Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[OH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH2:25][C:26](O)=[O:27])=[CH:19][C:18]=1[O:29][CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([O:23][CH3:24])[C:17]([OH:16])=[C:18]([O:29][CH3:30])[CH:19]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1O
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc(OC)c1O
Yield: 28.8 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (376 mg, 1.7 mmol), 2-(4-hydroxy-3,5-dimethoxyphenyl)acetic acid (350 mg, 1.7 mmol), PyBop (1 g, 2 mmol) and triethylamine (605 mg, 6 mmol) were stirred together in DMF (10 mL) at room temperature for 2 hours. The reaction mixture was diluted with aqueous 1N HCl (100 mL) and extracted with DCM (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3,5-dimethoxyphenyl)acetamide (189 mg, 29%) as a white solid. 1H NMR (CDCl3, 400 MHz) 2.10 (s, 3H), 2.36 (s, 3H), 3.40 (s, 2H), 3.70 (s, 6H), 5.07 (s, 2H), 6.53 (s, 2H), 7.39 (s, 1H), 7.92 (s, 1H), 8.18 (s, 1H), 10.03 (s, 1H). LC/MS; [M+H] calculated for C19H22N4O5; expected 387.16; found 387.6. Melting point: 187-188° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]#[N:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:16][CH2:17]Cl>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3([C:11]#[N:12])[CH2:17][CH2:16]3)[CH:5]=2)[CH2:1][CH2:2]1
Reactant: N#CCc1ccc2c(c1)CCC2
Reactant: ClCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc3c(c2)CCC3)CC1
Temperature: 60 °C
Yield: 15.9 %

Procedure:
To a stirred solution of 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile (50.0 g, 0.32 mol) in toluene (150 mL) was added sodium hydroxide (300 mL, 50 percent in water W/W), 1-bromo-2-chloroethane (92.6 ml, 1.12 mol) and (n-Bu)4NBr (5 g, 15.51 mmol). The mixture was heated at 60° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (400 mL) and, extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum and purified by column chromatography (petroleum ether:ethyl acetate=10:1) to yield 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile (9.3 g, 16%). 1H NMR (CDCl3, 300 MHz) δ 1.35-1.38 (m, 2H), 1.66-1.69 (m, 2H), 2.05-2.13 (m, 2H), 2.87-294 (m, 4H), 7.07-7.22 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.CN1C(=O)CCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH:27]1[CH2:29][C:28]1([F:31])[F:30]>C(OCC)(=O)C.O.O1CCOCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:26][CH:27]3[CH2:29][C:28]3([F:31])[F:30])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=c1sc2cc(Br)ccc2n1CC1CC1(F)F
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a round bottom flask was added 6-bromo-1,3-benzothiazol-2(3H)-one (11.1 g, 48.5 mmol), anhydrous NMP (10 mL), anhydrous 1,4-dioxane (100 mL), cesium carbonate (33.2 g, 102 mmol), followed by 2-(bromomethyl)-1,1-difluorocyclopropane (8.29 g, 48.5 mmol). The reaction mixture was then heated to 95° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 18 hours. The crude reaction mixture was then cooled to room temperature, suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was then purified by silica gel chromatography (0-30% EtOAc/Hex) to give 6-bromo-3-[(2,2-difluorocyclopropyl)methyl]-1,3-benzothiazol-2(3H)-one (1-1) as a white solid. HRMS (M+H)+: observed=319.9550, calculated=319.9551.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]([NH:8][NH:9][C:10](=O)[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:7].O.CO>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:10]([C:11]3[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=3)=[N:9][N:8]=2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1
Reactant: COc1cc(OC)cc(C(=O)NNC(=O)c2cc(OC)cc(OC)c2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: O
Product: COc1cc(OC)cc(-c2nnc(-c3cc(OC)cc(OC)c3)o2)c1
Yield: 83.5 %

