Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:23])[NH:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[CH:7]=[CH:6][C:5]=12.[OH-].[Li+]>O1CCCC1.CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:23])[NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=3)[CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccc3nccn3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 4-(3-imidazo[1,2-a]pyridin-6-ylureido)benzoate (2.1 g, 6.77 mmol) in tetrahydrofuran (18.05 ml) and methanol (9.02 ml) was treated with 2N lithium hydroxide (13.53 ml, 27.1 mmol) and the reaction was allowed to stir at room temperature for 16 hours. The mixture was concentrated, redissolved in 225 mL water and acidified to ˜pH 4 with 3N hydrochloric acid. The suspension was filtered with water washes to give the title compound after vacuum drying.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[C:28]([O:32][C:33]([NH:35][C@:36]([CH:70]1[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]1)([C:38]([N:40]1[CH2:69][CH2:68][CH2:67][C@H:41]1[C:42]([NH:44][CH2:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH:54]([NH:58]C1C=CC(OC)=CC=1)[CH:55]([F:57])[F:56])=[O:43])=[O:39])N)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O.CC#N>[NH2:58][CH:54]([CH:55]([F:57])[F:56])[CH2:53][C:47]1[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=1[CH2:45][NH:44][C:42](=[O:43])[C@@H:41]1[CH2:67][CH2:68][CH2:69][N:40]1[C:38](=[O:39])[C@H:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH:70]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75]1
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)[C@](N)(NC(=O)OC(C)(C)C)C2CCCCC2)C(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CC(N)C(F)F)C1CCCCC1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A solution of CAN (0.274 g, 0.50 mmol) in water (2.0 mL) was added to a stirred solution of 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylglycyl}-N-(5-chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-L-prolinamide (0.168 g, 0.25 mmol) in CH3CN (3.0 mL) at 0° C. and the resulting solution was warmed to ambient temperature. After 18 h the solution was partitioned between EtOAc(20 mL) and 10% aqueous NH4OH (10 mL). The resulting two phase suspension was filtered and the organic layer was washed with 10% sodium sulfite and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluting with 5% methylene chloride, 70% ethyl acetate/hexanes followed by ammonium hydroxide/methanol/chloroform, 1:9:90) to give N-[2-(2-amino-3,3-difluoropropyl)-5-chlorobenzyl]-1-{(2R)-2-[(tert-butoxycarbonyl)amino]2-cyclohexylethanoyl}-L-prolinamide (0.0801 g) as an oil; MS m/z=571.4.
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(Br)c1F
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2F)CC1

Procedure:
3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid was synthesised following the procedure in Example 2 (Step ii) using 3-bromo-2-fluorobenzoic acid and tert-butyl piperazine-1-carboxylate.
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-:10])=[O:9]>O.C1COCC1>[CH:1]([N:4]([CH3:5])[S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N+:8]([O-:10])=[O:9])(=[O:18])=[O:19])([CH3:3])[CH3:2]
Reactant: CNC(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer. The flask was charged with isopropylmethylamine (0.85 g, 11.6 mmol) followed by THF (50 mL). The mixture was cooled to 0° C. by placing the flask in an ice bath. Potassium hydroxide (23.2 mmol) was dissolved in water (20 mL) and added to the flask. An addition funnel was installed and charged with 2-nitrobenzenesulfonyl chloride (11.6 mmol) in THF (40 mL). The solution was added dropwise over 20 minutes, then the ice bath was removed. TLC (dichloromethane) indicated that the reaction was complete after addition of the 2-nitro-benzenesulfonyl chloride. The reaction was concentrated under diminished pressure, water (100 mL) was added, the mixture extracted with ethyl acetate (150 mL), dried (Na2SO4), and filtered. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a plug of silica gel (400 g in a 600 mL sintered glass funnel), and eluted with dichloromethane. Fractions were taken (100 mL) until the product eluted, as determined by TLC. Fractions containing the product were collected, and the solvent was removed in vacuo to yield N-(isopropyl)-N-(methyl)-2-nitrobenzenesulfonamide as a pale yellow oil. 3.08 g, (88%). 1H-NMR (CDCl3): δ 1.12-1.14 (d, 6H, J=6.7 Hz); 2.81 (s, 3H); 4.18-4.24 (m, 1H, J=6.7 Hz); 7.61-7.69 (m, 3H); 8.03-8.06 (m, 1H).
