH2:41][CH2:42]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C2C[C@@H](C)C(=O)O2)C(C)C)ccc1OC
Reactant: NCCN1CCC(O)CC1
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCN2CCC(O)CC2)C(C)C)ccc1OC

Procedure:
102 mg of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of N-(2-aminoethyl)-4-hydroxypiperidine are stirred for 2 hours at 80° C. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1). The title compound is obtained: Rf (dichloromethane/methanol=4:1)=0.16.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:7][CH2:6][CH2:5][C:4](Cl)([Cl:8])[C:3]1=[O:10].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:10]
Reactant: O=C1C(Cl)(Cl)CCCC1(Cl)Cl
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Product: Oc1c(Cl)cccc1Cl
Yield: 79.3 %

Procedure:
190 g (0.8 mol) of 2,2,6,6-tetrachlorocyclohexanone and 3 g (0.065 mol) of triphenylarsine were introduced into the reactor used in Example 1. The reaction mixture was heated at 150°-180° C., under stirring. Same was then treated as in Example 1 to yield 103.4 g of 2,6-dichlorophenol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[CH:34]=[CH:33][C:18]([CH2:19][NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([N:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([CH:12]2[CH2:14][CH2:13]2)=[CH:34][CH:33]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=1)=[O:6]
Reactant: FC(F)(F)c1cccc(CCNCc2ccc(C3CC3)cc2)c1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 53 mg of 2-amino-5-chloro-benzoic acid (0.33 mmol) and 105 mg (0.33 mmol) of (4-cyclopropyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 4.5 ml of DMF were added 171 mg of HBTU (0.45 mmol) and 0.1 ml (0.9 mmol) of 4-methyl-morpholine. After stirring the reaction mixture over night at RT it was diluted with 50 ml water and extracted with ethyl acetate. The combined organic phases were washed with 10% aqueous KHCO3 solution, 0.1M HCl solution and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The remaining oil was purified by column chromatography (silica gel; heptane/EtOAc 6:1) to give 127 mg (88%) of 2-amino-5-chloro-N-(4-cyclopropyl-benzyl)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide as a yellow oil. MS (ISP) 473 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:8]2[CH2:12][CH2:11][C@@H:10]([N:13]([C:21]3[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](=[O:38])[NH:30][O:31]C4CCCCO4)=[CH:23][N:22]=3)C(=O)OC(C)(C)C)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[ClH:47]>CO>[ClH:47].[ClH:47].[C:39]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:21]3[N:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29]([NH:30][OH:31])=[O:38])=[CH:25][CH:26]=3)[CH2:9]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CO
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(c3ccccc3)c3ccccc3)C2)nc1)NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl [(3R)-1-(diphenylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (94 mg) in methanol (2 mL) was added hydrogen chloride methanol reagent 10 (0.5 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 30 minutes. The solvent was evaporated to dryness and the residue was dissolved in the mixture of dioxane (3 ml) and methanol (1 ml). To this solution was added 4N-hydrogen chloride in dioxane (3 ml) and the mixture was stirred at ambient temperature for 3 hours. The solvent was evaporated to dryness and the residue was triturated with acetonitrile to give (2E)-3-(6-{[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (63 mg) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:8]Cl)=[N:4][CH:5]=[CH:6][N:7]=1.C[Si]([C:14]#[N:15])(C)C>C(#N)C>[Cl:1][C:2]1[C:3]([S:8][C:14]#[N:15])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: ClSc1nccnc1Cl
Solvent: CC#N
Product: N#CSc1nccnc1Cl
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.81 grams (0.01 mole) of 3-chloro-2-pyrazinesulfenyl chloride was dissolved in acetonitrile with stirring under nitrogen at 0° C. To the stirred solution, 0.99 gram (0.01 mole) of trimethylsilyl cyanide was added rapidly and the stirring continued for 18 hours. At the end of this period, the acetonitrile and residual trimethylsilyl cyanide were removed by blowing a stream of nitrogen over the reaction mixture and the desired product recovered as residue. The product was crystallized from ethanol to obtain a purified product, m.p. 70°-71° C., in an amount of 0.64 gram. The product had elemental analyses as follows.