Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:31](=[O:32])[N:4]2[C:5]([C:28]([OH:30])=[O:29])=[C:6]([CH2:9][O:10][C:11](=[O:27])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18](=[O:26])(=[O:25])[NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:7][S:8][C@H:3]12.ClCCl.CN(C)C=O.[N:41]1([CH2:46][C:47](Cl)=[O:48])[CH:45]=[N:44][N:43]=[N:42]1>O1CCCC1>[N:41]1([CH2:46][C:47]([NH:1][C@@H:2]2[C:31](=[O:32])[N:4]3[C:5]([C:28]([OH:30])=[O:29])=[C:6]([CH2:9][O:10][C:11](=[O:27])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[S:18](=[O:26])(=[O:25])[NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:7][S:8][C@H:3]23)=[O:48])[CH:45]=[N:44][N:43]=[N:42]1
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cn1cnnn1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1
Reaction time: 2 h
Yield: 38.5 %

Procedure:
7β-Amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (457 mg) is suspended in a mixed solution of dichloromethane (5 ml) and N,N-dimethylformamide (1.0 ml) and to the mixture, a solution of (1H-tetrazol-1-yl)acetyl chloride (161 mg) in tetrahydrofuran (2 ml) is added over a period of 20 minutes and stirred for 2 hours. The solvent is distilled off under reduced pressure and to the resultant viscous residue, ethyl acetate (50 ml) and water (20 ml) are added and stirred. After separation, the ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and concentrated. To the concentrate (5 ml), chloroform (50 ml) is added and the resultant precipitate is filtered off. The filtrate is concentrated and to the concentrate (5 ml), ether (50 ml) is added. The resultant precipitate is collected by filtration and dried over phosphorous pentoxide. The procedure provides 7β-(1H-tetrazol-1-yl)acetamido-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (216 mg).
Reaction SMILES: O1CCN([C:7](=S)[CH2:8][C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)CC1.[OH-:25].[K+].Cl.[OH2:28]>>[C:18]1([C:10]2[C:9]([CH2:8][C:7]([OH:28])=[O:25])=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O
Reactant: S=C(Cc1c(-c2ccccc2)nn2ccccc12)N1CCOCC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)Cc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 3-(2-morpholino-2-thioxoethyl)-2-phenylpyrazolo[1,5-a]pyridine (5.50 g), potassium hydroxide (85%, 6.45 g) and water (44 ml) was refluxed for 14 hours. After cooling, the reaction mixture was poured onto ice (110 g) and acidified with 6N-hydrochloric acid (pH ≈2) and the resulting precipitates were collected to give 2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acetic acid (4.20 g).
Reaction SMILES: CC1C=CC(N=C=O)=CC=1N=C=O.CC1C(N=C=O)=CC=CC=1N=C=O.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-])=O.[CH3:36][C:37]1([N:46]([C:70](N)=[O:71])[C:47](=[O:69])[N:48](C2(C)C=CC=CC2N=C=O)[C:49]2([CH3:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]2[N:55]=[C:56]=[O:57])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]1[N:43]=[C:44]=[O:45]>C1(C)C=CC=CC=1>[C:30]1([NH:27][C:70]([N:46]([C:37]2([CH3:36])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]2[N:43]=[C:44]=[O:45])[C:47]([NH:48][C:49]2([CH3:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]2[N:55]=[C:56]=[O:57])=[O:69])=[O:71])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC1(N(C(N)=O)C(=O)N(C2(C)C=CC=CC2N=C=O)C2(C)C=CC=CC2N=C=O)C=CC=CC1N=C=O
Reactant: O=[N+]([O-])c1ccccc1
Agent: Cc1c(N=C=O)cccc1N=C=O
Agent: Cc1ccc(N=C=O)cc1N=C=O
Solvent: Cc1ccccc1
Product: CC1(NC(=O)N(C(=O)Nc2ccccc2)C2(C)C=CC=CC2N=C=O)C=CC=CC1N=C=O

Procedure:
About 522 parts by weight of an isomeric mixture of about 80 parts of 2,4-toluene diisocyanate and 20 parts of 2,6-toluene diisocyanate, about 25 parts of nitrobenzene and about 600 parts by volume of toluene are treated and worked up as described in Example 1. A polyisocyanate mixture which consists substantially of 2 mols of tris-(1-methyl-2-isocyanatophenyl)biuret and 1 mol of N-phenyl-N',N"-bis-(1-methyl-2-isocyanatophenyl)biuret is obtained in a yield of about 480 parts; NCO content about 22.9%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.CC1C=C(C)N=C(S[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])N=1>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)=[O:29]
