Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[C:16]2[C:27]([C:28](=[O:32])[C:29]([NH2:31])=[O:30])=[C:26]([CH2:33][CH3:34])[N:25]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[N:18]=[C:19](S(C)(=O)=O)[N:20]=1>O1CCCC1>[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[C:16]2[C:27]([C:28](=[O:32])[C:29]([NH2:31])=[O:30])=[C:26]([CH2:33][CH3:34])[N:25]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:17]=2[N:18]=[C:19]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:20]=1
Reactant: Sc1ccccc1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(S(C)(=O)=O)nc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(Sc3ccccc3)nc2n1Cc1ccccc1
Temperature: 55 °C
Yield: 49 %

Procedure:
To a slurry of 5.4 mg (0.23 mmol) of sodium hydride in 1.0 mL of tetrahydrofuran was added 0.025 mL of thiophenol followed by 100 mg (0.21 mmol) of [[2-(methylsulfonyl)-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and the mixture heated to 55° C. for 18 hours. The reaction was cooled to ambient temperature and partitioned between 10 mL of methylene chloride and 10 mL of 0.2 M sodium hydrogen sulfate. The organic portion was dried with magnesium sulfate and concentrated to a solid. The crude material was purified by flash chromatography (5.0 g silica, ethyl acetate) to provide 52 mg (49%) of [[2-(phenylthio)-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.14 (t, J=7.4 Hz, 3H), 2.94 (q, J=7.4 Hz, 2H), 3.72 (s, 3H), 4.81 (s, 2H), 5.34 (s, 2H), 5.59 (s, 1H), 6.54 (s, 1H), 7.10 (m, 2H), 7.28 (m, 3H), 7.40 (m, 3H), 7.62 (m, 2H)
Reaction SMILES: [O:1]1C[C:2]21[CH:8]1[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]1)[CH2:4]2.B>O1CCCC1.[Cl-].[Na+].O>[N:5]12[CH2:10][CH2:9][CH:8]([CH2:7][CH2:6]1)[C:2](=[O:1])[CH2:4]2
Reactant: C1CN2CCC1C1(CO1)C2
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CN2CCC1CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A mixture of trimethylsulfoxonium iodide (16.10 g, 73.2 mmol) and a dispersion of sodium hydride (60% in oil, 3.00 g, 75.0 mmol) in anhydrous dimethyl sulfoxide was stirred at room temperature under nitrogen for 30 minutes. Quinuclidin-3-one (II) (7.05 g, 56.3 mmol) was then added as a solid portionwise, and the resulting mixture was stirred at 65–70° C. under nitrogen for 1 hour. The reaction mixture was cooled, water was added (200 ml), and the resulting solution was extracted with chloroform (3×200 ml). The chloroform extracts were combined, and back-extracted with water (4×200 ml). The chloroform layer was then dried (MgSO4), filtered, and evaporated under reduced pressure to afford spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (6.51 g, 46.8 mmol, 83%) as a clear, colorless liquid. To a stirred solution of spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (5.3 g, 38.1 mmol) in anhydrous tetrahydrofuran (100 ml) at 0° C. was added dropwise a solution of borane in tetrahydrofuran (1.0 M, 38.1 ml, 38.1 mmol), and resulting solution was stirred at 0° C. under nitrogen for 30 minutes. Brine (100 ml) was added cautiously to the reaction solution, and the resulting aqueous mixture was extracted with ethyl acetate (2×100 ml). The organic extracts were combined, dried (MgSO4), filtered, and evaporated under reduced pressure to afford the title compound (II) (4.3 g, 28.1 mmol, 74%) as a white solid: electrospray MS 152 ([M−H]+, 15).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=O)[C:3]=1[N+:9]([O-:11])=[O:10].P(Br)(Br)([Br:14])=O.C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C>[Br:14][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: Cc1ccnc(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.8 %

Procedure:
The 4-methyl-3-nitropyridin-2(1H)-one (110 g, 0.71 mol) was suspended in dichloroethane (1 L). The solution of phosphorus oxybromide (317 g, 1.1 mol) in dichloroethane (1 L) was added dropwise thereto at the ambient temperature. The reaction mixture was refluxed for 12 hours. The mixture was allowed to cool to room temperature, poured into ice water, and neutralized with potassium carbonate. The organic layer was separated, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated to provide the title compound (yield 71.8%).