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1.Cl>C1COCC1>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[O:3][C:4]3[C:5]([C:11](=[O:13])[CH:12]=2)=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=3)=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)c3cc(O)ccc3o2)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (19.7 mmol, 3 equivalents) is added in one portion to a well-stirred solution of 2′,5′-dihydroxyacetophenone (6.4 mmol) in dry THF (5 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 4-methoxybenzoyl chloride (6.5 mmol) in THF (10 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (150 g) and concentrated HCl (5 ml) and extracted with chloroform (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (30 ml) and sulfuric acid (0.2 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 4′-methoxy-6-hydroxyflavone. 1H NMR (250 MHz, d6-DMSO): δ=3.73 (s, 3H), 6.6–8.5 (m, 8 H), 12.5 (s, 10 H); NMR (250 MHz, d6-DMSO): δ=56 (s), 94.9 (s), 114.0 (s), 117.6 (s), 118.9 (s), 122.2 (s), 126.6 (s), 127.2 (s), 150.5 (s), 152.0 (s), 161.2 (s), 168.8 (s), 187.0 (s) EI-MS (70 eV) m/e (rel. abund.)=268; UV (2-propanol): λ=254 nm, 323 nm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[C:13]([CH2:15]C(O)=O)#[N:14].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[CH:15][C:13]#[N:14])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: N#CCC(=O)O
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CC(=CC#N)CC(=O)OC
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a solution of 3-oxo-pentanedioic acid dimethyl ester (523 g) in toluene (750 mL), cyanoacetic acid (511 g), NH4OAc (46.3 g) and acetic acid (90.1 g) were added and heated at reflux with dehydrating by Dean-Stark apparatus for 8 h. After cooling to room temperature, the reaction mixture was washed with water, saturated aqueous NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give crude 3-cyanomethylene-pentanedioic acid dimethyl ester (403 g) as an oil. 1H NMR (200 MHz, CDCl3) δ ppm 3.39 (d, J=0.88 Hz, 2 H), 3.62 (s, 2 H), 3.72 (s, 3 H), 3.74 (s, 3 H), 5.51 (s, 1 H).
Reaction SMILES: [Mg].O1CCCC1.Cl[CH2:8][C:9]([CH3:11])=[CH2:10].[CH:12]([C:15](=[CH2:18])[CH:16]=[O:17])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:11][C:9]([CH2:8][CH:16]([OH:17])[C:15](=[CH2:18])[CH:12]([CH3:14])[CH3:13])=[CH2:10]
Reactant: C=C(C=O)C(C)C
Reactant: C=C(C)CCl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)CC(O)C(=C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of magnesium turnings (146 grams) and tetrahydrofuran (2,000 grams) is heated to reflux with vigorous agitation. To this mixture is added a mixture of 3-chloro-2-methylpropene (500 grams), toluene (75 grams), and 3-methyl-2-methylenebutanal (500 grams prepared according to Example I), at such a rate as to maintain reflux. The addition requires approximately four hours. The mass is stirred at reflux for 30 minutes and is then cooled to room temperature and quenched into excess ice cold 10% aqueous acetic acid mixture. The organic layer is washed successively with an equal volume of water, saturated sodium carbonate solution and saturated salt solution. Rapid distillation at 3-12 mm/Hg pressure using a short column followed by careful redistillation (after bulking) through a 12"×1" Goodloe packed column yields 580 grams of 2,6-dimethyl-5-methylene-1-hepten-4-ol, boiling point range 73°-78° C. at 9 mm/Hg pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25]C)C(O)=O)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[C:18]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)[CH:22]=[CH:23][C:24]=1[OH:25])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(C(=O)O)cc1C(C)(C)C
Product: CC(C)(C)c1cc(-c2nc3ccc(O)cc3o2)ccc1O

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3-tert-butyl-4-methoxybenzoic acid and was obtained as a white solid, m.p. 220–222° C.; MS m/e 284 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:29]([O:36][CH2:37][C@@H:38]1[C@@H:43]([O:44][CH3:45])[C:42]([CH3:47])([CH3:46])[CH2:41][CH2:40][C@H:39]1[CH:48]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC>[CH3:45][O:44][C@H:43]1[C:42]([CH3:46])([CH3:47])[CH2:41][CH2:40][C@@H:39](/[CH:48]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C@@H:38]1[CH2:37][O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CO[C@@H]1[C@@H](COCc2ccccc2)[C@H](C=O)CCC1(C)C