Procedure:
A mixture of 20.5 g (0.057 mole) of N,N'-bis(3,5-dimethoxybenzoyl)hydrazine in 125 ml of phosphorus oxychloride was heated to reflux temperature. All material dissolved after a short time and the solution was held at reflux for 1 hr. before it was cooled and slowly poured into water. The damp precipitate was stirred with 250 ml of boiling methanol before the mixture was cooled and filtered to give 16.3 g (84%) of crude 2,5-bis(3,5-dimethoxyphenyl)-1,3,4-oxadiazole, mp 167°-170° C.; Crystallization of a small sample from methanol gave mp 173°-175° C. 1H NMR(acetone-d6): 3.98 (s, 12H), 6.83 (m, 2H), 7.43 (m, 4H). Anal. Calcd. for C18H18N2O5 : C, 63.15; H, 5.30; N, 8.18. Found: C, 62.73; H, 5.34; N, 7.98.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)O.[CH2:26](N(CC)CC)[CH3:27].S(Cl)(Cl)=O.C([Mg]Br)C.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(F)cc2)N1CC(F)(F)F
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC1(c2ccc(F)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a −15° C. solution of 6-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (6.20 g, 16.5 mmol) in anhydrous toluene (60 mL) was added triethylamine (11.5 mL, 82.7 mmol). The reaction was stirred for 5 min and then thionyl chloride (1.27 mL, 17.4 mmol) was added dropwise maintaining the temperature <−5° C. After 15 min, 1M ethylmagnesium bromide in THF (51.3 mL, 51.3 mmol) was added over 35 min maintaining the temperature <−5° C. The reaction was warmed from −15° C. to 0° C. over 30 min and then poured into a vigorously stirred mixture of aqueous 10% citric acid (30 mL), ice (30 g), and ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL), brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (0-25% EtOAc/hexanes) gave a crude light yellow oil. Crystallization of the oil from hexane gave racemic 6-chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid. 1H NMR (CDCl3, 400 MHz) 8.19 (s, NH); 7.39 (m, 2H, ArH); 7.09 (m, 3H, ArH); 6.68 (d, J=8.51 Hz, 1H, ArH); 6.46 (d, J=2.11 Hz, 1H, ArH); 3.84 (m, 1H, CH2); 3.56 (m, 1H, CH2); 2.40 (m, 1H, CH2); 2.22 (m, 1H, CH2); 0.90 (t, J=7.15 Hz, 3H, CH3); MS (Electrospray): m/z 387.1 (M+H). Racemic 6-chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (2.76 g) was resolved using chiral reverse phase chromatography (ChiralPak AD packing, 10-30% iPrOH/hexanes with DEA modifier at 1.0 mL/L). The enantiomers were obtained as crystalline solids from hexane to give (+) compound as Peak 1 and (−) compound as Peak 2. Data for Peak 2: 1H NMR (CDCl3, 400 MHz) 8.69 (s, NH); 7.39 (m, 2H, ArH); 7.09 (m, 3H, ArH); 6.70 (d, J=8.60 Hz, 1H, ArH); 6.45 (d, J=2.20 Hz, 1H, ArH); 3.81 (m, 1H, CH2); 3.59 (m, 1H, CH2); 2.40 (m, 1H, CH2); 2.22 (m, 1H, CH2); 0.90 (t, J=7.14 Hz, 3H, CH3); MS (Electrospray): m/z 387.0894 (M+H); [α]D=−8.5° (c0.0024, CH2Cl2). Data for Peak 1, the (+)-enantiomer, [α]D=+7.9° (c0.0027, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].CI.[CH2:15]1OCCOCCOCCOCCOCC[O:17][CH2:16]1.CC(C)([O-])C.[K+].[NH4+].[Cl-]>C1COCC1>[C:16]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:12])([CH3:1])[C:3]1=[O:11])(=[O:17])[CH3:15].[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: CC1(C)C(=O)Nc2ccccc21
Agent: [Cl-]
Solvent: CI
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)C(C)(C)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3,3-dimethylindolin-2-one: To a stirred solution of 22a (3.2 g, 18.29 mmol) in dry THF (100 mL) was added MeI (2.6 mL, 41.75 mmol, 2.3 eq), followed by the addition of 18-crown-6 (0.51 g, 4.57 mmol, 0.25 eq) at −78° C. under nitrogen. Potassium tert-butoxide (5.12 g, 45.73 mmol, 2.5 eq) was added portionwise. The resulting slurry was stirred at −78° C. for 1 h. The mixture was stirred at −78° C. to rt for 3 h. Cooled in an ice bath, sat'd NH4Cl was added. It was extracted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give pure 1-acetyl-3,3-dimethylindolin-2-one (1.3 g) (LC-MS ESI 204(M+H)) and pure 3,3-dimethylindolin-2-one (1.0 g) (LC-MS ESI 162 (M+H)) respectively. 1-Acetyl-3,3-dimethylindolin-2-one (1.3 g) was heated in 6N HCl at reflux for 1 h. After cooling, it was poured into crushed ice. It was extracted with Et2O, washed with sat'd NaHCO3, H2O, brine, dried over Na2SO4, filtered, and concentrated to dryness to give almost pure 3,3-dimethylindolin-2-one (1.0 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CC([O-])(C)C.[K+].CS([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][N:24]=1)(=O)=O.O>C1COCC1>[CH3:32][S:29]([C:26]1[CH:27]=[CH:28][C:23]([O:10][C:7]2[CH:6]=[CH:5][C:4]([S:3][C:2]([F:11])([F:1])[F:12])=[CH:9][CH:8]=2)=[N:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: Oc1ccc(SC(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(SC(F)(F)F)cc2)nc1
Temperature: 25 °C
Yield: 60 %

