Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1C=CC=[C:7]2[C:8]([NH:10]C(=O)[C:6]=12)=O)CCC.[O:16]=[C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[NH:18]1.NN>CO>[O:16]=[C:17]1[N:21]([CH:22]2[CH2:23][CH2:24][N:25]([CH2:5][CH2:6][CH2:7][CH2:8][NH2:10])[CH2:26][CH2:27]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[NH:18]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CCCCc1cccc2c1C(=O)NC2=O
Agent: NN
Solvent: CO
Product: NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(2-keto-1-benzimidazolinyl)piperidine butylphthalimide (1.42 g, 3.39 mmol) was dissolved in 30 mL of methanol. To this solution was added anhydrous hydrazine (426 mL, 13.57 mmol) and the reaction mixture was stirred at ambient temperature for 18 hours. The resulting precipitate was filtered and discarded. The filtrate was evaporated to dryness, and the residue was dissolved in dichloromethane and filtered again. The filtrate was evaporated to dryness to give the title compound as a solid.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=[N+]([O-])c1ccsc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccccc1Oc1sccc1[N+](=O)[O-]
Temperature: 105 °C

Procedure:
To a solution of 2-chloro-3-nitrothiophene (1.13 g, 6.93 mmol) in NMP (10 mL) in a pressure vessel was added 2-tert-butylphenol (1.04 g, 6.93 mmol) and K2CO3 (1.0 g, 10.1 mmol). The reaction was flushed with nitrogen, sealed and then heated to 105° C. for 48 h. The reaction was cooled to rt, diluted with EtOAc (˜150 mL) and washed twice with saturated aqueous NaCl (2×˜150 mL). The aqueous washes were then back extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated to yield the crude desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:4]=1[CH:5]=O.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[O:26][CH3:27].S(=O)(=O)(O)O.[Cl-].[Na+]>[OH-].[K+].[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:4]=1[CH:5]=[CH:24][C:23]([C:20]1[CH:21]=[CH:22][C:17]([OH:16])=[C:18]([O:26][CH3:27])[CH:19]=1)=[O:25]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: COc1ccc(-c2cccs2)cc1C=O
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Cl-]
Product: COc1cc(C(=O)C=Cc2cc(-c3cccs3)ccc2OC)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a suspension of 2-methoxy-5-(thien-2-yl)benzaldehyde (0.5 g, 2.3 mmol), obtained in the same manner as described in Ex-6A, in 5 N KOH solution was added cetyltrimethyl-ammonium chloride (CTACl, 25% in water, 4 mL, 3.0 mmol) followed by the addition of 4′-hydroxy-3′-methoxyacetophenone (0.38 g, 2.3 mmol). The mixture was stirred at room temperature overnight. Then it was acidified to about pH 1 with 6 M sulfuric acid, saturated with sodium chloride, and extracted with dichloromethane. The organic phase was washed with brine, dried and evaporated. Silica gel chromatography (hexane/ethyl acetate, 3:1 then 1:1) gave 0.61 g (73%) of a foam as the desired 3-[2-methoxy-5-(thien-2-yl)phenyl]-1-(4-hydroxy-3-methoxyphenyl)-2-propen-1-one product, m.p. 142-144° C. 1H-NMR (300 MHz, CDCl3): 8.21 (d, 1H), 7.82 (s, 1H), 7.55-7.75 (m, 4H), 6.85-7.15 (m, 4H), 6.14 (s, 1H), 4.00 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[H-].[Na+].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>CN(C)C=O>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([F:21])[CH:23]=1)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2[nH]1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 2.88 g (11.2 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate (obtained by Fisher indole synthesis from 4-(trifluoromethyl)phenylhydrazine) in 50 ml of dimethylformamide is added dropwise to a suspension of 0.58 g (14.56 mmol) of sodium hydride in 5 ml of dimethylformamide cooled in an ice bath. The mixture is stirred for 2 hours at room temperature and a solution of 2.54 g (13.44 mmol) of 3-fluorobenzyl bromide in 20 ml of dimethylformamide is then added. Stirring is continued for 24 hours. 