Reactant: CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCC/C=C/[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a stirred solution of n-octyltriphenylphosphonium bromide (313 mg) in dry tetrahydrofuran (0.5 ml) and dry HMPA (0.5 ml), n-BuLi (0.44 ml, 1.6M solution in n-hexane) was added at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (1R,2R,3R)-2-(benzyloxymethyl)-3-methoxy-4,4-dimethylcyclohexane-1-carbaldehyde (68 mg) in dry tetrahydrofuran (0.5 ml) was added to the resulting orange solution. The mixture was stirred at 0° C. for 30 min, and at room temperature for 2 hrs. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (using n-hexane:ethyl acetate= 10:1 as an eluent) to give benzyl [(1R,2R,6S)-2-methoxy-3,3-dimethyl-6-[(E)-1-nonenyl]cyclohexyl]methyl ether (54 mg 61%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].NC(N)=[S:17].C(O)C.[OH-].[Na+]>O>[SH:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: NC(N)=S
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCCCCCS
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.46 %

Procedure:
A mixture of 200 g of 11-bromoundecanoic acid, 60 g of thiourea and 600 mL of absolute ethanol was stirred and heated at reflux for two hours. After heating was stopped a solution of 80 g of sodium hydroxide in 250 mL of water was then added dropwise. The mixture was held overnight and then heated at reflux for three hours. After cooling to room temperature a solid precipitated from solution. The reaction mixture was poured into a mixture of ice and 200 g of concentrated hydrochloric acid. The solids were filtered from solution then slurried with ice water, isolated by filtration and washed twice. The off-white solid was stored in a crystallizing dish for one week, then dried under vacuum (~1 mm of Hg) at about 45° C. The product was distilled under vacuum (~1 mm of Hg at ~160° C.). NMR analysis indicated the desired product was obtained. The distilled product weighed 74.7 g representing 45.46% yield based upon the weight of starting 11-bromoundecanoic acid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:4]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]2[N:30]=[CH:31][CH:32]=[CH:33][N:34]=2)=[C:24]([C:25]([N:13]2[CH2:14][CH:15]3[CH:11]([CH2:10][N:9]([C:5]4[N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=[CH:7][N:6]=4)[CH2:16]3)[CH2:12]2)=[O:26])[CH:28]=1
Reactant: FC(F)(F)c1ccnc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Product: O=C(c1cc(F)ccc1-c1ncccn1)N1CC2CN(c3nccc(C(F)(F)F)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 33 and Intermediate 13. MS (ESI): mass calculated for C22H18F4N6O, 459.42; m/z found 459.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.74 (d, J=4.9, 2H), 8.60-8.28 (m, 2H), 7.23-7.04 (m, 3H), 6.84-6.75 (m, 1H), 4.03-2.97 (m, 10H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16](=O)[C:17]([CH3:23])([CH3:22])[C:18](OC)=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.O.[NH2:26][NH2:27]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[C:17]([CH3:23])([CH3:22])[C:18](=[O:19])[NH:26][N:27]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: NN
Solvent: O
Product: CC1(C)C(=O)NN=C1c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Prepared analogously as described for example C1 using methyl 3-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2,2-dimethyl-3-oxopropanoate (compound D3) and hydrazine hydrate as starting compounds.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]#[CH:17]>CC(C)=O>[CH2:17]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[C:16]#[CH:15]
Reactant: Oc1ccc(O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Hydroquinone (49.6 g; 450 mM) was dissolved in 700 ml of anhydrous acetone in a two liter, 3-necked, round bottom flask equipped with reflux condensor, air stirrer and nitrogen bubbler. Potassium carbonate (65.6 g; 460 mM) was ground finely and then added to the reaction followed by propargylbromide (53.6 g; 450 mM). The reaction was heated at reflux for three days, cooled to room temperature, filtered and the solvent removed. The residue was taken up in ether and extracted three times with 2.5N aqueous sodium hydroxide. The basic layers were acidified with concentrated hydrochloric acid while adding ice and extracted twice with ether. The combined ethereal layers were dried over magnesium sulfate, charcoal was added, and the mixture was filtered through celite. The solvent was removed in vacuo and the remaining dark brown sludge was purified by chromatography in two portions on a Waters Prep 500 equipped with two silica gel cartridges and eluted with 20% ethyl acetate in hexane after injecting in ether solution. This produced 21.4 g (64% of theory) of the desired p-propargyloxyphenol.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[Na].[N-:13]=[N+:14]=[N-:15]>CN(C)C=O>[N:13]([CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCCOCc1c[nH]cn1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCc1c[nH]cn1
