Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([F:30])[CH:18]=1)=O)(C)(C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH2:15])=[CH:18][C:19]=1[F:30])=[O:29]
Reactant: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CN)cc1F
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Add 4N hydrogen chloride in dioxane (2.7 mL, 10.8 mmol) to a solution of N-(tert-butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamine (296 mg, 0.92 mmol) in dichloromethane (11 mL) and stir for 4 h. Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend the solid in saturated aqueous NaHCO3 and stir for 30 min. Extract twice with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as an oil (175 mg, 82%).
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]([C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21]OC[CH2:18]3)[C:12]=2[N:13]=1)[CH3:7])(=[O:4])=[O:3].O[C@H](C1NC(=O)C2C=NN(C3CCOCC3)C=2N=1)C>>[CH3:1][S:2]([O:5][C@H:6]([C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:18]3)[C:12]=2[N:13]=1)[CH3:7])(=[O:3])=[O:4]
Reactant: C[C@H](OS(C)(=O)=O)c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: C[C@H](O)c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Product: C[C@H](OS(C)(=O)=O)c1nc2c(cnn2C2CCC2)c(=O)[nH]1

Procedure:
Compound C18 was prepared according to the general procedure for the synthesis of C5 in Example 1, except that C17 was used in place of C4, and the chromatographic purification was carried out with 0.5% to 1% MeOH in chloroform, rather than 0% to 5% MeOH in dichloromethane, to provide C18 as a solid. Yield: 6.0 g, 19.2 mmol, 79%. LCMS m/z 311.4 (M−1). 1H NMR (400 MHz, CDCl3) 1.85 (d, J=6.6 Hz, 3H), 1.93 (m, 2H), 2.46 (m, 2H), 2.78 (m, 2H), 3.23 (s, 3H), 5.29 (m, 1H), 5.69 (q, J=6.6 Hz, 1H), 8.08 (s, 1H), 11.65 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.93, 20.39, 29.84, 38.75, 51.07, 74.91, 104.98, 134.71, 151.07, 155.61, 159.27.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].C[O:12][CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=O>>[OH:12][C:13]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:15]([CH2:16][O:18][CH3:19])[CH:14]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: N#Cc1ccnc(NN)c1
Product: COCc1cc(O)n(-c2cc(C#N)ccn2)n1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-methoxy-3-oxobutanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C11H10N4O2, 231; Found, 231.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:19])[CH:6]=1)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:19])[CH:6]=1)=[O:4])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)c(F)c1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A solution of 2-bromo-1-[4-(benzyloxy)-3-fluorophenyl]ethanone (J. Med. Chem. 1980, 23, 738-744) (1 g) in dry DMF (2.5 mL) was cooled to 15° C. and treated portionwise with sodium azide (220 mg). After complete addition the reaction mixture was stirred for a further 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water and the combined aqueous phase back extracted with EtOAc. The combined organic phase was washed with sat. NaHCO3(aq) three times and the combined washes back extracted with EtOAc. The combined organic phase was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with hexane-EtOAc (4:1 and 2:1) to give the title compound (810 mg). LCMS RT=3.61 min.
Reaction SMILES: [C:1]([CH2:4][CH2:5]C(OC1C2C(=CC=CC=2)C=CC=1)C(O)=O)(=[O:3])[NH2:2].N12CCCN=C1CCCCC2.[CH2:32]([O:34][C:35](=[O:53])[CH:36]([O:42][C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][CH:44]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:33].C(N)(=O)C=C.Cl>C(#N)C.O>[CH2:40]([O:39][C:37](=[O:38])[C:36]([CH2:5][CH2:4][C:1](=[O:3])[NH2:2])([O:42][C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][CH:44]=1)[C:35]([O:34][CH2:32][CH3:33])=[O:53])[CH3:41]
Reactant: CCOC(=O)C(Oc1cccc2ccccc12)C(=O)OCC
Reactant: NC(=O)CCC(Oc1cccc2ccccc12)C(=O)O
Agent: C=CC(N)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(CCC(N)=O)(Oc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Carbamoyl-2(R,S)-α-naphthoxybutyric acid: 1.49 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene are added to a solution of 3 g of α-naphthoxymalonic acid diethyl ester (Example 36a) and 0.71 g of acrylamide in 5 ml of acetonitrile and the whole is stirred at room temperature for 24 hours. 25 ml of water are added to the reaction mixture, which is adjusted to pH 2 with 2N hydrochloric acid and extracted with ether. The ethereal phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation, leaving (2-carbamoylethyl)-α-naphthoxymalonic acid diethyl ester.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].[ClH:13].[H][H]>CO.[Pd]>[ClH:13].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C#N)nc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)c1ccc(CN)nc1
Yield: 89 %