Procedure:
To 4.95 g of 4-(trifluoromethylthio)phenol dissolved in a 20 ml THF/20 ml DMSO mixture was added 2.9 g of t-BuOK and then 6.0 g of 2,5-bis(methylsulfonyl) pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled to room temperature and added to approximately 3 to 4 volumes of water. The yellow-brown precipitate that formed was removed by filtration and then recrystallized from CH2Cl2 /ethanol. The purified product, 5-(methylsulfonyl)-2-(4-((trifluoromethyl)thio)phenoxy)pyridine, (60% yield), was recovered as tiny cream-white plates, m.p. 134°-135° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][N:10]=2)=[CH:5][CH:4]=1)#[CH:2].[CH:20]([N-:23]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.C1(OC#N)C=CC=CC=1>O1CCCC1.CCCCCC.O>[CH2:15]([C:12]1[CH:13]=[N:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:20]#[N:23])=[CH:8][CH:7]=2)=[N:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(C)[N-]C(C)C
Reactant: C#Cc1ccc(-c2ncc(CCCCC)cn2)cc1
Agent: N#COc1ccccc1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCc1cnc(-c2ccc(C#CC#N)cc2)nc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 22.5 %

Procedure:
A solution of 355 mg of 2-(p-ethynylphenyl)-5-pentylpyrimidine (prepared according to Example 8) in 30 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 15 minutes with a solution, cooled to about 0° C., of 152 mg of lithium diisopropylamide (prepared by adding 0.89 ml of a 1.60N solution of butyl lithium in hexane to a solution of 0.22 ml of diisopropylamine in 10 ml of absolute tetrahydrofuran at 0° C.) in 10 ml of absolute tetrahydrofuran. After 5 minutes, 182 μl of phenyl cyanate were added, the mixture was stirred at -78° C. for 90 minutes, then poured into 30 ml of water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the residue on silica gel with 5% ethyl acetate/petroleum ether gave 88 mg (22%) of p-(5-pentyl-2-pyrimidinyl)phenylpropiolonitrile as colourless crystals. Recrystallization from methanol yielded colourless needles (purity 99.4%); m.p. (C-N) 76.2° C., cl.p. (N-I) 128.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2S[C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(/C=C(/C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)\[OH:45])C=CN=1.C1C(=O)N(Br)C(=O)C1.N1(C(N)=O)CCCC1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:45][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: NC(=O)N1CCCC1
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)oc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.72 mmol, NBS (0.924 g, 5.19 mmol) and 1-pyrrolidinecarboxamide (1.077 g, 9.44 mmol) heated to 90° C. for 24 h the title compound of Step A was obtained as an orange solid (0.980 g). MS-ESI m/z 518 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C[NH:13][C@@H:14]1[CH2:19][CH2:18]CC[C@H:15]1[NH:20][CH3:21].BrC1C=C(N)C=NC=1>[Cu](I)I.O.CC(N(C)C)=O>[N:1]1([C:18]2[CH:19]=[C:14]([NH2:13])[CH:15]=[N:20][CH:21]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: I[Cu]I
Agent: Nc1cncc(Br)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cncc(-n2cccn2)c1
Temperature: 150 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
Pyrazole (42 mg), cesium carbonate (340 mg), trans-N,N′-dimethylcyclohexan-1,2-diamine (74 mg), and copper iodide (50 mg) were added to a DMAc (2 ml) solution containing 5-bromopyridin-3-amine (90 mg) in a nitrogen atmosphere, followed by stirring in a sealed tube at 150° C. for 15 hours. The reaction solution was adjusted to room temperature and water was added, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:MeOH=1:0 to 10:1). A brown solid of 5-(pyrazol-1-yl)pyridin-3-amine (56.7 mg) was thus obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:10][N:11]([CH2:13][C:14]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:12].I[CH2:34][CH3:35].O>CN(C=O)C>[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH2:34]([O:23][C:22]1[C:14]([CH2:13][N:11]([CH3:10])[CH3:12])=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:25])=[O:26])[CH:17]=[CH:16]2)[CH3:35]
Reactant: CN(C)Cc1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C

