Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C@@H:4]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)[C@@H:5]([CH3:17])[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:40][C:41]([CH3:66])([C:43]([NH:45][C@H:46]([C:50]([N:52]([C@@H:54]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:55]([O:60][CH3:61])[CH2:56][C:57](O)=[O:58])[CH3:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])[CH3:42])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:40][C:41]([CH3:66])([C:43]([NH:45][C@H:46]([C:50]([N:52]([C@@H:54]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:55]([O:60][CH3:61])[CH2:56][C:57]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:18]3[C@H:4]([O:3][CH3:2])[C@@H:5]([CH3:17])[C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:58])[CH3:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])[CH3:42])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a solution of #24 (104 mg, 0.256 mmol, 1 eq.) in dichloromethane (10 mL, 0.094 M) were added #32 (156 mg, 0.256 mmol, 0.9 eq.), diisopropylethylamine (135 μL, 0.768 mmol, 3 eq.) and HATU (120 mg, 0.307 mmol, 1.2 eq.). After stirring for 18 hours, the mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (10 mL), washed with 1 M aqueous hydrochloric acid solution (2×5 mL) and with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was diluted with dichloromethane and filtered. The filtrate was concentrated under reduced pressure onto silica and purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #55 (44 mg, 19%) as a white solid. LC-MS: m/z 884.5 [M+2H+], retention time=1.04 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCCCCBr)CC1
Temperature: 0 °C
Yield: 15 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (6 g) in N,N-dimethylformamide (30 ml) was portion wise added sodium hydride (60%, 1.6 g) at 5° C. with stirring. The mixture was stirred at room temperature for 0.5 hour and at 60° C. for an hour. To the reaction mixture was added dropwise 1,4-dibromobutane (19 g) at 5° C. with stirring. The mixture was stirred at room temperature for 4 hours and at 50° C. for 2 hours. The reaction mixture was poured into ice-water and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1). The organic layer was washed with saturated sodium chloride aqueous solution and dried over magnesium sulfate. The magnesium sulfate was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to give oil. The oil was subjected to column chromatography on silica gel (silica gel 60 F254, Merck) and eluted with a mixture of ethyl acetate and n-hexane (1:10-1:3). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 1-(tert-butoxycarbonyl)-4-[(4-bromo)butoxy]piperidine (1.5 g).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].O[C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23]CC)=[O:22]>>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:13][O:14][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([OH:23])=[O:22])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(CO)CC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(COc2cccc(C(=O)O)c2)CC1

Procedure:
Prepared from [4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-methanol and ethyl 3-hydroxybenzoate by a method similar to Example 1.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1ccccc1C(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1C(F)F

Procedure:
A solution of 2-(difluoromethyl)benzoic acid 53 (1.8 g, 10 mmol) in thionyl chloride (25 ml) was heated at reflux for 3 h. The reaction mixture was concentrated and dried under vacuum to give 54. The crude acid chloride was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:22]([Cl:23])=[C:21]([Cl:24])[C:20]([Cl:25])=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:27])[CH3:2].[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1.C(OC(=O)C)(=O)C>C1C=CC=CC=1>[CH3:37][N:36]([CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH3:39])[CH3:28])[CH:35]=[CH:34][C:33]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:18])[O:17]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc21
Temperature: 25 °C
Yield: 12.7 %

Procedure:
A stirred mixture of 8.86 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid, prepared as described in part A above, 4.0 g of N,N,N',N'-tetramethyl-m-phenylenediamine, and 10.0 ml of acetic anhydride was heated at reflux for a period of three hours. The reaction was then allowed to cool to room temperature, and the tan precipitate which formed was filtered and washed with isopropanol. The material thus obtained was dissolved in 500 ml of benzene and the resulting solution extracted with 70 ml of 10 percent aqueous sodium hydroxide. The benzene solution was filtered and evaporated to dryness at ambient temperature yielding 1.5 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R0 =R1 =R2 =R3 =Cl; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3 ; Y1 =H), a white solid which melted with decomposition at 227°-229° C. A significant infrared maximum occurred at 1770 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was in complete agreement with the assigned structure. A benzene solution of this product spotted on silica gel developed an intense purple color.
Reaction SMILES: C([N:8]([CH2:22][C@H:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19](=[O:21])[NH2:20])[CH:13]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:19]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[OH:18])[O:11][CH2:10][CH2:9][NH:8][CH2:22][C@H:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:21])[NH2:20]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)C[C@H](O)c2ccccc2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNC[C@H](O)c2ccccc2)ccc1O