2.44 mmol of 3-fluorobenzyl bromide are added and the mixture is stirred for a further 4 hours. The solvent is evaporated off under reduced pressure and the residue is taken up in water and ethyl acetate. After separation of the phases by settling, the organic phase is separated out and then washed with twice 50 ml of water and then with 50 ml of saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered, and then the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel. 2.74 g of product are obtained.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[CH:12][C:13]([F:34])=[C:14]([N:16]2[CH2:33][CH2:32][C:19]3([C:23](=[O:24])[N:22]([C@H:25]4[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[CH:15]=1.[N:35]1([C:40]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][N:43]=2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1>O.O1CCOCC1.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>[F:34][C:13]1[CH:12]=[CH:11][C:10]([C:45]2[CH:44]=[N:43][C:42]([C:40]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:41])=[CH:47][CH:46]=2)=[CH:15][C:14]=1[N:16]1[CH2:33][CH2:32][C:19]2([C:23](=[O:24])[N:22]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[CH2:18][CH2:17]1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCCC3)nc2)OC1(C)C
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCN(c1cc(Br)ccc1F)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(-c2ccc(F)c(N3CCC4(CC3)CCN([C@H]3CC[C@@H](O)CC3)C4=O)c2)cn1)N1CCCC1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
Potassium phosphate (0.017 g, 0.078 mmol) in water (0.10 mL) was added to a mixture of 8-(5-bromo-2-fluorophenyl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (15.0 mg, 0.0353 mmol), 2-(pyrrolidin-1-ylcarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (16 mg, 0.053 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.0 mg, 0.001 mmol) in 1,4-dioxane (0.30 mL). The resulting mixture was heated and stirred at 120° C. for 20 min. The mixture was filtered. The filtrate was diluted with methanol, and was purified by mass-guided reverse phase chromatography to afford the desired product. LCMS: (M+H)+=521.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([O:9]CC)=O)[S:5][CH:6]=1.[NH2:12][NH2:13]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:7]([NH:12][NH2:13])=[O:9])[S:5][CH:6]=1
Reactant: CCOC(=O)c1nc(C)cs1
Reactant: NN
Solvent: CCO
Product: Cc1csc(C(=O)NN)n1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-methyl-1,3-thiazole-2-carboxylate (I120) (208 mg, 1.215 mmol) in ethanol (6.028 ml) was stirred at room temperature under an atmosphere of argon. Hydrazine (0.046 ml, 1.458 mmol) was added and the solution was heated to reflux for 18 hours. The solution was cooled to room temperature and then the solvent was removed under reduced pressure to give a pale yellow coloured solid of desired product in 115 mg.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][C:9]2[CH:14]=[N:13][C:12]([CH:15]3[CH2:17][CH2:16]3)=[CH:11][N:10]=2)[CH2:5][N:4]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CO>[CH:15]1([C:12]2[N:13]=[CH:14][C:9]([O:8][C@H:6]3[CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:3]([CH2:2][NH:1][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:7]3)=[N:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CNC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
A solution of the product from Example 174D (2 g, 5.98 mmol) in methanol (3 mL) was treated with triethylamine (1.834 mL, 13.16 mmol) and methyl 2-bromoacetate (0.608 mL, 6.58 mmol), and the mixture was stirred at 65° C. for 3 hours. The resulting material was partitioned between water and ethyl acetate. The organic extract was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on a 24 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes to afford the title compound as a colorless oil (1.10 g, 45.2%).