Reaction SMILES: C(O[C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][O:19][C:17]([C:15]1[O:14][C:11]2[CH2:12][NH:13][CH:8]([CH3:6])[CH2:9][C:10]=2[N:16]=1)=[O:18]
Reactant: COC(=O)c1nc2c(o1)CNC(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc2c(o1)CNC(C)C2
Reaction time: 0.17 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (500 mg) in methylene chloride (15 ml) was added trifluoroacetic acid (15 ml) at room temperature, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure. To the resulting residue were added methylene chloride (20 ml), triethylamine (495 μl), acetic acid (205 μl), formalin (230 μl) and sodium triacetoxyborohydride (570 mg) at room temperature. After stirring for 15 minutes, methylene chloride (20 ml) and a saturated aqueous solution (50 ml) of sodium bicarbonate were added to the reaction mixture to separate it into layers. The water layer was extracted with methylene chloride (3×20 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (chloroform:methanol=20:1→10:1), whereby the title compound (257 mg) was obtained as a colorless transparent oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([N+]([O-])=O)[C:15]([CH3:22])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:26][CH3:25])[C:15]([CH3:22])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c([N+](=O)[O-])c3C)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
5-Methoxy-2-[(3,5-dimethyl-4-nitro-2-pyridinyl)methylthio]-1H-benzimidazole (IX) (50 gm, 0.145 mole) was dissolved in methanol and heated to 45° C. A solution of sodium methoxide (50 gm, 0.925 mole) in methanol (150 ml) was added dropwise over a period of 3 hours at 45-60° C. Stirring was continued for another 2 hours and then methanol was distilled off under reduced pressure. To the cooled residue was added water (200 ml) followed by concentrated HCl (65 ml) until the pH of the mixture was 7.5. The reaction mixture was extracted with dichloromethane and the dichloromethane layer was washed with water (2×100 ml). The dichloromethane layer was dried over sodium sulfate and concentrated to yield the product as an amber color syrup. Yield was 40.1 gm, about 83.8% of theoretical. A solid sample was obtained by trituration of the syrup several times with petroleum ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][N:4]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[C:3]1=[O:13].[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][N:4]([C:7]2[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]([CH3:12])[N:8]=2)[C:3]1=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cn1ccc(N2CCC(C)(C)C2=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CCC(C)(C)C2=O)n1
Temperature: 0 °C

Procedure:
To a solution of 3,3-dimethyl-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (170 mg) in acetic anhydride (2.1 mL) was added fuming nitric acid (0.073 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (170 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.Br[CH2:28][C:29]#[N:30].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:28][C:29]#[N:30])[CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c1C(=O)N(C1CCNCC1)C2=O)c1ccc(Cl)s1
Reactant: N#CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg (0.26 mmol) of 5-chloro-N-[1,3-dioxo-2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-4-yl]-2-thiophenecarboxamide, 0.022 ml (0.31 mmol) of α-bromoacetonitrile and 0.072 ml (0.51 mmol) of triethylamine in 2.5 ml of DMF are stirred at room temperature overnight. The mixture is concentrated and the residue is taken up in dichloromethane, washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The product is crystallized with ether, filtered off with suction and dried under high vacuum. Alternatively, the product can be purified by chromatography on silica gel (dichloromethane/methanol mixtures).
Reaction SMILES: [H-].[Na+].C(=O)=O.CO.[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[N:13][CH:14]=1.Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br>C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:12]=[N:13][CH:14]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1cncc(Br)c1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(c2cncc(Br)c2)CCOCC1
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Under argon, NaH (60% in mineral oil, 0.497 g, 12.4 mmol) is added into THF (10 mL). The reaction mixture is cooled on a bath of dry ice/CH3OH. A solution of (5-bromo-pyridin-3-yl)-acetonitrile (1.0 g, 5.0 mmol) and 2-bromoethyl ether (0.719 mL, 5.15 mmol) in THF (4.5 mL) is added dropwise. The reaction is stirred for 30 min. The dry ice/MeOH bath is removed and the mixture is stirred at room temperature for 14 hrs. The reaction is quenched by slow addition of MeOH (5 mL). The mixture is then concentrated. The resulting crude product is purified by normal phase chromatography using 0-3% MeOH in DCM as the gradient to afford 4-(5-bromo-pyridin-3-yl)-tetrahydro-pyran-4-carbonitrile (1.07 g, 79% yield).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[O:18][CH2:19][C:14]=3[C:13]([C:24]([OH:26])=O)=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:27]>CO>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[O:18][CH2:19][C:14]=3[C:13]([C:24]([NH2:27])=[O:26])=[N:12]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: N