Procedure:
A solution of 23 g of crude (R)-α-[N-benzyl-N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol in 230 ml of methanol is hydrogenated, with the addition of 5 g of palladium-charcoal catalyst (5%), under normal conditions until 1 mol-equivalent of hydrogen has been absorbed. The catalyst is subsequently filtered off, is washed with methanol, and the combined methanolic solutions are concentrated under reduced pressure. The crystalline residue is recrystallised from methanol and yields (R)-(-)-α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol, m.p. 166°-172°; [α]D =-23°±1° (C=0.6% in methanol).
Reaction SMILES: C([NH:3][CH:4]1[C:30](=[O:31])[N:6]2[C:7]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[C:8](/[CH:11]=[CH:12]\[C:13]3[N:14]=[N:15][S:16][CH:17]=3)[CH2:9][S:10][C@H:5]12)=O.Cl>CO>[NH2:3][CH:4]1[C:30](=[O:31])[N:6]2[C:7]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[O:19])=[C:8](/[CH:11]=[CH:12]\[C:13]3[N:14]=[N:15][S:16][CH:17]=3)[CH2:9][S:10][C@H:5]12
Reactant: COc1ccc(COC(=O)C2=C(/C=C\c3csnn3)CS[C@@H]3C(NC=O)C(=O)N23)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(COC(=O)C2=C(/C=C\c3csnn3)CS[C@@H]3C(N)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
The said ester (0.6 g, 1.3 mmol) was dissolved in methanol (10 ml). By addition of concentrated hydrochloric acid (0.1 ml) it was stirred at room temperature for 2 hours. After the solvent was distilled off, a small amount of water was added to the residue and aqueous saturated sodium bicarbonate solution was added to adjust to pH 8-9. It was dissolved by addition of ethyl acetate and the oganic layer was separated. The organic layer was dried and the solvent was dissolved off, and the residue was purified by silica gel column chromatography thereby p-methoxybenzyl 7-amino-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (0.21 g) was obtained as a yellow powder solid.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Cl:18][S:19](O)(=[O:21])=[O:20]>P(Cl)(Cl)(Cl)(Cl)Cl>[N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:19]([Cl:18])(=[O:21])=[O:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(N3CCCCC3)ncnc2c1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc2ncnc(N3CCCCC3)c2c1
Temperature: 150 °C

Procedure:
In a mixture of 18.1 ml of chlorosulfonic acid and 5.4 g of phosphorus pentachloride was gradually added 8.6 g of 4-piperidinoquinazoline, and the mixture was heated at 150° C. for 20 hours. The reaction solution was poured into 200 g of a mixture of ice and water and extracted with chloroform. The chloroform layer was washed with water, then with a saturated sodium bicarbonate solution, and dried with Glauber's salt. The chloroform layer thus obtained was condensed under reduced pressure to give 6.0 g of 4-piperidino-6-quinazolinesulfonyl chloride as an oily substance.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10](=[O:11])[NH:9][C:8]2[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[CH:14][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:29][C:30]1[N:31]([CH3:35])[N:32]=[CH:33][N:34]=1>CN(C)C=O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]2[CH:14]=[N:13][N:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]2=[N:9][C:10]=1[O:11][CH2:29][C:30]1[N:31]([CH3:35])[N:32]=[CH:33][N:34]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc2cnn(-c3ccccc3)c2[nH]c1=O
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cnn2-c2ccccc2)cc1C(C)(C)C
Temperature: 60 °C
Yield: 71.1 %

