Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[CH3:15])=[CH:5][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:18])=[O:17].CCN(C(C)C)C(C)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:38]([NH:37][CH2:35][CH3:36])=[O:39])=[N:11][C:10]=2[CH3:15])=[CH:5][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: Cc1nc(N)sc1-c1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1
Reactant: CCN=C=O
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(Cl)c(S(=O)(=O)N3CCN(C)CC3)c2)s1
Temperature: 120 °C

Procedure:
A stirred solution of 5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-ylamine hydrobromide (174d) (0.1 g, 0.26 mmol) in DMF (1 ml) at room temperature is treated with DIPEA (0.07 g, 0.52 mmol) and ethyl isocyanate (0.025 ml, 0.33 mmol). The reaction mixture is heated to 120° C. for 1 hour and then allowed to cool to room temperature. Purification by preparative LC-MS affords the titled compound.
Reaction SMILES: [O:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][PH:12]([OH:14])=[O:13].O>C1(C)C(C)=CC=CC=1>[P:12]([O:10][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9])([OH:14])([OH:13])=[O:11]
Reactant: CC(O)Oc1ccccc1
Reactant: O=[PH](O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(Oc1ccccc1)OP(=O)(O)O

Procedure:
1 mol of phenoxyethanol is esterified azeotropically in the presence of 1.1 mol of H3PO3 in xylene on a water separator. The reaction product which precipitates on cooling is filtered off, washed with petroleum ether and dried to give a white powder. The amount of the phosphoric diester (2-phenoxyethanol hydrogensulphate, 0-50%) which may be formed in this reaction in addition to phenoxyethanol phosphate (phenoxyethanol dihydrogenphosphate) does not interfere in the polycondensation which subsequently takes place; it is also incorporated into the polycondensate.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:10][O:11][C:12](=[O:33])[CH:13]=[CH:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)nc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(Br)nc1
Yield: 97.5 %

Procedure:
To 6-bromo-pyridine-3-carboxaldehyde (300 mg, 1.61 mmol) in toluene was added methyl(triphenylphosphoranylidene)acetate (647 mg, 1.94 mmol) and the solution was refluxed for 6 hrs. The reaction mixture was diluted with EtOAc and then washed three times with H2O, brine, dried. Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield 3-(6-bromo-pyridin-3-yl)-acrylic acid methyl ester (380 mg, 97%).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]([CH3:23])([CH3:22])[CH2:6]1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:33].[Na+].OO>O1CCCC1.O.CCOCC>[CH2:14]([O:13][N:8]1[C:7]([CH3:22])([CH3:23])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH2:3][OH:33])[CH2:10][C:9]1([CH3:11])[CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [OH-]
Reactant: C=CCOC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCON1C(C)(C)CC(OCCCO)CC1(C)C
Temperature: 20 °C
Yield: 88.8 %

Procedure:
A solution of 14.9 grams (45.9 mmol) of 4-allyloxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 10A) in 20 ml of anhydrous tetrahydrofuran is added over a 10-minute period to a solution of 5.6 grams (45.9 mmol) of 9-borabicyclo [3.3.1]nonane in 20 ml of tetrahydrofuran under a nitrogen atmosphere The reaction mixture is cooled to 20° C., and a solution of 1.84 gram (45.9 mmol) of sodium hydroxide in water is added over a 10-minute period. A solution of 15.3 ml of 30% aqueous hydrogen peroxide is then added over 30 minutes while the reaction mixture is cooled in an ice-water bath. The reaction mixture is diluted with ether (50 ml) and the organic layer is separated and dried over potassium carbonate. Solvent is evaporated and the residue is purified by flash chromatography (silica gel; 2:1 heptane:ethyl acetate) to afford 14.0 grams (89 % yield) of the title compound is a colorless syrup.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CC(C)(C)N
Product: CC(C)(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 50.9 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (5.0 g, 19.45 mmol) in tert-butylamine (20 ml, 0.19 mol) was stirred for 20 h at 125° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (25 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water, and then redissolved in 1 N sodium hydroxide (130 ml) followed by treatment with decolorising charcoal. After filtration, the clear solution was acidified to pH 2 and the precipitate was filtered off and recrystallised from methanol to give 2.91 g (52%) of the pure title compound; mp 368-372° C.; 1H-NMR (DMSO-d6): δ1.37 (s, 9H), 6.79 (br s, 1H), 7.11 (s, 1H), 10.55 (br s, 1H); MS: m/e 293/295 (M+); (C9H12N3Cl1O2S2) calc. C, 36.79; H, 4.12; N, 14.30; Cl, 12.07; S, 21.83; found C, 36.90; H, 4.11; N, 14.18; Cl, 12.05; S, 21.89.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[O-:7][Si:8]([O-:11])([O-:10])[O-:9].[K+].[K+].[K+].[K+].[Si]([O-])([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+]>>[O-:3][Si:2]([O-:4])=[O:1].[Na+:5].[Na+:5].[Si:8]([OH:11])([OH:10])([OH:9])[OH:7]
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: O=[Si]([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: O[Si](O)(O)O