Reaction SMILES: [CH2:1]([Li])CCC.O=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:11]([O:12][CH3:13])[C:9]=1[OH:10]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:13][O:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:8]([CH:7]=[CH2:1])[C:9]=1[OH:10]
Reactant: [Li]CCCC
Reactant: COc1cccc(C=O)c1O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(OC)c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (19.7 g, 55.0 mmol) in anhydrous tetrahydrofuran (200 mL) was cooled to 0° C. and n-butyllithium (2.5 M in hexanes, 24.0 mL, 60.0 mmol) was added during 5–10 minutes with stirring. The resulting clear, orange solution was stirred at 0° C. for an additional 30 minutes and then was added via cannula to a solution of o-vanillin (3.80 g, 25.0 mmol) in tetrahydrofuran (100 mL) at 23° C. After 3 hours, the reaction was quenched with saturated aqueous ammonium chloride solution (100 mL), diluted with water (300 mL), and the aqueous phase was extracted with ether (3×200 mL). The organic phase was washed with water (300 mL) and brine (300 mL), dried over magnesium sulfate and filtered through a plug of silica gel (10 cm diam×5–6 cm H). Concentration under reduced pressure provided crude 2-methoxy-6-vinyl-phenol as a clear, colorless oil (4.20 g) that was used without further purification. 1H NMR (DMSO): δ3.79 (s, 3 H, OCH3), 5.19 (dd, 1H, CH═CHH), 5.74 (dd, 1H, CH═CHH), 6.74 (t, 1H, ArH), δ6.86 (dd, 1H, ArH), 6.96 (dd, 1H, CH═CHH), 7.04 (dd, 1H, ArH), and 8.74 (s, 1H, ArOH).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:13])[N:6]=1>CO>[CH3:1][O:2][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:13])[N:6]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)ccc1C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C#N)c(C)n1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
Sodium methoxide (20 g, 0.4 mol) was added to a solution of 6-chloro-2-methylnicotinonitrile (132, 10 g, 66 mmol) in methanol (150 mL), and the mixture was heated at reflux for 1.5 h and cooled to room temperature. The precipitate was removed by filtration, and the filtrate was concentrated to dryness. The crude solid was redissolved in chloroform; and the resulting solution was filtered through a layer of silica gel, washing with extra portions of chloroform. The combined filtrates were evaporated to dryness to yield 41 (8.3 g, 87%): mp 81-82° C. (lit. (Synthesis 1991, 894-896) mp 80-80.5° C.). 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=8.5 Hz, 1H), 6.59 (d, J=8.5 Hz, 1H), 3.94 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH3:13][C@@:14]12[C@@H:23](CC[C@@](O)(C=C)C)[C@@:22]([OH:32])([CH3:31])[CH2:21][CH2:20][C@H:19]1[C:18]([CH3:34])([CH3:33])[CH2:17][CH2:16][CH2:15]2>>[OH:32][C:22]1([CH3:31])[CH2:21][CH2:20][CH:19]2[C:18]([CH3:33])([CH2:17][CH2:16][CH2:15][C:14]2([CH3:13])[CH3:23])[CH:34]1[CH2:3][CH2:2][OH:1]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=C[C@](C)(O)CC[C@@H]1[C@@]2(C)CCCC(C)(C)[C@@H]2CC[C@@]1(C)O
Product: CC1(C)CCCC2(C)C1CCC(C)(O)C2CCO
Reaction time: 84 h

Procedure:
Four flasks, each containing an aqueous solution (100 mL) of 0.1% NH4NO3, 0.1% H2KPO4, 0.05% MgSO4.7H2O, trace minerals, and Vitamin B complex were sterilized at 120° C. for 20 minutes. A 50% aqueous solution of dextrose (5 mL) and Tween-80 (0.1 mL), containing Sclareol (4) (10 mg) was added to each flask. Each flask was inoculated with 5% by volume of three days grown cells CBS 214.83 (ATCC 20624). The cultures were then incubated at 25±1° C. on a rotary shaker (200 rpm) for 3 to 4 days. After the initial incubation period a mixture of Sclareol dissolved in Tween-80 (8.0 g) was added in portions during the next 5 days, afterwhich the incubation was continued for a further 4 days. At the end of the incubation period the contents of the four flasks were combined, extracted with ethyl acetate (3×200 mL) and dried (Na2SO4). Evaporation of the solvent provided a crude extract (4.0 g), which was crystallized from hexane/chloroform to provide decahydro-2-hydroxy-2,5,5,8a-tetramethylnaphthaleneethanol (3) (2.4 g), mp 130.5°-131.5° C., (lit. 132°-133° C.) GLC purity 100%, H-NMR (CDCl3) δ0.79 (6H, 2s), 0.87 (3H, 2), (3H, 2), 0.9-20 (16H, m), 3.41-3.49 (1H, m), 3.72-3.79 (1H, m). IR (CHCl3) νmax, 3580, 3360, 2950, 1460, 1380 cm. MS m/e 236, 221, 117, 137, 109. [α]22D =-16.8° (CHCl3). [Literature 132°-133° C., [α]D22.5 =-17.3° (CHCl3).] [See M. Stoll and M. Hinder Helv. Chim. Acta (1953) 36 1955-2008.]