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
To a clear solution of L-hydroxyproline methyl ester hydrochloride (27.2 g, 0.15 mol) and triethylamine (50 ml, 0.36 mol) in chloroform (500 ml) was added 4,6-dimethyl-2-(4-nitrobenzyloxycarbonylthio)pyrimidine (40.7 g, 0.13 mol) and then the resulting solution was stirred at room temperature for 12 hours, sequentially washed with H2O (200 ml), 0.5N NaOH (400 ml) and brine (200 ml) and dried (MgSO4). Concentration followed by silicagel column chromatography (Wakogel® C-300, ethyl acetate) afforded (2S, 4R)-4-hydroxy-N-(4-nitrobenzyloxycarbonyl)proline methyl ester (34.5 g, 70.9% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.[NH3:17]>C(O)C>[CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([NH:8][C:9]([NH2:17])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N=C=S)c1N1CCOCC1
Reactant: N
Solvent: CCO
Product: Cc1cccc(NC(N)=S)c1N1CCOCC1

Procedure:
React on of 3-methyl-2-morpholinophenyl isothiocyanate (8 g) in ethanol (5 ml) with a saturated solution of ammonia in ethanol (60 ml) at room temperature for 4 hours gave 1-(3-methyl-2-morpholinophenyl)thiourea (m.p. 178°-179° C.).
Reaction SMILES: [C:1]([N:4]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[C:6]2([CH2:11][CH2:10]S[CH2:8][CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2].O[O:20][S:21]([O-:23])=O.[K+].[NH4+].[Cl-]>CO.O.CC(C)=O>[C:1]([N:4]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[C:6]2([CH2:7][CH2:8][S:21](=[O:23])(=[O:20])[CH2:10][CH2:11]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CC(=O)N1CC2(CCSCC2)c2ccc(Br)cc21
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)N1CC2(CCS(=O)(=O)CC2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred ice-cooled suspension of crude 1-acetyl-6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran] (0.68 g, 2.1 mmol) in MeOH (40 mL), H2O (5 mL) and acetone (10 mL) was added oxone (2.58 g, 4.20 mmol) in H2O (15 mL). The resulting mixture was stirred at rt for 20 h. After this time the mixture was poured into ice and saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 1-acetyl-6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro-[indole-3,4′-thiopyran]1′,1′-dioxide as a white solid. Mass Spectrum (ESI) m/e=358.0 [(M+1) (79Br)] and 360.0 [(M+1) (81Br)].
Reaction SMILES: [O:1]=[O+][O-].N#N.S(C)C.F[C:10](F)(F)[C:11]([O-:13])=[O:12].C([NH2+]C[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C1C=CC=CC=1>CO>[O:12]=[C:11]1[O:13][CH:30]2[CH2:25][C:27]([CH:26]=[O:1])=[CH:28][CH:29]2[CH2:10]1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=[O+][O-]
Reactant: c1ccc(C[NH2+]Cc2ccccc2)cc1
Agent: N#N
Solvent: CO
Solvent: CSC
Product: O=CC1=CC2CC(=O)OC2C1
Reaction time: 0.17 h

Procedure:
A solution of (±)-19 (250 mg, 1.81 mmol) in MeOH (2 ml) was cooled to −78° C. and a stream of ozone passed through until a blue colour persisted. N2 was then passed through the solution until the blue colour faded and excess ozone was removed. Me2S (1.12 g, 1.33 ml, 18.1 mmol) was added and stirring continued at −78° C. for 10 min before the cooling bath was removed and the reaction mixture stirred for 50 min. An N2 stream was then used to concentrate the reaction mixture. The residue was dissolved in THF (2 ml) and dibenzylammonium trifluoroacetate (113 mg, 0.36 mmol) added and the resulting solution stirred at room temperature for 22 h. An N2 stream was then used to concentrate the reaction mixture and the residue purified by column chromatography, eluting with 2:1 EtOAc:petrol, to afford the aldehyde (±)-20 (141 mg, 51%) as an orange oil. 1H NMR of this material showed it to be of sufficient purity for further reaction. A sample was re-columned to provide an analytical sample as a white solid.