Procedure:
Colloidal silica particles commonly used as polishing particles are made by a wet chemical method, which includes the steps of: preparing a dilute solution of a water glass (e.g., sodium water glass and potassium water glass, which are primarily composed of sodium silicate and potassium silicate, respectively) solution; passing the water glass solution through a cationic exchange resin to remove metallic ions, such as Na+ and K+, from the water glass solution to form an aqueous active silicic acid solution; adding a basic agent to the silicic acid solution for alkalization at appropriate temperature and pH value to conduct polycondensation of active silicic acid to form particles of colloidal silica; and ultra-filtering the particles of colloidal silica to obtain a silica sol. In consideration of safety, operating convenience, and production costs, the alkalization is usually conducted using sodium hydroxide or sodium water glass.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH3:10])[C:3]1=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.P(Cl)(Cl)(Cl)=O.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C1C=CC=CC=1.CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH3:10])[C:3]1=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: COCCN1CCN(C)C1=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COCCN1CCN(C)C1=Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 1-methyl-3-(2-methoxyethyl)-2-imidazolidinone (11.4 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7.2 ml) for 30 hours at 80°-85° C. gave an oil a portion of which (1.8 g) was dissolved in methanol (10 ml) and treated with fumaric acid (0.9 g) to give 4-{2-[1-methyl-3-(2-methoxyethyl)-2-imidazolidinylideneamino]phenyl}morpholine monofumarate (m.p. 127°-129° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[OH-].[Na+].[CH:14]([CH:16]=[CH2:17])=[O:15].O=CC1C=CC=C(OC)C=1O.O.Cl>O>[CH3:8][O:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:3]2[C:4]=1[O:5][CH2:17][C:16]([CH:14]=[O:15])=[CH:2]2
Reactant: COc1cccc(C=O)c1O
Reactant: C=CC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1OCC(C=O)=C2