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:17][C:16]1([CH3:30])[CH3:29])=O)(C)(C)C>C(Cl)Cl>[CH3:29][C:16]1([CH3:30])[CH2:17][N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C:19](=[O:21])[CH2:20][NH:15]1
Reactant: Cc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1N1CC(C)(C)NCC1=O
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
0.97 ml of trifluoroacetic acid (12.6 mmol) was added to a solution of 0.4 g of 2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (51c) (1.26 mmol) in methylene chloride (1.9 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 230 mg of the title compound (yield: 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[N+:11]([O-:13])=[O:12].O[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1)[CH:6]=[C:5]2[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1c[nH]c2ccc(F)cc12
Reactant: OC1CCOC1
Product: O=[N+]([O-])c1cn(C2CCOC2)c2ccc(F)cc12
Yield: 18 %

Procedure:
The title compound was prepared from 5-fluoro-3-nitro-indole and 3-hydroxytetrahydrofuran in 18% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.21-2.27 (1H, m), 2.60-2.69 (1H, m), 3.95-4.01 (1H, m), 4.05-4.09 (1H, m), 4.20-4.25(2H, m), 5.07-5.10 (1H, m), 7.13 (1H, td, J=2.4, 8.8 Hz), 7.44 (1H, dd, J=4.0, 8.8 Hz), 7.98 (1H, dd, J=2.4, 9.2 Hz), 8.28 (1H, s).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26](O)[N:21]2[N:20]=1)(=[O:18])=[O:17]>C(#N)C>[Cl:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26]([Cl:3])[N:21]2[N:20]=1)(=[O:18])=[O:17]
Reactant: Cc1cc(O)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Reaction time: 24 h

Procedure:
A solution of 100 ml of phosphoryl chloride in 400 ml of dry acetonitrile was added to 12.0 g (30.9 mmol) of N-(2,6-dichloro-3-methylphenyl)-7-hydroxy-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide and heated to reflux with stirring. After about 24 hours, the mixture became a solution which appeared to contain little or no starting material by thin layer chromatography. The volatiles were largely removed by evaporation under reduced pressure and the residue poured onto about one liter of ice and water with stirring using fresh acetonitrile as a transfer solvent. The solid in the resulting mixture was collected by filtration, washed with water, and dried under reduced pressure at 70° C. overnight. The resulting solid, which was found to be the title compound by NMR analysis, amounted to 8.4 g (67 percent of theory).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][C:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([CH3:17])[CH3:16])([CH3:10])([CH3:9])[CH3:8].Cl[C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][N:28]=1>CN(C)C=O.[Cl-].[Na+].O>[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][C:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:27]2[CH:35]=[CH:34][C:30]([C:31](=[O:32])[NH2:33])=[CH:29][N:28]=2)=[CH:22][CH:23]=1)([CH3:17])[CH3:16])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
Add cesium carbonate (2.15 g, 6.60 mmol) to a stirred solution of [2-(4-hydroxy-phenyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (0.86 g, 3.24 mmol) in dimethylformamide (20 mL). Stir for 30 minutes under nitrogen at room temperature. Then add 6-chloronicotinamide (0.51 g, 3.26 mmol) and heat to 100° C. under nitrogen for 6 h. Cool the reaction to room temperature, pour into brine (100 mL), extract with ethyl acetate (3×75 mL), dry the ethyl acetate extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform to yield 0.5043 g (40%) of {2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-2-methyl-propyl}-carbamic acid tert-butyl ester: mass spectrum (ion spray): m/z=386.2 (M+1); 1H NMR (CDCl3): 8.64 (d, 1H), 8.20 (dd, 1H), 7.40 (d, 2H), 7.12 (d, 2H), 6.98 (d, 1H), 4.38 (br s, 1H), 3.34 (d, 2H), 1.75 (br s, 2H), 1.41 (s, 9H), 1.34 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[N:9]=[C:10]2[N:14]([CH:15]=1)[CH:13]=[C:12](Br)[S:11]2)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:53])[NH:21][C@H:22]([C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]1[NH:34][C:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[CH:36][N:37]=1)=[O:27])[CH:23]([CH3:25])[CH3:24]>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[N:9]=[C:10]2[N:14]([CH:15]=1)[CH:13]=[C:12]([C:41]1[CH:42]=[CH:43][C:38]([C:35]3[NH:34][C:33]([C@@H:29]4[CH2:30][CH2:31][CH2:32][N:28]4[C:26](=[O:27])[C@@H:22]([NH:21][C:20]([O:19][CH3:18])=[O:53])[CH:23]([CH3:25])[CH3:24])=[N:37][CH:36]=3)=[CH:39][CH:40]=1)[S:11]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cn2cc(Br)sc2n1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cn4cc(NC(=O)OC(C)(C)C)nc4s3)cc2)[nH]1)C(C)C
Yield: 22 %

Procedure:
Compound A35 was synthesized from compound 10 (0.126 mmol) and compound 8 (0.164 mmol), following the procedure as described for compound A1, as a white lyophilized solid in 22% yield. MS (ESI, EI+) m/z=608.35 (MH+).
Reaction SMILES: [OH-:1].[Na+:2].[C:3]1(=[O:9])[O:8][C:6](=[O:7])[CH:5]=[CH:4]1>>[C:3]([O-:8])(=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:1])=[O:7].[Na+:2]
Reactant: [OH-]
Reactant: O=C1C=CC(=O)O1
Agent: [Na+]
Product: O=C([O-])/C=C\C(=O)O

Procedure:
102 g (1.224 mol as pure sodium hydroxide) of 48% aqueous sodium hydroxide solution was added to an aqueous solution containing 117.6 g (1.2 mol) of maleic anhydride to obtain 50 wt. % aqueous solution of monosodium maleate. The whole quantity of the aqueous solution was transferred into a 500 ml autoclave. Nitrogen was introduced therein under stirring and the temperature of the reaction system was elevated to 90° C. 10.13 g (8.104 g as pure t-butyl peroxide) of 80% t-butyl peroxide (molecular weight: 90) was introduced into the reaction system as a polymerization initiator through a sample-inlet tube. Thereafter, the introduction of nitrogen was stopped. The autoclave was closed and the temperature was elevated to 130° C. The stirring was continued at that temperature for 2 h and the reaction system was cooled to 90° C. At this time, the aqueous solution had a pH of 5.2 and a concentration of 3%. Hydrochloric acid was added to the mixture through another sample-inlet pipe to control the pH of the 3% aqueous solution to 4.1, since a pH in the range of 3.5 to 5.0 is preferred for accelerating the reaction. Additional 10.13 g of 80% t-butyl hydroperoxide was introduced in the reaction system through the sample-inlet tube. The autoclave was closed and the temperature was elevated to 130° C. The stirring was effected at this temperature for 1.5 h. Then, the reaction system was cooled to 90° C. 5.4 g of 80% t-butyl hydroperoxide was added to the mixture. The pH of the 3% aqueous solution was controlled to 4.12 with hydrochloric acid. The temperature was elevated to 130° C. and the mixture was stirred at this temperature for 1.5 h to complete the reaction. The quantity of the polymerization initiator was about 0.23 mol per mol of maleic anhydride. A filter aid (trade name: Radiolite #900) was added to the reaction mixture to effect filtration through a glass filter and obtain 3% aqueous solution of monosodium polymaleate having a solid content of 43% and a pH of 4.4. The polymerization rate was determined from the results of determination of maleic acid residue according to the bromine/bromide method.