Reaction SMILES: [C:1](=[S:3])=S.[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C>CC(C)=O.[Hg](Cl)Cl>[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[O:14][CH2:15][CH2:16][CH2:17][N:18]=[C:1]=[S:3])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: S=C=S
Agent: Cl[Hg]Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: S=C=NCCCOc1cccc(CN2CCCCC2)c1
Temperature: -14 °C

Procedure:
A solution of carbon disulphide (3.3 ml) in acetone (8 ml) was added dropwise to a solution of 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (12.4 g) in acetone (30 ml) over a 15 minute period, between -5° and -10° C. The solution was cooled to -14° C. and mercury (II) chloride (13.6 g) in acetone (30 ml) was added, during 45 minutes. Triethylamine (16 ml) was added at 0° C. during 15 minutes, and the mixture was heated at reflux for 45 minutes. The resulting suspension was purified by filtration and the filtrate evaporated in vacuo. The residue was purified by column chromatography using methanol as eluant to give the title compound (6 g) as an amber oil. TLC silica/cmethanol Rf 0.4.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[O:35][C:15]2([CH2:32][CH2:31][C:30]3[C:29]4[C@H:20]([C@H:21]5[C@@:25]([CH2:27][CH:28]=4)([CH3:26])[C@@H:24]([OH:33])[CH2:23][CH2:22]5)[C@@H:19]([CH3:34])[CH2:18][C:17]=3[CH2:16]2)[O:14][CH2:13]1>C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH2:13]1[O:14][C:15]2([CH2:32][CH2:31][C@:30]34[O:9][C@:17]3([CH2:18][C@H:19]([CH3:34])[C@@H:20]3[C:29]4=[CH:28][CH2:27][C@@:25]4([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]4[OH:33])[CH2:16]2)[O:35][CH2:12]1
Reactant: C[C@H]1CC2=C(CCC3(C2)OCCO3)C2=CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1C[C@@]23CC4(CC[C@@]2(O3)C2=CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21)OCCO4
Temperature: -35 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
11.6 g of solid sodium hydrogen carbonate and 15.8 g of m-chloroperbenzoic acid were added consecutively scoopwise at -35° C. to a cooled solution of 22 g of 17β-hydroxy-7β-methyloestr-5(10),9(11)-dien-3-one-3-ethyleneacetal in 350 ml of methylene dichloride. After being stirred for 1 hour at -35° C., the reaction mixture was diluted with a saturated sodium hydrogen carbonate solution followed by extraction with methylene dichloride. The organic layer was washed with 0.2M sulphite solution and with water until neutral, dried on sodium sulphate, filtered and evaporated to dryness in vacuo. After purification by chromatography through silica gel, 8.8 g of 5α,10α-epoxy-17β-hydroxy-7β-methyloestr-9(11)-en-3-one-3-ethyleneacetal were obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)ccc2c1=O
Reactant: C1CNCCN1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)ccc2c1=O

Procedure:
Analogously to Example C, 7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted with piperazine to give 1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 298° to 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCCCO
Product: O=S(=O)(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
Sodium 4-chlorobenzenesulfinate (306 mg, 1.54 mmol) and benzyl bromide (0.18 ml, 1.54 mmol) were added to n-butanol (15 ml). The resulting mixture was stirred at 70° C. for 5 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure. To the residue were added ethyl acetate. The resulting mixture was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, whereby from the fraction eluted with hexane:ethyl acetate (=8:1), the title compound (299 mg, 73%) was obtained as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][OH:32]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([CH3:27])[CH:29]=2)[CH:7]=1
