Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][NH:9][C:10](=[O:12])[CH3:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[S:4]
Reactant: CC(=O)NCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)NCC(=NNC(N)=S)c1ccccc1
Yield: 78 %

Procedure:
Thiosemicarbazide (1.98 g, 20 mmol) was added to a solution of N-(2-oxo-2-phenyl-ethyl)-acetamide (3.84 g, 20 mmol, prepared in the previous step, in 70 ml of methanol plus 5.4 ml of 1N HCl plus 5.0 ml of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration and dried to give 3.9 g (78%) of the title compound as a white solid, mp 208-211° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[CH:40]([NH:41][C:42](=[O:77])[C:43]([C:52]3[N:53]=[C:54]([NH:57][C:58]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[S:55][CH:56]=3)=[N:44][O:45][CH:46]3[CH2:50][CH2:49][O:48][C:47]3=[O:51])[C:39](=[O:78])[N:21]2[C:22]=1[C:23]([O:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:14])[CH3:13]>C(Cl)Cl>[O:9]=[S:19]1[C@@H:20]2[CH:40]([NH:41][C:42](=[O:77])[C:43]([C:52]3[N:53]=[C:54]([NH:57][C:58]([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[S:55][CH:56]=3)=[N:44][O:45][CH:46]3[CH2:50][CH2:49][O:48][C:47]3=[O:51])[C:39](=[O:78])[N:21]2[C:22]([C:23]([O:25][CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[C:17]([CH2:16][O:15][C:12](=[O:14])[CH3:13])[CH2:18]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC3CCOC3=O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC3CCOC3=O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2S(=O)C1
Reaction time: 1 h

Procedure:
A solution of 0.420 g of m-chloro-perbenzoic acid in 8 ml of methylene chloride was added under an inert atmosphere to a stirred solution of 1.525 g of the product of Step A in 8 ml of methylene chloride cooled on an ice bath to 0° to 5° C. and the mixture was stirred for one hour at that temperature. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in 20 ml of ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate solution and then with aqueous sodium chloride until the wash waters were neutral, dried and evaporated to dryness under reduced pressure at a temperature less than 30° C. The residue was taken up in 10 ml of ether and the mixture was vacuum filtered at room temperature. The product was rinsed with ether to obtain 1.390 g of the syn isomer of diphenylmethyl 1-oxo-3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-oxo-3-tetrahydrofuranyloxyimino)-acetamido]-ceph-3-eme- 4-carboxylate in the form of a yellow product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[CH2:23][N:24]1[C@@H:28]([CH3:29])[C@@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:26][C:25]1=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[CH2:43]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]2[C@@H:28]([CH3:29])[C@@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C:25]2=[O:36])[CH:4]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To {4-hydroxy-3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid (0.07 g, 0.14 mmol) and cesium carbonate (0.09 g, 0.28 mmol) in DMF was added benzyl bromide (0.03 mL, 0.28 mmol), and the reaction was stirred at room temperature for 3 days. The mixture was partitioned between H2O and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].O>CN(C=O)C>[C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[N:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc2c1CCCC(=O)N2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCCc2c(OC(C)=O)cccc21
Yield: 99 %

