Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[N:25].C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:7]1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C#N)cc2)CCN1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (2.5 g, supplier Atlantic Scitech) and DIPEA (5.45 ml, 31.2 mmol) in dry dichloromethane (DCM) (60 ml) at 0° C. under argon was added 4-cyanobenzenesulfonyl chloride (2.64 g, 13.11 mmol) and the resulting clear solution stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (100 mL) was added, the layers separated, then the organic layers washed with 2M aqueous HCl (100 mL) and passed through a hydrophobic frit. The solution in DCM was cooled to 0° C., then TFA (8.87 ml, 115 mmol) was added. The resulting very pale yellow solution was allowed to warm to room temperature over 1 h, then stirred for 18 h. Aqueous 2M NaOH (100 mL) was added cautiously with cooling (0° C.) and layers were separated. The organic layer was extracted with 1M aqueous HCl (3×30 mL). With cooling (0° C.), the combined acidic aqueous layers were adjusted to pH 7 by addition of solid NaOH, and then extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a white solid (2.35 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][NH2:33].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:33][CH2:32][C:23]4[CH:24]=[CH:25][C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:22]=4)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: NCc1ccc2ccccc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5ccccc5n4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (150 mg, 0.52 mmol) and quinolin-2-ylmethanamine hydrochloride (206.0 mg, 1.058 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (1 mL, 6 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (30-60% acetonitrile-water [10 mM DEA]) to afford a light yellow solid.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[N:25]#[C:26]Br.O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][C:26]([NH2:25])=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH2:23][CH3:24]
Reactant: N#CBr
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(N)=NC2=N1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A partial solution of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.1 g), cyanogen bromide (0.33 g), and sodium acetate trihydrate (0.42 g) in 50% aqueous ethanol (44 ml) was stirred at room temperature for 2 hours then allowed to stand overnight. The stirred mixture was then heated in a water bath (temperature 65° C.) for 3 hours, extra cyanogen bromide (0.05 g) added, and the mixture heated for a further 2 hours. The suspension was subjected to partial evaporation under reduced pressure then ammonium hydroxide was added to pH 5. The crude product was collected by filtration and recrystallised from acetonitrile to give the pure title compound, 0.6 g, m.p. 322-335° C. dec. (after melting about 200° C.). NMR (DMSO-d6; 250 MHz) δ: 0.9 (3H, t) ; 1.6 (2H, m) ; 3.9 (2H, t); 6.8 (2H, s); 6.8 (2H, s); 6.9-7.1 (2H, m); 7.3-7.5 (3H, m).
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=[O:16].O>CN(C=O)C>[O:16]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[CH2:14][N:6]1[C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: Oc1nc2c(s1)CCCC2
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cn2c3c(sc2=O)CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of 2-hydroxy-4,5,6,7-tetrahydrobenzothiazole (335 mg, 2.16 mmol) in DMF (3 mL) was added NaH (101 mg, 2.52 mmol). After stirring 10 minutes at room temperature, a solution of 2-bromo-4′-methylacetophenone (668 mg, 2.82 mmol) in DMF (5 mL) was added and the mixture was stirred overnight. Water was added and the mixture was extracted with EtOAc, dried over MgSO4 and the solvent was evaporated. The oil recovered was purified by flash chromatography on silicagel (CH2Cl2) to give 29 as a solid in 65% yield: mp 108-110° C.; 1H-NMR (DMSO-d6) 1.73 (s, 4H), 2.19 (s, 2H) 2.40 (m, 5H), 5.23 (s, 2H), 7.39 (d, 2H), 7.95 (d, 2H); Anal. (C16H17NO2S) C, H, N.
Reaction SMILES: [NH3:1].CO[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[O:27][C:21]=2[CH2:20]1)=[O:5]>CN(C)C=O>[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[O:27][C:21]=2[CH2:20]1)(=[O:5])[NH2:1]
Reactant: N
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 1 h