Procedure:
One mole of o-vanillin was stirred with 3 liter H2O and 0.05 mole NaOH. A stream of nitrogen was bubbled through 1.5 moles acrolein and then into the o-vanillin-water mixture. When all the acrolein had been driven into the solution (16 hours) the mixture was acidified with 0.06 mole of HCl and the intermediate product (a light yellow crystalline solid) was filtered off and washed with H2O.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][C@H:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[S:17])[N:13]([CH:36](O)[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])[C:12]1=[O:51])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.S(Cl)(Cl)=O.[C:64]1([P:70]([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][C@H:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[S:17])[N:13]([C:36](=[P:70]([C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=2)=[O:38])[C:12]1=[O:51])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H](CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: C[C@H](CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a solution of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-1-[1-hydroxy-1-(p-nitrobenzyloxycarbonyl)methyl]-4-[(R)-1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethylthio(thiocarbonyl)]thioazetidin-2-one (12.6 g, 16.1 mmole) in tetrahydrofuran (150 ml) were added at -15° C., in turn, 2,6-lutidine (2.00 g, 18.7 mmole) and thionyl chloride (2.11 g, 17.7 mmole), and the mixture was stirred at the same temperature for 15 minutes. 2,6-Lutidine (3.45 g, 32.2 mmole) and triphenylphosphine (12.6 g, 48.1 mmole) were then added and the mixture was stirred at 65° C. under a nitrogen stream for a further 35 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate; washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography (250 g of silica gel); eluted with a 15-20% v/v solution of ethyl acetate in benzene; giving the desired compound (10.9 g; 66%) in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH:39](O)[CH3:40])=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH:39](/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:32][CH:33]=1)[CH3:40])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(O)/C=C/c1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 228 mg (1 mM) of (E)-4-{4-(1-imidazolylmethyl)phenyl)-3-buten-2-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column. Two kinds of diastereomers were eluted by silica gel column chromatography with a eluate consisting of a mixture of hexane, ethyl acetate and methanol in a ratio of 5:5:1. The first eluted moiety is referred to as "Compound a", and the later eluted moiety is referred to as "Compound b".
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[N:13]=[C:12]([CH3:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[CH3:7])=[O:5])C.[OH-].[K+]>C(O)C>[C:4]([CH:6]([O:8][C:9]1[N:13]=[C:12]([CH3:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)Oc1nc(C)n(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(OC(C)C(=O)O)nn1-c1ccccc1

Procedure:
Ten g of the compound of Example 7 was refluxed for 4 hours with 4.1 g of potassium hydroxide in 150 ml of ethanol and the product was collected by extraction with ethyl acetate. The extract was washed with water, dried and evaporated under vacuum, and the residue was recrystallized from toluene to obtain 2.1 g of the desired product, m.p. 157°-159°.
Reaction SMILES: Br[C:2]1[C:3]([Cl:29])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[F-].[Cs+].CO[CH2:34][CH2:35]OC.CO>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:3]1[C:2]([CH:34]=[CH2:35])=[CH:17][CH:16]=[C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(OCc1ccccc1)c1c(NS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1Cl
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1Cl

Procedure:
A mixture of Example 226E (160 mg, 0.32 mmol), dibutyl vinylborate (88 mg, 0.48 mmol), CsF (146 mg, 0.96 mmol), Pd(PPh3)4 (37 mg, 0.03 mmol), DME (3.2 mL) and methanol (1.6 mL) was purged with argon, sealed in a vial and microwaved at 150° C. for 240 seconds. The mixture was diluted with ethyl acetate (50 mL), washed with brine, dried (Na2SO4), filtered, concentrated and purified on a Biotage silica gel cartridge (40 g) with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 446 (M+H)+, 463 (M+NH)+, 468 (M+Na)+; (ESI(−)) m/e 444 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.76 (m, 3H), 7.38 (m, 7H), 7.10 (d, 1H), 6.93 (dd, 1H), 5.86 (d, 1H), 5.51 (d, 1H), 5.26 (s, 2H).
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.O>C(O)C>[Cl:1][CH:2]([Cl:17])[C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)[N:24]([C:23]2[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=2)[N:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(C(=O)CC(=O)C(Cl)Cl)cc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(C(Cl)Cl)nn2-c2ccc(S(N)(=O)=O)cc2)cc1F
Yield: 62.7 %