Reactant: Cc1cccc(CO)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: Cc1cccc(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-methylbenzyl alcohol (99 mg; 0.789 mmol), example 83 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:9][CH2:8][N:7]2[C:10](=[O:23])[CH:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:12](=[O:13])[N:6]2[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][O:2][N:3]1[CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])=[C:10]([O:23][C:33](=[O:34])[C:32]([CH3:37])([CH3:36])[CH3:31])[N:7]2[CH2:8][CH2:9]1
Reactant: CON1CCN2C(=O)C(c3c(C)cc(C)cc3C)C(=O)N2CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON1CCn2c(OC(=O)C(C)(C)C)c(-c3c(C)cc(C)cc3C)c(=O)n2CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (162 mg, 0.51 mmol), triethylamine (0.107 ml, 78 mg, 0.77 mmol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (4 ml) at 0° C. was added 2,2-dimethyl-propionyl chloride (pivaloyl chloride, 0.082 ml, 80 mg, 0.67 mmol) dropwise. The suspension was stirred at 0° C. for 45 minutes, the solvent evaporated and the residue diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. Yield: 160 mg of 2,2-dimethyl-propionic acid 3-methoxy-9-oxo-8-(2,4,6-trimethyl-phenyl)-2,3,4,5-tetrahydro-1H,9H-pyrazolo[1,2-a][1,2,5]triazepin-7-yl ester (title compound P1.1) as an off-white solid, mp 147-148° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([N:20]2[CH:24]=[N:23][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.C(OCC)C.[NH3:37]>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([O:10][C:9]1[CH:8]=[C:7]([N:20]2[CH:24]=[N:23][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)[S:6][C:5]=1[C:3]([NH2:37])=[O:2])[CH3:12]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1OC(C)c1ccccc1Cl
Solvent: CO
Solvent: CCOCC
Product: CC(Oc1cc(-n2cnc(Nc3ccccc3)n2)sc1C(N)=O)c1ccccc1Cl
Temperature: 100 °C
Yield: 27 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(3-phenylamino-[1,2,4]triazol-1-yl)-thiophene-2-carboxylic acid methyl ester (66 mg, 0.15 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 100° C. in a pressure tube for 3 days. The solvent was removed in vacuo and the product isolated by column chromatography (10% MeOH/DCM) followed by tritruation from diethyl ether to give the title compound as an off-white solid (17 mg, 0.04 mmol, 27%); 1H NMR (400 MHz, d-6 DMSO) δ. 1.72 (3H, d), 5.88 (1H, q), 6.88 (1H, t), 7.03 (1H, br s), 7.26 (1H, s), 7.30 (2H, t), 7.36-7.43 (2H, m), 7.52 (1H, dd), 7.57 (2H, d), 7.66 (1H, dd), 7.75 (1H, br s), 9.02 (1H, br s), 9.65 (1H, s).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[OH:39])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:40])[C@@H:7]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[C@@H:45]([N:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH2:6][CH2:5][CH2:4]1.[P:52](Cl)([O:56]CC)[O:53][CH2:54][CH3:55].C1(C)C=CC=CC=1.CCOC(C)=O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:54]([O:53][P:52]([O-:56])[O:47][CH2:46][CH3:48])[CH3:55].[CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[OH:39])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:40])[C@@H:7]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[C@@H:45]([N:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOP(Cl)OCC