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)c3c2-c2ccccc2OC3)cc1
Solvent: CO
Product: NC(=O)c1nn(-c2ccc(S(N)(=O)=O)cc2)c2c1COc1ccccc1-2
Temperature: 60 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
To a suspension of methyl ester of 1-[4-(aminosulfonyl)phenyl]-1,4-dihydro-[1]benzopyrano[4,3-c]pyrazole-3-carboxylic acid (0.77 g, 2.0 mmol) in MeOH (50 ml) in a pressure tube, liquid NH3 (5 ml) was added. The pressure tube was sealed at RT and then heated to 60° C. overnight. The suspension became clear solution. After 24 h, the solution was cooled to RT and pressure was relieved. The solvent was removed under reduced pressure. The resulting white solids were recrystallized in MeOH, to yield pure product 1-[4-(aminosulfonyl)phenyl]-1,4-dihydro-[1]benzopyrano[4,3-c]pyrazole-3-carboxamide (0.3584 g, 48%). Mass (MH+) 137. Anal. Calc'd for C17H14O4N4S+0.4H2O: C, 54.08; H, 3.95; N, 14.86. Found: C, 54.13; H, 3.90; N, 14.86.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.O1CCOCC1.[OH-].[K+]>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: CCOC(=O)CCN[C@H]1CC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](NCCC(=O)O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 80 °C

Procedure:
A mixture of cis-ethyl 3-({4-[4-amino-3-(4-{[2-fluoro-4-trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoate (0.23 g, 0.36 mmol), p-dioxane (15 mL), potassium hydroxide (0.10 g, 1.81 mmol) and water (1.5 mL) were heated at 80° C. for 3 hours. The solvents were evaporated and the residue was purified by preparative HPLC to yield cis-3-({4-[4-amino-3-(4-{[2-fluoro-4-trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoic acid (0.11 g, 0.18 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz). 9.91 (dd, 1H), 8.31 (d, 1H), 8.25 (s, 1H), 8.00 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 6.89 (br, 2H), 4.79 (m, 1H), 3.95 (s, 3H), 2.46-3.00 (m, 7H), 2.29 (m, 2H), 1.91 (m, 2H), 1.80 (m, 2H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile—0.05M ammonium acetate over 10 min, 1 mL/min) Rt 6.06 min. MS: MH+ 616.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: NC1CCc2ccccc21
Reactant: Clc1nc2ccccc2[nH]1
Product: c1ccc2c(c1)CCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 1-aminoindane by Procedure A (15 min at 200° C.). The product was isolated by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 195.5-197° C.). MS(ES+) m/z 250 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.90 (m, 1 H), 2.55 (m, 1 H), 2.83 (m, 1 H), 2.95 (m, 1 H), 5.36 (m, 1 H), 6.82-6.97 (m, 3H), 7.11-7.31 (m, 6H), 10.70 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH3:9][C:10]1([CH3:27])[O:14][C@H:13]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][O:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][C:10]1([CH3:27])[O:14][C@H:13]([CH2:15][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:12][O:11]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared as in Example 5, 12.0 g, 106 mmol) in N,N-dimethylformamide (150 mL) was treated with para-toluenesulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl ester (25.5 g, 89.0 mmol), and potassium carbonate (24.5 g, 178 mmol). The reaction mixture was heated to 90° C. for 6 h under nitrogen. After this time, the reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. Purification by ISCO flash chromatography (128 g, 5-30% ethyl acetate/hexanes) afforded 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-3-nitro-1H-pyrazole (14.5 g, 73%) as a light yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[Cl:13][C:14]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:15]=1[O:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]=[CH:20][O:19]1>O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:13][C:14]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:15]=1[O:16][CH2:17][C@@H:18]1[O:19][C@@H:20]([O:12][CH:3]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=2[Cl:11])[CH2:2][Br:1])[CH2:21][CH2:22][CH2:23]1
Reactant: OC(CBr)c1ccc(Cl)cc1Cl