Procedure:
4,4-Dichloro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from Step 2 (2.8 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours. The mixture was cooled and water was added until crystals slowly appeared. Filtration yielded a light tan solid (2.7 g, 63 %) : mp 190°-193° C.; 1H NMR (DMSO-d6) 7.84 (d, J=8.4 Hz, 2H), 7.53 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.47 (brs, 2H), 7.3-7.0 (m, 3H), 6.95 (s, 1H), 3.85 (s, 3H). Anal. Calc'd for C17 H14N3SO3FCl2 : C, 47.45; H, 3.28; N, 9.76. Found: C, 47.68; H, 3.42; N, 10.04.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 4-bromobenzyl bromide (5 g, 20 mmol) and phenol (2.26 g, 24 mmol) was added potassium carbonate (8.29 g, 60 mmol). This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (4.69 g, 89%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:60][CH3:61])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[N:53]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[N:53]=2)[C:47]1=[O:59])[CH:41]([CH3:40])[CH2:60][CH3:61])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 7B (0.020 g, 0.048 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate, to give the title compound (0.025 g, 81% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (m, 16 H), 1.29 (m, 2 H), 1.55 (m, 1 H), 1.80 (m, 1 H), 2.44 (s, 3 H), 2.71 (m, 5 H), 3.09 (m, 3 H), 3.54 (m, 4 H), 3.85 (m, 3 H), 4.18 (m, 1 H), 4.33 (s, 2 H), 4.56 (d, J=6.99 Hz, 1 H), 6.88 (d, J=9.56 Hz, 1 H), 7.01 (d, J=7.35 Hz, 1 H), 7.12 (m, 6 H), 7.23 (d, J=8.09 Hz, 2 H), 7.32 (m, 2 H), 7.64 (t, J=7.72 Hz, 1 H), 7.88 (m, 5 H), 8.64 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>CC(N(C)C)=O.O>[S:14]([NH2:1])([NH2:15])(=[O:17])=[O:16].[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: NS(=O)(=O)Cl
Agent: CC(C)Nc1cccc(N)c1C#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: NS(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-6-(isopropylamino)benzonitrile (Example 157b) (0.09 g, 0.54 mmol) in DMA (3 mL) was added sulfamoyl chloride (0.19 g, 1.62 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 hours, diluted with H2O (5 mL) and extracted with EtOAc. Solvents of the combined organic phases were evaporated and the residue was purified by preparative thin layer chromatography using a Hexane/EtOAc (3:2) solution as eluant, to give 2-amino-6-(isopropylamino)benzonitrile sulfamide (0.14 g). MS 255 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6](/[N:10]=[C:11](/[NH:17]/[N:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[N:30]=[CH:29][N:28]([C:31]4[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=4)[N:27]=3)=[CH:22][CH:21]=2)\[S:12][CH2:13][C:14]([OH:16])=[O:15])=[C:5]([CH3:42])[CH:4]=1.C[O-].[Na+:45]>C1COCC1>[Na+:45].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6](/[N:10]=[C:11](/[NH:17]/[N:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[N:30]=[CH:29][N:28]([C:31]4[CH:32]=[CH:33][C:34]([O:37][C:38]([F:40])([F:41])[F:39])=[CH:35][CH:36]=4)[N:27]=3)=[CH:22][CH:21]=2)\[S:12][CH2:13][C:14]([O-:16])=[O:15])=[C:5]([CH3:42])[CH:4]=1
Reactant: COc1cc(C)c(/N=C(/N/N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC(=O)O)c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C)c(/N=C(/N/N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC(=O)[O-])c(C)c1

Procedure:
To a solution of 2-((Z)-(4-methoxy-2,6-dimethylphenylimino)((E)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinyl)methylthio)acetic acid (77.7 mg, 0.130 mmol) in THF (10 mL) was added slowly sodium methanolate (0.5 M in methanol; 260 μL, 0.130 mmol) at room temperature. The mixture immediately turned a darker yellow and was then evaporated at room temperature under vacuum giving a light orange solid. This material was triturated with Et2O (2×) and isolated by decanting using a centrifuge and drying under a nitrogen stream and then under high vacuum. The title compound was isolated as a light orange solid (32 mg, 39%). mp 146-154° C.; 1H NMR (400 MHz, methanol-d4) δ 9.11 (s, 1H), 8.64-7.68 (m, 7H), 7.51 (m, 2H), 6.70 (s, 2H), 3.85-3.70 (m, 4H), 3.61 (m, 1H), 2.29 (s, 6H); ESIMS m/z 599 (M+H).