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](OC)[C@H]5O)C[C@@H]34)[C@@H]2CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOP([O-])OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound Spinosyn H (351 mg, 0.489 mmol) was dissolved in dry pyridine (5 ml). DMAP (62 mg, 0.51 mmol) was added and stirring at RT under nitrogen was continued for 5 min. Diethyl chlorophosphite (157 mg, 0.145 ml, 1.0 mmol) was added. After 30 min. toluene (50 ml) and EtOAc (50 ml) were added. The solution was washed successively with brine (2×) and 5% aq. NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was separated over a flash SiO2 column (100 g/EtOAc) to give compound 2'R)-(diethyl)phosphite of Spinosyn H; 306 mg, 75% CI MS m/z 838 (M+1); 1H-NMR (CDCl3) δ 6.69 (1H, bs), 4.40 (1H, m), 3.83 (4H, 2× CH2, m), 1.18 (6H, 2× CH3, m); Elemental Analysis: for C44H72NO12P calc. C 63.06, H 8.66, N 1.67 found: C 62.94, H 8.88, N 1.71.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].[Si:13]([O:20][CH2:21][C:22]([CH3:36])([CH3:35])[CH2:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH2:23][C:22]([CH3:35])([CH3:36])[CH2:21][O:20][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)=[O:11])=[CH:4][C:3]=1[F:12]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(NC(=O)Cc2ccc(Br)c(F)c2)cc1C(F)(F)F
Yield: 61.4 %

Procedure:
A solution of 2-(4-bromo-3-fluorophenyl)acetic acid (50 mg, 0.215 mmol), 4-(3-((tert-butyl dimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (78 mg, 0.215 mmol), DIEA (83 mg, 0.644 mmol), HOBt (49.3 mg, 0.322 mmol) and EDC hydrochloride (61.7 mg, 0.322 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=3/1) to yield 2-(4-bromo-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (80 mg, 0.132 mmol, 61.4% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.0 Hz, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.15 (dd, J=9.7, 1.8 Hz, 1H), 7.01 (d, J=6.8 Hz, 1H), 3.62 (s, 2H), 2.70 (s, 2H), 2.07 (s, 2H), 0.86 (s, 9H), 0.76-0.69 (m, 6H), 0.05-0.02 (m, 6H); ES-LCMS m/z 576.0 (M+H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]#[N:20])[CH:13]=2)[N:5]=1)=[O:3].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N=[C:31]=[N:32][CH:33]([CH3:35])[CH3:34])(C)C.Cl>CN(C=O)C>[C:19]([C:14]1[CH:13]=[C:12]([N:6]2[C:7]([C:9]([N:21]3[C:22]4[C:24](=[CH:23][CH:35]=[C:33]([N:32]5[CH2:31][CH2:9][CH2:7][CH2:8][CH2:4][C:2]5=[O:3])[CH:34]=4)[CH2:25][CH2:26]3)=[O:11])=[CH:8][C:4]([C:2]([NH2:1])=[O:3])=[N:5]2)[CH:17]=[CH:16][C:15]=1[F:18])#[N:20]
Reactant: c1ccncc1
Reactant: CC(C)N=C=NC(C)C
Reactant: N#Cc1cc(-n2nc(C(N)=O)cc2C(=O)O)ccc1F
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-n2nc(C(N)=O)cc2C(=O)N2CCc3ccc(N4CCCCCC4=O)cc32)ccc1F
Reaction time: 14 h
Yield: 29 %

Procedure:
Part D. To the product from Part C (90 mg, 0.39 mmol), was added 3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid (89 mg, 0.33 mmol), 3.0 mL of pyridine and 1.0 mL of DMF. 1,3-Diisopropylcarbodiimide (0.056 mL, 0.36 mmol) was added, and the resulting solution was stirred for 14 h. The red mixture was poured into 1N aqueous HCl (70 mL) and washed with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. Concentration of the filtrate and purification of the resulting residue by preparative LC/MS (C18 reverse phase, eluted with 0.05% TFA in CH3CN/H2O) gave 1-(3-cyano-4-fluorophenyl)-5-{[6-(2-oxo-hexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide (67, 29% mg) as a white foam. LC/MS (ESI+): 487.2 (M+H)+.