Procedure:
0.02 mol of concentrated ammonia (D=0.9) is added dropwise to a solution of 4.02 g of 2-[4-(5-methoxycarbonyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine in 30 ml of dimethylformamide at 20°. The mixture is stirred at 20° for 1 hour, the usual working up is carried out and 2-[4-(5-carbamoyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[N:12]=1.S(Cl)(Cl)=O.[CH3:26][N:27]([CH:29]=O)C.[CH2:31]1COCC1>>[N:27]1([C:16]([C:15]2[CH:14]=[C:13]([C:11]3[N:12]=[C:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[S:9][CH:10]=3)[CH:21]=[CH:20][CH:19]=2)=[O:18])[CH2:29][CH2:31][CH2:26]1
Reactant: CN(C)C=O
Reactant: Cc1ccncc1-c1nc(-c2cccc(C(=O)O)c2)cs1
Reactant: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1ccncc1-c1nc(-c2cccc(C(=O)N3CCC3)c2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[2-(4-Methylpyridin-3-yl)-1,3-thiazol-4-yl]benzoic acid (238 mg) was suspended in THF (10 ml) and thionyl chloride (0.09 ml) and DMF (0.05 ml) were added. The mixture was heated under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure and re-dissolved in THF (10 ml). To this solution was added a solution of azetidine hydrochloride (0.54 g) dissolved in 1N NaOH (10 ml), and the mixture was stirred at room temperature for 30 min. The reaction mixture extracted with ethyl acetate and the organic layer was dried and concentrated. The obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate) for purification and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (148 mg) as colorless powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][CH2:22][N:8]3[C:7](=[O:23])[C:6]=2[CH:24]=1.O[CH2:26][CH:27]1CC1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH:19]4[CH2:27][CH2:26]4)=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][CH2:22][N:8]3[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: OCC1CC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(Cl)ccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(Cl)ccc1-2
Reaction time: 0.33 h

Procedure:
6.92 g (20 mmol) of ethyl (S)-7-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 20 g of hydroxymethyl-cyclopropane and 1 g of tetraethyl orthotitanate are heated to 130° for 16 hours, evaporated in vacuo, the residue is taken up in chloroform and the solution is poured into about 20 percent hydrochloric acid. The mixture is stirred for 20 minutes, the chloroform phase is separated, washed successively with 1N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate there is obtained cyclopropylmethyl (S)-7-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 146°-148°.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26](S(C)(=O)=O)[N:25]=1>O1CCCC1.CCCCCC>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:14]([CH2:15][CH2:16][CH3:17])[C:13]([O:19][CH2:20][CH3:21])=[O:18])[N:25]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCCCC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(C(=O)OCC)c1nc(OC)cc(OC)n1
Reaction time: 0.5 h

Procedure:
4,2 g (30 mmol) Diisopropylamine in 100 ml tetrahydrofuran, under nitrogen at -78° C., was treated with 19 ml (30 mmol) 1.6M butyllithium in hexane. The mixture was stirred for 30 minutes and then at -60° C., a solution of 3.5 g (27 mmol) ethyl pentanoate, dissolved in 20 ml tetrahydrofuran, was added dropwise. The mixture was stirred for a further hour and 5.9 g (27 mmol) 4,6-dimethoxy-2-methylsulphonylpyrimidine was added, portionwise. The temperature of the mixture rose over 2 hours to +10° C. The reaction mixture was then washed with saturated aqueous ammonium chloride and sodium chloride. The aqueous phase was extracted with ethyl acetate. The organic phases were dried over magnesium sulphate and concentrated. The resulting yellow oil was finally purified on silica gel using a hexane/ethyl acetate mixture (0 to 20% ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])cnc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-amino-4-methyl-3-nitropyridine (25.6 g, 167 mmol) in conc. H2SO4 (50 mL) at 0° C. was added HNO3 (7.77 mL, d=1.49) drop-wise over 30 min. The mixture was warmed to r.t. for 1 h then heated to 50° C. for 60 min. The reaction mixture was cooled and poured into 500 g of ice. The resulting precipitate was filtered, washed with 50 mL of H2O, and air dried to give 2-amino-4-methyl-3,5-dinitro-pyridine as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].C(=O)([O-])O.[Na+].[Cl:21]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:21][CH2:14][C:5]1[C:6]([C:10]([F:13])([F:12])[F:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:15]
Reactant: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Reactant: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(CCl)c1OC(F)F