Reactant: Clc1ccc(OCC2CCC=CO2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(OC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)c(Cl)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 10 ml of an ethereal solution of 425 mg of α-bromomethyl-2,4-dichlorobenzyl alcohol and 340 mg of 2-(2,4-dichlorophenoxymethyl)-3,4-dihydro-2H-pyran was added a catalytic amount (2 drops) of phosphorus oxytrichloride, and the mixture was stirred at room temperature for 4 days. 3 drops of triethylamine were then added and the solvent was evaporated off under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 40:2:1 by volume mixture of hexane, benzene and ethyl acetate, to give 681 mg of the isomer of lesser polarity of trans-6-(2,4-dichlorophenoxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran as colorless crystals melting at 104°-105° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=1.[CH2:17]1[O:25][C:24]2[CH:23]=[CH:22][C:21]([N:26]=[C:27]=[O:28])=[CH:20][C:19]=2[O:18]1>N1C=CC=CC=1>[O:25]1[C:24]2[CH:23]=[CH:22][C:21]([NH:26][C:27]([NH:16][C:12]3[CH:11]=[C:10]([C:2]4[O:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:15]=[CH:14][N:13]=3)=[O:28])=[CH:20][C:19]=2[O:18][CH2:17]1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccn1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: c1ccncc1
Product: O=C(Nc1ccc2c(c1)OCO2)Nc1cc(-c2nc3ccccc3o2)ccn1

Procedure:
A microwave vial was charged with 4-benzoxazol-2-yl-pyridin-2-ylamine (0.05 g, 0.2 mmol), 3,4-(methylenedioxy)phenyl isocyanate (0.04 g, 0.2 mmol) and 1 mL of pyridine. The mixture was subjected to microwave irradiation at 160° C. for 15 minutes. Upon cooling, a precipitate formed. The solid was filtered and then triturated with hot methanol. The undissolved material was filtered, and the precipitate that formed in the mother liquor was filtered and dried to afford the desired product as a white solid. (Calc'd for C20H14N4O4: 374.36, [M+H]+ found: 375.1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:57])[N:32]([CH2:41][C:42]1[C:47]([F:48])=[CH:46][CH:45]=[C:44]([NH:49][S:50]([CH2:53][CH2:54][CH3:55])(=[O:52])=[O:51])[C:43]=1[F:56])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][N:34]=1)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1>[C:26]([O:30][C:31](=[O:57])[N:32]([CH2:41][C:42]1[C:47]([F:48])=[CH:46][CH:45]=[C:44]([NH:49][S:50]([CH2:53][CH2:54][CH3:55])(=[O:52])=[O:51])[C:43]=1[F:56])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]([OH:40])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[CH:35][N:34]=1)([CH3:28])([CH3:27])[CH3:29]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)c1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncccc34)cn2)c1F
Temperature: 15 °C

Procedure:
To a solution of 3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.644 g, 1.61 mmol) in tetrahydrofuran (10.0 mL) at −40° C. under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.80 mL) was added slowly. The reaction was allowed to warm to 15° C. over 100 minutes, then cooled to −40° C., followed by adding [2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (560, 0.100 g, 0.21 mmol, prepared as described in Example 60, Scheme 175) in tetrahydrofuran (2.0 mL). The reaction was allowed to warm to 5° C. over 2 hours, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow solid (574, 75 mg, 47%). MS (ESI) [M+H+]+=744.7.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14].[N:16]([O-])=O.[Na+]>C(O)(=O)C.Cl.O>[C:7]1([N:6]2[C:2]3[N:1]=[N:16][NH:15][C:13](=[O:14])[C:3]=3[CH:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=O)c1cnn(-c2ccccc2)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]nnc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
1 g of 5-amino-1-phenyl-4-pyrazolecarboxamide in 18 ml of glacial acetic acid and 10 ml of concentrated hydrochloric acid was stirred at 0° C. during the addition of a solution of 0.4 g of sodium nitrite in 6 ml of water. The mixture was held at 0° C. for 20 minutes, then allowed to warm to room temperature and stirred for a further 2 hours. The precipitated product was filtered off and recrystallized from ethanol to yield 580 mg of 7-phenyl-7H-pyrazolo[3,4-d]-1,2,3-triazin-4(3H)-one of melting point 150°-151° C.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][OH:29])[CH:22]=1)[CH2:19][NH2:20]>C(O)C.[Pd]>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][OH:29])[CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1ccc(O)c(CO)c1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-carbomethoxymethoxyphenyl)propan-2-one (1.5 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine (1.23 g) in ethanol (80 ml) was refluxed 0.5 hours, cooled to ambient temperature, 10% Pd/C added and the mixture hydrogenated at 75 psi and 50°-60° for 8 hours. The solution was filtered, evaporated, the residue taken up in ethyl acetate and filtered again. Removal of the solvent gave an oil which was crystallised and recrystallised from benzene to give the title compound, 0.47 g, mp 60°-63° as a 52:48 mixture of diastereoisomers. τ(d6DMSO) 9.1 (3H, d, J=6 Hz), 6.6-7.8 (5H, m), 6.4 (3H, s), 5.72 (1H, t, J=6 Hz), 5.54 (2H, s), 5.3 (2H, s), 7.2-6.4 (7H, m), 7.6-5.5 (4H, broad, disappears with D2O).