Procedure:
To a solution of 1,7-dihydro-5-(1,1-dimethylethyl)-1-phenylpyrazolo[3,4-b]pyridin-6-one (26 mg, 0.097 mmol) in dry N,N-dimethylformamide (4 ml) under nitrogen was added cesium carbonate (95 mg, 0.29 mmol) followed by 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (25 mg, 0.15 mmol). The reaction mixture was heated at 60° C. for 17 h. The mixture was then allowed to cool and partitioned between water and diethyl ether. The aqueous phase was extracted a second time with diethyl ether and the combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a white solid (25 mg, 71%), m.p. 143-145° C. δH (400 MHz; CDCl3) 1.40 (9H, s), 3.93 (2H, s), 5.69 (1H, s), 7.29-7.32 (1H, m), 7.49-7.53 (2H, m), 7.93 (1H, s), 7.98 (1H, s), 8.05 (1H, s), 8.19-8.21 (2H, m); m/z (ES+) 363 (M+H+)
Reaction SMILES: FC(F)(F)C1C=CC(C2C=CC=C(CO)C=2)=CC=1.C[O:20][C:21](=[O:51])[CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33][CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[CH:38]=[CH:39][CH:40]=2)=[C:29]2[C:25]=1[CH2:26][CH2:27][CH2:28]2>>[F:50][C:47]([F:48])([F:49])[C:44]1[CH:45]=[CH:46][C:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([CH2:34][S:33][C:30]3[CH:31]=[CH:32][C:24]([O:23][CH2:22][C:21]([OH:51])=[O:20])=[C:25]4[C:29]=3[CH2:28][CH2:27][CH2:26]4)[CH:36]=2)=[CH:42][CH:43]=1
Reactant: COC(=O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)c2c1CCC2
Agent: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Product: O=C(O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 48A. MS m/z 236 (M+1-Cl). Step 3. Preparation of [7-(4′-Trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester (Compound 48C)
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1.[OH:24]/[N:25]=[C:26](\Cl)/[C:27]1[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:29][N:28]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:23])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]4([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[O:24][N:25]=[C:26]([C:27]5[C:31]([C:32]([F:35])([F:33])[F:34])=[C:30]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[O:29][N:28]=5)[CH:12]4[CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(c2ccc3c(n2)CCC=C3N2CCOCC2)O1
Reactant: O/N=C(\Cl)c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCC(c2ccc3c(n2)CCC2C(c4noc(-c5ccccc5)c4C(F)(F)F)=NOC32N2CCOCC2)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5-yl)morpholine (Preparation 15F, 0.194 g, 0.613 mmol) in dichloromethane (2 mL) was added a solution of (Z)—N-hydroxy-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbimidoyl chloride (Intermediate 13, 0.210 g, 0.613 mmol) in dichloromethane (1 mL). The reaction mixture was cooled to 0° C., and triethylamine (0.093 mL, 0.674 mmol) was added dropwise over 2 min. The ice-bath was removed, and the resulting cloudy solution was stirred at room temperature for 30 min. The reaction mixture was diluted with dichloromethane (30 mL), washed with water (15 mL), dried over anhydrous sodium sulfate, and concentrated to give the morpholino-intermediate, 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(5-phenyl-4-(trifluoromethyl)-isoxazol-3-yl)-3a,4,5,9b-tetrahydroisoxazolo[5,4-f]quinoline, as an orange oil. To the oil was added dichloroethane (3 mL) and TFA (0.071 mL, 0.920 mmol), and the reaction mixture was heated at 80° C. for 60 min. The reaction mixture was stirred overnight at room temperature. Additional TFA (0.071 mL, 0.920 mmol) was added, and the reaction mixture was heated at 80° C. for 6 h. The reaction mixture was diluted with dichloromethane (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (15 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by trituration with methanol with sonication afforded 44 mg of a 3:7 mixture of 1-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinolin-7-yl)ethane-1,2-diol and 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinoline as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:16][S@@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.B(F)(F)F.CCOCC.[CH2:39]([Mg]Cl)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([NH:16][S@@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:11])[F:12])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N=C(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: Cl[Mg]Cc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N[C@@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(R)—N-((3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (150 mg, 0.34 mmol) was stirred in anhydrous CH2Cl2 (7 mL) at −78° C. for 5 min under Argon. BF3.Et2O (0.10 mL, 2.0 eq) was added dropwise. The mixture was stirred at −78° C. for 10 min. Benzylmagnesium chloride (1.0 M in Et20, 1.4 mL, 3.0 eq) was added slowly at −78° C., and the resulting mixture was stirred at −78° C. for 1.5 h. The reaction mixture was quenched with sat. NH4Cl and then extracted with Et2O (2×). The combined organic portion was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes=0-30%) to give the fast eluting fraction corresponding to (R)—N-((5)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (29 mg): 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 9H) 3.63 (d, J=12.4 Hz, 1H), 3.94 (d, J=12.4 Hz, 1H), 4.21 (s, 1H), 6.90 (m, 1H), 5.90 (m, 1H), 6.94-7.09 (m, 4H), 7.16-7.20 (m, 4H), 7.31-7.39 (m, 2H); LC-MS (ESI) 530.36 (M+H), retention time=4.11 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run); and the slow eluting fraction corresponding to (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (146 mg, total yield: 96.4%): 1H NMR (400 MHz, CDCl3) δ ppm 7.35-7.43 (m, 2H), 7.13-7.20 (m, 3H), 7.07 (t, J=8.72 Hz, 2H), 6.93 (dd, J=7.58, 1.77 Hz, 2H), 6.84 (d, J=8.59 Hz, 1H), 6.70 (m, 2H), 5.85 (tt, J=52, 4 Hz, 1H), 4.25 (s, 1H), 4.02 (d, J=12.63 Hz, 1H), 3.58 (d, J=12.63 Hz, 1H), 1.20 (s, 9H); 13C NMR (CDCl3) δ ppm 23.02, 46.99, 56.53, 65.70, 104.55, 104.96, 105.37, 107.06, 107.47, 107.92, 108.17, 109.56, 109.97, 112.32, 112.55, 115.37, 115.58, 116.13, 116.41, 116.69, 119.12, 127.21, 128.14, 130.91, 130.99, 132.07, 134.34, 137.48, 137.51, 149.09, 149.21, 150.52, 150.45, 161.20, 163.67; LC-MS (ESI) 530.36 (M+H), retention time=4.11 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run).
Reaction SMILES: C([NH:5]CP)C([O-])=O.[NH4+].[CH2:9]([NH:13][CH2:14][P:15]([OH:18])([OH:17])=[O:16])[C:10]([OH:12])=[O:11].[NH4+]>O>[NH3:5].[CH2:9]([NH:13][CH2:14][P:15]([OH:18])([OH:17])=[O:16])[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])CNCP
Agent: O=C(O)CNCP(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: N