Procedure:
NaH (95%) (101 mg, 4.23 mmol), was added to a solution of 4-[(dimethylamino)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol (700 mg, 2.11 mmol; Example 131) in DMF (20 ml) at ambient temperature. The mixture was stirred for 15 min before iodoethane (0.203 ml, 2.54 mmol) was added. After 1 h water was added and the mixture extracted with Et2O. A small portion was purified on Gilson HPLC using 20-50% MeCN in 0.1% TFA. Yield: 65 mg; colorless oil. MS (ESI+) for C19H22N2O3S m/z 359 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[NH2:15][C:16]1[NH:17][CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:20]=1[C:21]([NH2:23])=[O:22]>O1CCCC1.O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([C:19]2[C:20]([C:21]([NH2:23])=[O:22])=[C:16]([NH:15][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[NH:17][CH:18]=2)=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Reactant: CCN=C=O
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reaction time: 16 h
Yield: 46.7 %

Procedure:
0.074 cm3 (0.891 mmol) of ethyl isocyanate and 0.005 mg (0.040 mmol) of dimethylaminopyridine are added, at a temperature close to 25° C., to a solution of 0.2 g (0.81 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 15 cm3 of tetrahydrofuran. After stirring for 16 hours at a temperature close to 60° C., the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 100 cm3 of water and then extracted with three times 50 cm3 of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (95/2.5/2.5 by volume)]. After concentrating the fractions under reduced pressure, 0.120 g of 4-(4-nitrophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide is obtained in the form of a yellow powder. ES+: m/z=318 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][S:5][C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:7][CH:8]=1.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C.CCCCCC>[Si:11]([O:10][CH2:9][C:6]1[S:5][S:4][C:3]([CH2:2][O:1][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:28])([F:27])[F:18])=[CH:8][CH:7]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC1=CC=C(COc2ccccc2C(F)(F)F)SS1
Temperature: 0 °C
Yield: 37 %

Procedure:
To a stirred solution of 3-(hydroxymethyl)-6-[(tert-butyldimethylsilyloxy)methyl]-1,2-dithiin (U.S. Ser. No. 08/212,096) (200 mg, 0.69 mmol) in 5 mL dry THF was added a solution of 2-(trifluoromethyl)phenol (223 mg, 1.37 mmol) in 5 mL THF, followed by addition of triphenylphosphine (234 mg, 0.89 mmol) The resulting solution was cooled to 0° C., then 140 μL (156 mg, 0.89 mmol) of diethylazodicarboxylate was added, and the reaction mixture was kept at 0°-5° C. until TLC analysis showed the reaction to be complete. For isolation of the products, the reaction mixture poured directly onto a silica gel column using ethyl acetate-hexane, 1:3, to provide 110 mg (37%) of 3-[(tert-butyldimethylsilyloxy)methyl]-6-[(2-trifluoromethylphenyloxy)methyl]-1,2-dithiin; 1H NMR (CDCl3):δ7.56 (d, J=8.0, 1 H), 7.45 (t, J=8.0, 1 H), 7.01 (m, 2 H), 6.49 S (d, J=6.0 Hz, 1 H), 6.37 (d, J=6.0 Hz, 1 H), 4.71 (s, 2 H), 4.26 (s, 2 H), 0.88 (s, 9 H), 0.07 (s, 6 H); 13C NMR (CDCl3):δquaternary carbons missing, 136.19, 133.24, 127.23, 123.57, 120.81, 113.15, 69.58, 64.85, 25.79, 18.34, -5.38; MS (LSIMS) (M+) 434.1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].NC(N)=S.C[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.Cl>>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1
Reactant: COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: NC(N)=S
Agent: [Al+3]
Product: O=[N+]([O-])c1ccc(O)cc1
Temperature: 40 °C
Yield: 81.2 %