Procedure:
To a solution of 1.00 g (4.35 mmol) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole in 10 ml of carbon tetrachloride was added 0.55 g (6.52 mmol) of sodium hydrogen carbonate, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light and chlorine gas was introduced in a suitable amount while the amount of the aimed compound formed was confirmed by gas chromatography. After the completion of the reaction, a gas chromatographic analysis was conducted to confirm that 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was formed in an amount of 61.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH2:15]>CCOCC>[CH3:14][NH:15][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Product: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a suspension of 4-nitrobenzenesulfonyl chloride (5 g, 22.56 mmol) in ether (250 ml), methylamine (5 ml, 40% aq. solution, 56.4 mmol) was added, and the mixture was stirred at room temperature. After 16 hr. the reaction mixture was concentrated to remove the solvent and the residue was resuspended in methylene chloride. After washing with 2N HCl and brine, the organic fractions were dried (MgSO4), filtered and concentrated to give N-methyl-4-nitrobenzenesulfonamide (4.8 g, 98%): mp (DSC) 109° C. Anal Calc'd. for C7H8N2O4S: C, 38.89; H, 3.73; N, 12.96. Found: C, 38.83; H, 3.72; N, 12.96.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[OH2:13].OO.N=O>C(O)(C)(C)C>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:3][C:4]([OH:13])([CH3:12])[CH3:11])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: O
Agent: N=O
Agent: OO
Solvent: CC(C)(C)O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 45 °C
Yield: 90 %

Procedure:
2,2'-Dipyridyl (0.16 g, 1.0 mmol) and 2.54 g (0.80 mmol) of 5% ferric chloride on silica gel are stirred together in 30 mL of tert-butyl alcohol which is heated to 45° C. To the mixture are added 3.44 g (20.0 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 10 mL of water. A solution of 9.4 g (138 mmol) of 50% aqueous hydrogen peroxide mixed with 20 mL of tert-butyl alcohol is added over four hours at 45-50° C. to the reaction mixture. The temperature is maintained at 45-50° C. for 30 minutes. Analysis by gas chromatography shows that the starting nitroxyl compound is completely reacted to form greater than 90% of the title compound.
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[N:18]([CH3:19])[CH:17]=[CH:16][C:11]3=[N:12][C:13]=2[C:14]#[N:15])[CH2:4][CH2:3]1.[CH3:21][Mg]Br.CCOCC.[BH4-].[Na+]>C1COCC1>[NH2:15][CH:14]([C:13]1[N:12]=[C:11]2[CH:16]=[CH:17][N:18]([CH3:19])[C:10]2=[CH:9][C:8]=1[N:5]1[CH2:6][CH2:7][C:2]([CH3:20])([OH:1])[CH2:3][CH2:4]1)[CH3:21]
Reactant: C[Mg]Br
Reactant: Cn1ccc2nc(C#N)c(N3CCC(C)(O)CC3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-(4-hydroxy-4-methylpiperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (245 mg, 0.906 mmol) in THF (5 mL) at 0° C. was slowly added 3M methylmagnesium bromide in ether (1.21 mL, 3.63 mmol). The resulting yellow solution was stirred at 0° C. for 2.5 hours. The reaction was quenched with MeOH (5 mL) and stirred for 15 minutes at RT. Sodium borohydride (68.6 mg, 1.81 mmol) was added. The reaction was stirred for 1 hour, quenched with 1M HCl (5 mL), and then stirred for an additional 15 minutes. The mixture was subsequently diluted with EtOAc and washed with saturated aqueous NaHCO3 (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C16H24N4, 289; found 289.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([CH2:26][C:4]([C:3]2[CH:8]=[C:9]([NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18])[CH:10]=[CH:11][C:2]=2[F:1])=[O:6])[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)OC)c1
Product: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1
Yield: 69.9 %