Procedure:
5-(Methylsulfonyl)pyridine-2-carbonitrile (2.15 g, 11.8 mmol) was dissolved in methanol (230 ml). 6M HCl. (1 ml) and 10% palladium on carbon (234 mg) were added and the mixture was stirred under an atmospheric pressure of hydrogen overnight. The catalyst was removed by filtration through celite and the solvent was evaporated, water was added and the solution was freeze-dried to afford the title compound as a yellow powder (2.34 g, 89%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1)(=[O:33])[CH3:32]
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Reactant: CC(=O)NC1CCNCC1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2cc(NC(=O)C3CC3c3ccccc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 0.612 mmol) and N-(piperidin-4-yl)acetamide (87 mg, 0.612 mmol) in NMP (2 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (40-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a pink solid (71 mg, 27%). 1H NMR (DMSO-d6) δ: 10.94 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.08-7.38 (m, 5H), 6.07 (s, 1H), 4.28 (br. s., 2H), 3.86 (br. s., 1H), 3.08-3.24 (m, 2H), 2.38-2.46 (m, 1H), 2.35 (s, 3H), 1.85-1.95 (m, 2H), 1.82 (s, 3H), 1.45-1.64 (m, 3H), 1.36-1.43 (m, 1H). ESI-MS: m/z 433.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([OH:20])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].O.C(=O)([O-])O.[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O:20][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3csc4cncn34)C[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3csc4cncn34)C[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 42.1 mg of (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylic acid 10 ml of water was added 1.3 ml of a 0.1 N aqueous sodium hydrogen carbonate solution, and the mixture was stirred at room temperature for 1 hour to form a solution, which was then lyophilized. The lyophilized product was dissolved in 1 ml of dry DMF, 0.034 ml of iodomethyl pivalate was added under the atmosphere of argon at −30° C., and the mixture was stirred for 1.5 hours during which the temperature was raised up to −10° C. The reaction mixture was diluted with 20 ml of ethyl acetate, and washed with semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 3 ml, The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=15:1) and on Sephadex LH-20 (chloroform:methanol=1:1) in this sequence to give 27.2 mg of the title compound.
Reaction SMILES: [C:1]([O:6][C:7](=O)[C:8](C)=C)(=[O:5])[C:2]([CH3:4])=[CH2:3].OC(=C)C([O-])=O>>[C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC(=O)C(=C)C
Agent: C=C(O)C(=O)[O-]
Product: C=C(C)C(=O)O
Product: C=C(C)C(=O)OCC

Procedure:
It is just as possible to use an excess of methacrylic anhydride, for example 20 mol %. In this case, after the reaction of the hydroxyacrylate (II) is as complete as possible, the excess methacrylic anhydride is destroyed by adding a low molecular weight alcohol such as methanol, ethanol, or isopropanol. This method is particularly recommended with longer-chained compounds (n=3-100). The excess methacrylic anhydride guarantees the most complete possible conversion of the hydroxy compound; the subsequent reaction of the methacrylic anhydride to give ethyl methacrylate and methacrylic acid, for example, ensures easier separation of these components with lower boiling points than methacrylic anhydride.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Cc1nc(-c2cc3cccc(O)c3o2)no1
Product: Cc1nc(-c2cc3cccc(OC[C@@H]4CO4)c3o2)no1
Yield: 90 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 3-(7-hydroxybenzo(b)furan-2-yl)-5-methyl-1,2,4-oxadiazole (1.5 g) and (S)-glycidyl nosylate (1.8 g), the title compound (1.7 g) was obtained as white crystals.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][C:16](O)=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:25][CH:26]([C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:29]=1[NH2:30])[CH3:27].N1C=CC=CC=1>ClCCl.CN(C)C=O>[CH3:37][CH:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:28]([CH:26]([CH3:27])[CH3:25])[C:29]=1[NH:30][C:16](=[O:17])[CH2:15][CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:36]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CC1c2ccccc2Oc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 51 mg (0.21 mmol) of 2-(9H-xanthen-9yl)acetic acid in 2 ml of dichloromethane were added 0.1 ml (1.1 mmol) of oxalyl chloride and one drop of N,N-dimethylformamide with ice-cooling, and the resulting mixture was stirred for 3 hours and freed from the solvent and an excess of the reagent by distillation under reduced pressure. The residue was again dissolved in 2 ml of dichloromethane, and 93 mg (0.53 mmol) of 2,6-bis(1-methylethyl)aniline and 0.2 ml of pyridine were added thereto with ice-cooling, followed by stirring at room temperature for 5 hours. After distilling off the solvent, the residue thus obtained was purified by column chromatography through 15 g of silica gel using a 30:0-1 mixture of dichloromethane and ethyl acetate as an eluent to give 78 mg (92%) of the desired compound as crystals.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[C:12]([O-:15])(O)=[O:13].[Na+].[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]C2C(=O)N(C([O-])=O)C=CC=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C1COCC1>[OH:11][C@@H:6]([C:7]([CH3:8])([CH3:10])[CH3:9])[C@@H:2]([NH:1][C:12]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])O
Reactant: O=C([O-])n1cccc(CCCCCc2ccccc2)c1=O
Reactant: CC(C)(C)[C@H](O)[C@@H](N)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 70.1 %