Procedure:
A process is provided for preparing ammonium glyphosate powder suitable for downstream processing by extrusion to make a granular formulation comprising ammonium glyphosate and surfactant. The process comprises (a) mixing (i) solid particulate glyphosate acid, (ii) water in an amount of about 0.5 to about 3 parts by weight per part by weight of glyphosate acid, and (iii) a base that supplies ammonium cations, in an amount of about 0.8 to about 1.25 mole equivalents of ammonia per mole of glyphosate acid, to form an aqueous reaction medium; (b) allowing the glyphosate acid to react with the base in the reaction medium to form a reaction product comprising a concentrated aqueous solution of ammonium glyphosate; (c) drying the reaction product, for example with a drum dryer, to recover a particulate solid; and (d) accelerating the particulate solid in a turbulent high-velocity gas stream, for example in a jet mill, to form by particle-particle attrition an ammonium glyphosate powder having a mean particle size of about 5 to about 20 μm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20](F)=[C:21]([Cl:23])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8].[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([O:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:21]([Cl:23])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(Oc3ccccc3)c(Cl)c2)cc1F
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 66.2 %

Procedure:
To a solution of 5-chloro-4-[(5-chloro-6-fluoropyridin-3-yl)oxy]-2-fluoro-N-(methylsulfonyl)benzamide (Example 19, 100 mg, 0.25 mmol) and phenol (71 mg, 0.76 mmol) in DMSO (1 mL) was added Cs2CO3 (246 mg, 0.76 mmol) at room temperature under N2. The resulting mixture was stirred at 100° C. for 45 minutes. The reaction mixture was allowed to cool to room temperature. The reaction was quenched with water, and acidified with 1N aqueous citric acid solution. The mixture was extracted with DCM (3×3 mL) and filtered through a phase separation cartridge. The organic phase was washed with brine (3 mL), and filtered through a phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product that was purified by reverse phase column chromatography eluting with 5-95% CH3CN in water to give a crude white solid. The solid was purified using trituration with heptane/acetone 9/1 to give the title compound (78 mg, 65%) as a white solid.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO>[OH:17]/[N:16]=[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)\[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: NO
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC/C(=N\O)c1ccccc1
Yield: 90.9 %

Procedure:
A mixture of methyl 3-benzoylpropionate (15.0 g), hydroxylamine hydrochloride (6.50 g), sodium acetate (9.60 g) and methanol (150 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and methyl E-4-hydroxyimino-4-phenylbutyrate (14.7 g, yield 91%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:29]=[CH:28][C:12]2[CH:13]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:11]=2[CH:10]=1)C.C1COCC1.[OH-].[Li+]>O.CO>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][CH2:22][CH:13]1[C:12]2[CH:28]=[CH:29][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:10][C:11]=2[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]1=2
Reactant: CCOC(=O)CCCOc1ccc2c(c1)CCc1ccccc1C2CCCN(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 875 mg of 7 (2.1 mmol) in 10 ml of freshly distilled THF was added a solution of 875 mg of lithium hydroxide in 10 ml of water and 5 ml of methanol. The reaction was allowed to stir at room temperature 18 hours and concentrated to remove THF and methanol. The aqueous residue was adjusted to pH 6 with 6N HCl. This was extracted with 3×100 ml of dichloromethane. The pH of the aqueous part was readjusted to 6 again after first extraction. The combined organic part was dried (Na2SO4) and concentrated to give 790 mg (2.0 mmol, 97%) of 8 as white amorphous solid.