Procedure:
6-acetoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine (252 mg) was dissolved in DMF (5 ml), and the resultant solution was stirred at room temperature. Potassium carbonate (509 mg) and methyl bromoacetate (0.22 ml) were added to the solution at room temperature. After disappearance of the raw materials was confirmed, water (20 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=1/1) to obtain the object compound ml (333 mg, yield 99%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22].O>ClCCl>[Cl:19][CH2:20][C:21]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:11]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(CNC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of commercially available 4-tert-butylbenzylamine (8.16 g, 50 mmol) and potassium carbonate (7.95 g, 57.5 mmol) in dichloromethane (100 ml) was added drop wise a solution of 2-chloroacetyl chloride (6.21 g, 55 mmol) in dichloromethane (25 ml) at room temperature. After stirring the reaction mixture at room temperature for 30 min, the reaction mixture was refluxed for 4 h. The reaction mixture was cooled and water (100 ml) was added. The phases were separated and the organic phase was dried over MgSO4 and evaporated in vacuo. The title compound was obtained as a white crystalline material which was used in the next step without any further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:21]([O-:23])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Pd]>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:15]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:21](=[O:23])[C:10]=3[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C1=C(Nc2ccc(Nc3ccccc3)cc2)CCCC1
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1c2ccccc2[nH]c2ccc(Nc3ccccc3)cc12
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Dowtherm® A (100 ml) was brought to reflux in a mechanically stirred flask with a steam-heated condenser and nitrogen atmosphere. A solution of 30 g of a mixture of the methyl and ethyl esters of 2-{4'-[(phenyl)amino]phenyl}aminocyclohexenecarboxylate in 300 ml of Dowtherm® A was added dropwise over 2 hours. Reflux was continued for 1/2 hour after the addition was complete. The reaction was cooled slightly and 1.5 g of 10% palladium on carbon was added. The mixture was refluxed for an additional 6 hours. The mixture was cooled. The precipitate that formed was filtered. The precipitate was washed with petroleum ether. The precipitate was dissolved in 150 ml of warm dimethylformamide (DMF). The DMF solution was filtered and the solid remaining on the funnel was washed with an additional 75 ml of DMF. The combined DMF filtrates were diluted to 2 liters with water. The product precipitated and was collected on a funnel and was washed well with water. Vacuum oven drying at 80° C. for 2 days gave 25 g (96% yield) of 2-(phenyl)amino-9(10H)acridinone.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:16])[CH2:12]1.C(N(CC)CC)C>O1CCOCC1>[F:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH:11]2[CH2:12][N:13]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([N:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:27]4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[O:16])[CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: NCC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(CNc2cccc(F)n2)C1
Temperature: 80 °C

Procedure:
Add 2,6-difluoropyridine (55 μL, 70 mg, 0.61 mmol, 2.0 equiv) to a solution of (3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone (134 mg, 0.301 mmol, 1 equiv) and triethylamine (120 μL, 87 mg, 0.86 mmol, 2.9 equiv) in 1,4-dioxane (3 mL) and heat at 80° C. for 16 h. Mass spec shows no desired product. Add more triethylamine (120 μL) and 2,6-difluoropyridine (110 μL). After 32 h at 80° C., LC/MS shows a small amount of desired product. Add more triethylamine (200 μL) and 2,6-difluoropyridine (110 μL). After 38 h, add more triethylamine (200 μL) and 2,6-difluoropyridine (110 μL). After 100 h, transfer the reaction solution to a column of silica gel (80 mm×20 mm dia.) and elute (50-65% EtOAc/hex) to yield 65 mg (40%) of [3-[(6-fluoro-pyridin-2-ylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a white foam. MS (m/e): 541.02 (M+1); 539.17 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24]CCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCC1CC[N:67]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:66][CH2:65]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:19][CH2:24][N:67]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:66][CH2:65]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCBr)CC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 11 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetic acid salt (for example, as prepared for Intermediate 6) and phenylmethyl 4-(2-bromoethyl)-1-piperidinecarboxylate (for a preparation, see J. Med. Chem., 2003, 46(13), 2606).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Li]c1ccccc1
Reactant: BrCCCCCCCCCCBr
Solvent: C1CCOC1
Product: BrCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a 250 mL flask in ice-water bath was added 1,10-dibromodecane (46.0 g, 153 mmol) and anhydrous THF (100 ml) under nitrogen. Phenyl lithium (1.8 M in dibutyl ether, 28.5 mL, 51 mmol) was added dropwise. After addition was completed, the reaction mixture was stirred for 1 hour and warmed to room temperature. After 48 hours, it was quenched with H2O (200 mL), extracted with CH2Cl2 (200 mL×2) and dried. After concentration, the residue was distilled to give a colorless oil (9.35 g, yield 61.7%) at 130° C./0.07 mmHg. 1H NMR (CDCl3, 500 MHz) δ=7.27-7.32 (m, 2H), 7.20 (d, J=6.5 Hz, 3H), 3.43 (t, J=7.0 Hz, 2H), 2.62 (t, J=8.0 Hz, 2H), 1.84-1.96 (m, 2H), 1.60-1.68 (m, 2H), 1.41-1.52 (m, 2H), 1.24-1.41 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21]([O:24][C@@H:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>>[C:21]([O:24][C@@H:25]([CH3:29])[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methylpyridine-2-carbonyl)indole (Example 70) and (S)-(−)-2-acetoxypropionyl chloride. m.p.: 213-214° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 57.7 %