Procedure:
To a stirred diastereomeric mixture containing (2R*,3R*)- and (2R*,3S*)-2-amino-3-hydroxy-4,4-dimethyl-pentanoic acid (0.23 g, 1.38 mmol) and NaHCO3 (0.118 g, 1.4 mmol) in H2O (5.0 mL), at rt, the isomeric mixture containing 5-phenyl-pentyl-2-pyridyl-carbonate and 5-phenyl-pentyl-2-oxopyridine-1-carboxylate (0.57 g, 2.0 mmol) [prepared as for example 32, step 1] in THF (5.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.34 g, 70% over 2 steps), as a diastereoisomeric mixture (anti:syn=9:1), as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z: 352 [M−H]+; (ESI) m/z: 350 [M−H]−. 1H NMR (DMSO-d6) δ 0.87 (s, 9H), 1.27-1.41 (m, 2H), 1.57 (q, J=7.46 Hz, 4H), 2.57 (t, J=7.70 Hz, 2H), 3.36 (t, J=7.52 Hz, 2H, under water signal), 3.85-4.15 (m, 3H), 7.13-7.32 (m, 5H), 7.32 (d, J=8.56 Hz, 1H), 11.91 (s, 1H) (reported data refer to the major anti diastereoisomer).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH:8]=[CH2:9].[OH-].[K+].Cl>O.CO>[CH2:9]=[CH:8][CH2:7][CH2:6][CH:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=1)[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCCC(CCC=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCC(CCC=C)OCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reaction time: 5 h
Yield: 94.4 %

Procedure:
2.3 g of the compound (8) and 1.1 g of potassium hydroxide were dissolved in a solution mixture of 14 ml of water and 6 ml of methanol, and reflux was then carried out for 5 hours. The reaction solution was added into 100 ml of water, and the pH was adjusted approximately to 1 with concentrated hydrochloric acid. The waxen matter generated therein was washed with water and was then dried at 40° C. under reduced pressure, to obtain 2.1 g of the compound (9). (Yield: 93%)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[O:4][C:1](=[O:3])[CH3:2])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CC(C)(C)N
Product: CC(=O)Oc1ccccc1C(=O)NC(C)(C)C