Procedure:
Using multiple iterations of a procedure analogous to the procedure described in Intermediate 11 using methyl 2-fluoro-5-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (104 g, 411 mmol) and 2-chloro-4-methylpyrimidine (59 g, 493 mmol), the title compound of Step B was obtained (100 g, 69.9% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.67-13.75 (br, 1H), 8.50-8.53 (m, 0.3H), 8.31-8.38 (m, 1H), 7.50-7.82 (m, 2.6H), 6.56-7.20 (m, 3.5H), 6.20-6.25 (m, 1H), 5.82-6.01 (1.3H), 5.20-5.40 (m, 2.6H), 4.50-4.61 (m, 2.6H), 4.31-4.41 (m, 0.9H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([NH2:29])([CH3:28])[CH3:27].[C:30]([C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[C:50]4[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=4[N:44]([CH3:51])[N+:43]=3[O-:52])[N:40]=2)[N:35]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:34]=1)(O)=[O:31]>CN(C=O)C>[C:26]([NH:29][C:30]([C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[C:50]4[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=4[N:44]([CH3:51])[N+:43]=3[O-:52])[N:40]=2)[N:35]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:25]
Reactant: Cn1c2c(c(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)[n+]1[O-])CCCC2
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1c2c(c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)[n+]1[O-])CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (46.3 mg, 122 μmol.20) and 2-methylpropan-2-amine (29.7 mg, 406 μmol) then 3-(7-carboxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (45 mg, 101 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 30 min to yield 3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (43 mg, 86.2 μmol, 85.0%) as a clear foam. MS (M+H)+=499 (>90% purity); 1H NMR (CDCl3) δ: 7.82 (s, 1H), 6.21 (s, 1H), 4.52 (s, 2H), 2.36-2.45 (m, 2H), 2.30 (s, 3H), 1.23-1.37 (m, 2H), 0.95-1.12 (m, 2H), 0.89 (dd, J=10.9, 5.6 Hz, 2H), 0.72-0.85 (m, 2H), 0.37 (s, 9H), −0.29-−0.17 (m, 2H), −1.20 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:9][CH:8]=1)CO.[CH:19](=[O:22])[CH2:20][CH3:21].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[N:14]1([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH:5]3[CH2:2][O:1][C:19]([CH3:23])([CH2:20][CH3:21])[O:22]3)=[CH:12][CH:11]=2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: CCC=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(O)COc1ccc(Cn2cccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1(C)OCC(Oc2ccc(Cn3cccn3)cc2)O1
Reaction time: 4 h

Procedure:
A mixture of this 2-hydroxy-3-[4-(1-pyrazolyl)methylphenoxy]propanol (941 mg), propionaldehyde (308 mg), dry toluene (20 ml) and a catalytic amount of p-toluenesulfonic acid was heated at reflux under stirring for 4 hours. Then, the reaction mixture was poured into ice-cooled 5% aqueous sodium hydrogencarbonate (100 ml), followed by two extractions with ethyl acetate (50 ml). The organic layers were combined, washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 723 mg of 4-[4-(1-pyrazolyl)methylphenoxy]-methyl-2-ethyl-1,3-dioxolane (compound 38). Yield, 66% (based upon 2-hydroxy-3-[4-(1-pyrazolyl)methylphenoxy]propanol).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17].[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[CH3:18][O:8][C:4]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1Oc1c(N)n(C)[nH]c1=O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(OC)nn(C)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.3 %

Procedure:
A mixture of 5-amino-4-(2-methoxyphenoxy)-1-methyl-1,2dihydro-3H-pyrazol-3-one (Preparation 69) (300 mg), caesium carbonate (1.25 g) and iodomethane (200 mg) in dry dimethylformamide (5 ml) was stirred under a nitrogen atmosphere for 24 hours at room temperature. The reaction mixture was partitioned between ethyl acetate (7×25 ml) and water (40 ml) and the combined organic extracts were dried (magnesium sulfate) and concentrated under vacuum. The residue was purified by chromatography on a Biotage Flash™ 40s silica cartridge (40 g silica) using neat ethyl acetate and then 1% methanol/dichloromethane as eluants to give the title compound as a brown solid (90 mg), Rf 0.57 (10% methanol/dichloromethane).
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([C@H:15]([OH:18])[C:16]#[CH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:17]=[C:16]([C@H:15]([OH:18])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C#C[C@@H](O)c1ccccc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc([C@H](O)c3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 67 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with (R)-1-phenyl-2-propyn-1-ol to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 67% yield: mp 146-149° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.50-7.31 (m, 10H), 6.13-6.08 (m, 2H), 4.61 (d, J=6.0 Hz, 2H), 2.96 (d, J=3.0 Hz, 1H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.8, 155.2, 152.9, 152.3, 140.9, 137.3, 128.8, 128.7, 128.2, 127.9, 127.7, 126.3, 124.5, 118.9, 68.9, 44.2, 17.2; MS (ES+) m/z 406.3 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NCCCSc1ccncc1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)NCCCSc1ccncc1
Yield: 93.1 %

Procedure:
To a solution of 1.21 g (5.00 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.79 ml (20.0 mmol) of triethylamine in 50 ml of methylene chloride was added 1.02 ml (6.00 mmol) of caproyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.24 g of the desired compound (84.2%, colorless powder), mp: 48.0°-49.0° C.