Procedure:
tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (0.74 g, 3.2 mmol) and methyl thiosalicylate (1.1 g, 6.4 mmol) were dissolved in toluene (3 ml). Triethylamine (1.4 ml, 9.7 mmol) was added thereto. The reaction mixture was refluxed for 7.5 hrs, subjected to a silica gel (75 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol-hexane to give the titled compound (0.68 g, 57%) as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]=[C:3]1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][CH:5]=1
Reactant: BrBr
Reactant: Cn1c(Nc2ccccc2)nccc1=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cn1c(Nc2ccccc2)ncc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.104 g, 0.517 mmol) in CHCl3 (5 mL)/MeOH (1 mL) at 0° C. was added bromine (0.027 mL, 0.517 mmol). The reaction mixture was stirred for 30 minutes at room temperature and then quenched with 10% aqueous sodium bisulfite solution. The reaction mixture was partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.145 g; 100%) as a white solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.94 (s, 1H), 7.47 (m, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.14 (t, J=7.4 Hz, 1H), 3.53 (s, 3H). LRMS (ESI pos) m/e 280, 282 (M+1, Br pattern).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH2:6][CH:7]=[CH:8][CH2:9][PH:10](=[O:14])[O:11][CH2:12][CH3:13].[CH3:21][C:22]1([CH3:38])[C:26]([CH3:28])([CH3:27])[O:25][B:24]([C:29]2[CH:30]=[N:31][N:32]([CH2:34]CCO)[CH:33]=2)[O:23]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH2:6][CH:7]=[CH:8][CH2:9][PH:10](=[O:14])[O:11][CH2:12][CH2:13][CH2:34][N:32]1[CH:33]=[C:29]([B:24]2[O:25][C:26]([CH3:28])([CH3:27])[C:22]([CH3:38])([CH3:21])[O:23]2)[CH:30]=[N:31]1
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Reactant: CCO[PH](=O)CC=CCc1ccc([N+](=O)[O-])c(OC)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(CC=CC[PH](=O)OCCCn2cc(B3OC(C)(C)C(C)(C)O3)cn2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
A suspension of (3-methoxy-4-nitrobenzyl)prop-2-en-1-ylphosphinic acid (Compound 37E, 241 mg, 0.888 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 224 mg, 0.888 mmol) in 1,2-Dichloroethane (19 mL) and DIPEA (0.928 mL, 5.33 mmol) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (1387 mg, 2.665 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (20 mL). The organic layer was washed with NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a yellow oil. The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a light yellow oil. The material was re-purified on a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a light yellow solid (189.6 mg, 42%). 1H NMR (CDCl3, 400 MHz): δ=7.81-7.87 (m, 2H), 7.71 (s, 1H), 7.11 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 5.73-5.86 (m, 1H), 5.19-5.32 (m, 2H), 4.27 (t, J=6.4 Hz, 2H), 3.90-4.04 (m, 5H), 3.20 (d, J=16.2 Hz, 2H), 2.61 (dd, J=7.6, 17.4 Hz, 2H), 2.15-2.25 (m, 2H), 1.33 (s, 12H). MS (ESI): m/z 506.63 [M+H]+. UPLC: tR=1.23 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:13][C:14](=[N:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH:29]([F:31])[F:30])(=[O:21])=[O:20])OCC)[CH3:12]>O1CCCC1.CCOCC>[F:31][CH:29]([F:30])[O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:14](=[N:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1)[O:13][CH2:11][CH3:12])(=[O:21])=[O:20]
Reactant: CCOC(=NS(=O)(=O)c1ccccc1OC(F)F)OCC
Reactant: COc1cc(C)nc(N)n1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=Nc1nc(C)cc(OC)n1)NS(=O)(=O)c1ccccc1OC(F)F
Temperature: 25 °C