Procedure:
Following the procedure of Example 1 above and using 2-acetoxybenzoyl chloride and tert-butylamine, the title compound was prepared.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC.O>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:44][CH2:45][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][S:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:47][CH2:48]2)=[CH:39][CH:38]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSCC12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc2N2CCSCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (Compound 86C; 100 mg, 0.36 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (86.1 mg, 56%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.44-10.83 (m, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.30-7.38 (m, 2H), 7.23-7.29 (m, 2H), 6.99 (d, J=2.0 Hz, 1H), 4.83-4.91 (m, 1H), 4.22-4.29 (m, 1H), 3.33 (s, 3H), 2.96-3.07 (m, 1H), 2.83-2.94 (m, 2H), 2.65-2.83 (m, 3H), 2.39-2.48 (m, 1H), 1.91-2.06 (m, 2H), 1.66-1.78 (m, 2H), 1.49-1.66 (m, 2H) [M+H] calc'd for C22H25ClN4OS, 429; found, 429.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH3+:16])[CH:5]=[C:6]([C:8](=[O:15])[NH:9][CH:10]([CH3:14])[CH2:11][O:12][CH3:13])[CH:7]=1.[N-:17]=[N+:18]=[N-:19].[Na+].[CH:21](OCC)(OCC)OCC>CC(O)=O>[I:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N:16]2[CH:21]=[N:19][N:18]=[N:17]2)[CH:3]=1)[C:8]([NH:9][CH:10]([CH3:14])[CH2:11][O:12][CH3:13])=[O:15]
Reactant: CCOC(OCC)OCC
Reactant: COCC(C)NC(=O)c1cc([NH3+])cc(I)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCC(C)NC(=O)c1cc(I)cc(-n2cnnn2)c1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a solution of 3-Iodo-5-(2-methoxy-1-methyl-ethylcarbamoyl)-phenyl-ammonium (7.47 g, 22.4 mmol) and NaN3 (2.68 g, 41.2 mmol) in AcOH (100 mL) was added HC(OEt)3 (18.3 mL, 110 mmol) at room temperature. The reaction mixture was brought to reflux for 4 hours, then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by silica-gel chromatography to give 3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-tetrazol-1-yl-benzamide as a white solid (6.30 g, 72%). MS (M+H)=388.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH3:23]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(O)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 8: 3-(3,4-difluorophenyl)pyrrolidin-3-ol (0.38 g, 1.9 mmol), acetonitrile (20 mL), sodium carbonate (0.26 g, 4.75 mmol), iodoethane (0.29 g, 1.9 mmol). Refluxed 2 h. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 35:65 to 50:50). Yield: 0.26 g. The amine was converted to the fumaric acid salt and recrystallized from 2-propanol/diisopropyl ester: M.p. 157-158° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 26), 212 (18), 141 (30), 127 (23), 113 (22), 71 (bp).
Reaction SMILES: [CH3:1][C@H:2]1[C:24](=[O:25])[C:23]2[C@H:12]([C@H:13]3[C@@H:21]([CH:22]=2)[C@H:20]2[C@@H:16]([CH2:17][C@@H:18]([O:26][C@@H:27]4[O:32][C@@H:31]([CH3:33])[C@H:30]([O:34][CH3:35])[C@@H:29]([O:36][CH3:37])[C@H:28]4[O:38][CH3:39])[CH2:19]2)[CH:15]=[CH:14]3)[CH2:11][C:9](=[O:10])[O:8][C@@H:7]([CH:40]2[CH2:43][CH2:42][CH2:41]2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:44][C@@H:45]1[O:50][C@H:49]([CH3:51])[C@@H:48]([N:52]([CH3:54])[CH3:53])[CH2:47][CH2:46]1>C1(C)C=CC=CC=1.C(O)C>[CH3:1][C@H:2]1[C:24](=[O:25])[C:23]2[C@H:12]([C@H:13]3[C@@H:21]([CH:22]=2)[C@H:20]2[C@@H:16]([CH2:17][C@@H:18]([O:26][C@@H:27]4[O:32][C@@H:31]([CH3:33])[C@H:30]([O:34][CH3:35])[C@@H:29]([O:36][CH3:37])[C@H:28]4[O:38][CH3:39])[CH2:19]2)[CH2:15][CH2:14]3)[CH2:11][C:9](=[O:10])[O:8][C@@H:7]([CH:40]2[CH2:43][CH2:42][CH2:41]2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:44][C@@H:45]1[O:50][C@H:49]([CH3:51])[C@@H:48]([N:52]([CH3:53])[CH3:54])[CH2:47][CH2:46]1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](O[C@H]2C[C@H]3[C@@H]4C=C5C(=O)[C@H](C)[C@@H](O[C@H]6CC[C@H](N(C)C)[C@@H](C)O6)CCC[C@H](C6CCC6)OC(=O)C[C@H]5[C@@H]4C=C[C@@H]3C2)[C@@H]1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](O[C@@H]2C[C@H]3CC[C@@H]4[C@@H](C=C5C(=O)[C@H](C)[C@@H](O[C@H]6CC[C@H](N(C)C)[C@@H](C)O6)CCC[C@H](C6CCC6)OC(=O)C[C@H]54)[C@@H]3C2)[C@@H]1OC
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A solution of 21-desethyl-21-cyclobutyl spinosyn A (3.1 mg, 0.004 mmol) in 2 mL of toluene and 0.5 mL of ethanol was purged with a slow stream of nitrogen for 20 minutes, then 2 mg of chlorotris(triphenylphosphine) rhodium was added and the solution hydrogenated at 60° C. and 1 atm. for 16 hours. After cooling and removal of solvent, the residue was chromatographer using a 10 cm×2 cm silica gel column, eluting with 5×25 mL fractions of dichloromethane containing 0%, 2%, 3%, 4%, and 5% MeOH respectively. The product-containing fractions were combined and concentrated to give 2.1 mg of 5,6-dihydro-21-desethyl-21-cyclobutyl spinosyn A. MS M+ 760.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH3:22][O:23][C:24]1[C:29]2[CH:30]([NH2:33])[CH2:31][O:32][C:28]=2[CH:27]=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[C:29]2[CH:30]([NH:33][C:20]3[O:8][CH2:9][C:10]4[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:11]=4[N:19]=3)[CH2:31][O:32][C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1c(N=C=S)cccc1[N+](=O)[O-]
Reactant: COc1cccc2c1C(N)CO2
Product: COc1cccc2c1C(NC1=Nc3cccc(N)c3CO1)CO2

Procedure:
The title compound, MS (ISP) m/e=312.0 [(M+H)+], was prepared from tert-butyl-(2-isothiocyanato-6-nitro-benzyloxy)-dimethyl-silane (intermediate 2) and 4-methoxy-2,3-dihydro-benzofuran-3-ylamine according to the procedure described for example 1 and 2.