Procedure:
To a mixture of 5.32 g (40 mmol) of aluminium chloride and 1.52 g (20 mmol) of thiourea 1.53 g (10 mmol) of 1-methoxy-4-nitrobenzene is added. The reaction mixture is heated to 40° C. and maintained at this temperature of 2 hours, then cooled to room temperature and 20 ml of 5 wt % hydrochloric acid is added. The precipitated product is filtered, washed and dried giving 1.13 g (81.2%) of 1-hydroxy-4-nitrobenzene.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[C:10]([F:25])[C:9]=1[F:26])(=[O:6])/[CH:2]=[CH:3]/[CH2:4]C.C(OC1C=CC(C23CCC(CCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CCCC.C(OC1C=CC(C23CCC(CCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CCCCC.C(OC1C=CC(C23CCC(CCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/C.C(OC1C=CC(C23CCC(CCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CC.C(OC1C=CC(C23CCC(CCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CCC.C(OC1C=CC(C23CCC(CCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CCCC.C(OC1C=CC(C23CCC(CCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CCCCC.C(OC1C=CC(C23CCC(CCCCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/C.C(OC1C=CC(C23CCC(CCCCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CC.C(OC1C=CC(C23CCC(CCCCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CCC.C(OC1C=CC(C23CCC(CCCCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CCCC.C(OC1C=CC(C23CCC(CCCCCCC)(CC2)CC3)=C(F)C=1F)(=O)/C=C/CCCCC>>[C:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]23[CH2:19][CH2:18][C:17]([CH2:22][CH2:23][CH3:24])([CH2:20][CH2:21]2)[CH2:16][CH2:15]3)=[C:10]([F:25])[C:9]=1[F:26])(=[O:6])/[CH:2]=[CH:3]/[CH3:4]
Reactant: CC/C=C/C(=O)Oc1ccc(C23CCC(CCC)(CC2)CC3)c(F)c1F
Agent: C/C=C/C(=O)Oc1ccc(C23CCC(CCCCC)(CC2)CC3)c(F)c1F
Agent: C/C=C/C(=O)Oc1ccc(C23CCC(CCCCCCC)(CC2)CC3)c(F)c1F
Agent: CC/C=C/C(=O)Oc1ccc(C23CCC(CCCCC)(CC2)CC3)c(F)c1F
Product: C/C=C/C(=O)Oc1ccc(C23CCC(CCC)(CC2)CC3)c(F)c1F

Procedure:
1-(4-[(E)-Pent-2-enoyloxy]-2, 3-difluorophenyl)-4-propylbicyclo[2.2.2]octane. 1-(4-[(E)-Hept-2-enoyloxy]-2, 3-difluorophenyl)-4-propylbicyclo[2.2.2]octane. 1-(4-[(E)-Oct-2-enoyloxy]-2, 3-difluorophenyl)-4-propylbicyclo[2.2.2]octane. 1-(4-[(E)-But-2-enoyloxy]-2, 3-difluorophenyl)-4-pentylbicyclo[2.2.2]octane. 1-(4-[(E)-Pent-2-enoyloxy]-2, 3-difluorophenyl)-4-pentylbicyclo[2.2.2]octane. 1-(4-[(E)-Hex-2-enoyloxy]-2, 3-difluorophenyl)-4-pentylbicyclo[2.2.2]octane. 1-(4-[(E)-Hept-2-enoyloxy]-2, 3-difluorophenyl)-4-pentylbicyclo[2.2.2]octane. 1-(4-[(E)-Oct-2-enoyloxy]-2, 3-difluorophenyl)-4-pentylbicyclo[2.2.2]octane. 1-(4-[(E)-But-2-enoyloxy]-2, 3-difluorophenyl)-4-heptylbicyclo[2.2.2]octane. 1-(4-[(E)-Pent-2-enoyloxy]-2, 3-difluorophenyl)-4-heptylbicyclo[2.2.2]octane. 1-(4-[(E)-Hex-2-enoyloxy]-2, 3-difluorophenyl)-4-heptylbicyclo[2.2.2]octane. 1-(4-[(E)-Hept-2-enoyloxy]-2, 3-difluorophenyl)-4-heptylbicyclo[2.2.2]octane. 1-(4-[(E)-Oct-2-enoyloxy]-2, 3-difluorophenyl)-4-heptylbicyclo[2.2.2]octane.