Procedure:
To a solution of 11.2 g (0.1 mol) of potassium tertbutylate in 125 ml of tetrahydrofuran are added at room temperature, with stirring, 13.9 g (0.1 mol) of 2-amino-4-methoxy-6-methylpyrimidine. Stirring is maintained for 2 hours at room temperature, and 32.3 g (0.1 mol) of N-(2-difluoromethoxy-benzenesulfonyl)-imido carbonic acid diethyl ester (obtained according to Example 1) are then added, the reaction mixture being stirred for a further 20 hours. The mixture is subsequently concentrated by evaporation, and the residue is taken up in water and rendered acid with hydrochloric acid. The acid solution is extracted with ehtyl acetate; the organic phases are then collected, dried, and concentrated by evaporation to leave a solid residue, which is suspended in ether and again filtered off. The yield is 34.5 g (83% of theory) of the above sulfonylisourea, m.p. 131°-133° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[C:13](Cl)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 12.5 °C
Reaction time: 0.25 h

Procedure:
165.7 g (1.2 mol) of para-hydroxybenzoic acid were first dissolved in 400 ml of water and 600 ml of isopropanol and this solution was admixed at 10 to 15° C. with 276.1 g of KOH solution (50% strength by weight aqueous solution, 2.46 mol). The resulting pH was 14. Metered into this solution over the course of two hours, then, at 10 to 15° C., were 228.8 g (1.2 mol) of decanoyl chloride, and the batch was stirred for 15 minutes at 10 to 15° C. thereafter. At the end of the after-stirring, the pH of the reaction mixture was 9.5. The reaction mixture was subsequently admixed at 10 to 15° C. with 30 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 55 to 60° C. and then adjusted to a pH of 1.5 to 3 using 120 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to 20 to 25° C. and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 314.4 g (89.6% of theory). According to HPLC and NMR measurement, the product was free from decanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].S(=O)(=O)(O)O.[CH2:22]=[C:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:15]
Reactant: C=C(C)C
Reactant: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 96 %

Procedure:
Into a 200-ml four-necked flask, were charged 22.2 g of 2-methyl-4-t-butyl-5-hydroxyphenylacetic acid, 100 ml of toluene and 1 ml of concentrated sulfuric acid, and isobutene was blown into the mixture at 50° to 60° C. for a period of 3 hours. After completion of the reaction, the reaction mixture was freed from the catalyst (sulfuric acid) by washing with water and freed from the solvent under reduced pressure to obtain 26.7 g (96% yield) of yellow t-butyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate, which was recrystallized from n-hexane to obtain white crystals melting at 105.0° to 106.0° C.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>CCCCCC>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CC(O)C(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Yield: 81.3 %

Procedure:
A mixture of 53 g of 1,1,1-trichloro-2-hydroxy-4-methyl-3-pentene, 28 g of acetic anhydride, and 1.23 ml of pyridine was heated at 95°-100° for one hour. The reaction mixture was then dissolved in 500 ml of hexane. This solution was washed thrice with 150 ml portions of water and dried over anhydrous magnesium sulfate. After stripping the hexane, the residue was distilled under reduced pressure, yielding 52 g of 1,1,1-trichloro-2-acetoxy-4-methyl-3-pentene; bp 85°-90°/4-4.3 mm. An nmr spectrum of this product was consistent with the assigned structure.