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A stirred suspension of 4-(2-chloroethoxymethyl)imidazole hydrochloride (14.7 g.) and sodium size azide (9.8 g.) in dry dimethylformamide (103 ml.) was maintained at 95° for 5 hours and then set aside overnight at room temperature. Following dilution with water and filtration, the filtrate was concentrated and the residue purified by chromatography on a dry column of alumina using ethanol. The product was basified with potassium carbonate (6.5 g.) in water (3 ml.) and the anhydrous residue was extracted with isopropyl alcohol (3×50 ml.). Concentration of the extracts afforded 4-(2-azidoethoxymethyl)imidazole (7.2 g.). Hydrogenation of the azido compound (7.2 g.) in isopropyl alcohol (142 ml.) over platinum oxide catalyst (3.0 g.) gave 4-(2-aminoethoxymethyl)imidazole (6.48 g.). A sample of the monopiocrate monohydrochloide had m.p. 139°-140° (from nitromethane). (Found: c, 35.4; H, 3.8; N, 20.5; Cl, 8.8. C12H15ClN6O8 requires: C, 35.4; H, 3.7; N, 20.7; Cl, 8.7).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14]1.[C:19]([O:23][C:24]1[C:29]([F:30])=[CH:28][N:27]=[C:26](F)[C:25]=1[O:32][CH3:33])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]1[C:29]([F:30])=[CH:28][N:27]=[C:26]([CH:16]([CH:13]2[CH2:15][CH2:14]2)[C:17]#[N:18])[C:25]=1[O:32][CH3:33])([CH3:22])([CH3:21])[CH3:20]
Reactant: N#CCC1CC1
Reactant: COc1c(F)ncc(F)c1OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1c(C(C#N)C2CC2)ncc(F)c1OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
A −78° C. solution of diisopropylamine (1.3 mL, 9.0 mmol), under a nitrogen atmosphere in dry tetrahydrofuran (20 mL), was treated dropwise with 2.5 N n-butyllithium (3.6 mL, 9.0 mmol) and stirred for 10 minutes. The solution was treated dropwise with cyclopropylacetonitrile (0.8 g, 3.5 mmol) and stirred at −78° C. for 15 minutes. A solution of 4-tert-butoxy-2,5-difluoro-3-methoxypyridine (0.8 g, 3.5 mmol)[Example 7] in dry tetrahydrofuran (5 mL) was added and stirred for 1 hour at −78° C. followed by 1 hour at 0° C. The mixture was quenched with saturated ammonium chloride and extracted with diethylether. The combined extracts were washed with brine, dried over sodium sulfate, and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexanes (1:4) to afford the title compound (0.9 g). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 3.98 (s, 3H), 3.77 (d, 1H), 1.55-1.48 (m, 1H), 1.42 (s, 9H), 0.62-0.54 (m, 2H), 0.50-0.42 (m, 1H), 0.35-0.30 (m, 1H). MSCI: m/z=279 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 4-bromobenzenesulfonamide [CAS 701-34-8](307 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (325 mg, 64%). MS (ISP) 511.3 [(M+H)+]; mp 266–267° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15]C)=O)=[CH:4][C:3]=1[CH3:19].[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C@@H:8]3[C@@H:9]([CH2:10][CH2:11][CH2:12]3)[C:13]([OH:15])=[C:35]([C:30]3[NH:29][C:28]4[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=4[S:32](=[O:33])(=[O:34])[N:31]=3)[C:36]2=[O:37])=[CH:4][C:3]=1[CH3:19]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(C)c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@@H]3CCC[C@@H]32)ccc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of methyl (1R,2S)-2-[(4-fluoro-3-methylbenzyl)amino]cyclopentanecarboxylate (120 mg, 0.45 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 150 mg, 0.45 mmol) in anhydrous N,N-dimethylformamide (4 mL) under a nitrogen atmosphere, N-methylmorpholine (0.15 mL, 1.40 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) were added sequentially. The mixture was stirred at 25° C. for 2.5 h, and then poured into 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate, which was used directly in the next step without further purification.