Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:28]1([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:32][CH2:31][C:30](=[O:33])[O:29]1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][O:15][N:14]([C:28]2([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[O:35])[CH2:32][CH2:31][C:30](=[O:33])[O:29]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)O1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)O1
Reaction time: 0.25 h
Yield: 56 %

Procedure:
In 4 ml of dichloromethane was dissolved 60 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution were added under ice-cooling 0.08 ml of diisopropyl ethylamine and 90 mg of the Compound (15) obtained in Example 15. The mixture was stirred for 15 minutes under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was washed with water, which was dried (Na2SO4), then the solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (1:1) to give 71 mg of the subject Compound (8) as colorless foamy product. The IR and NMR spectra of this product were in agreement with those of the Compound (8) obtained in Example 8.
Reaction SMILES: [C-]#N.[Na+].C1N2CC[N:6](CC2)[CH2:5]1.[Br:12][C:13]1[CH:14]=[N:15][C:16](Cl)=[N:17][CH:18]=1>CS(C)=O.O>[Br:12][C:13]1[CH:14]=[N:15][C:16]([C:5]#[N:6])=[N:17][CH:18]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 522.6 %

Procedure:
To a solution of sodium cyanide (168.35 mg, 3.36 mmol), triethylenediamine (60 mg, 0.52 mmol) in a mixture of DMSO (0.7 mL) and water (1.4 mL) was added a solution of 5-bromo-2-chloropyrimidine (500 mg, 2.59 mmol) in DMSO (1.3 mL). The solution was stirred at rt overnight, diluted with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give 5-bromopyrimidine-2-carbonitrile (500 mg, yield 100%, crude).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[S:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([OH:43])[CH:41]=[CH:42][C:35]1=2.[C:44]([O:48][C:49](N1CCC[C@H]1CO)=[O:50])([CH3:47])([CH3:46])[CH3:45].[CH2:58]([N:60]([CH2:63][CH3:64])[CH2:61][CH3:62])C>ClCCl>[S:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([O:43][CH2:58][N:60]3[CH2:63][CH2:64][CH2:62][CH:61]3[C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])[CH:41]=[CH:42][C:35]1=2
Reactant: Oc1ccc2sccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CCN(CC)CC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCN1COc1ccc2sccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 103.6 %

Procedure:
Polymer supported triphenyl phosphine (5.12 g, 13.32 mmol, 2.6 mmol/g loading) was suspended in dichloromethane (15 mL) cooled to 0° C. in an ice/water bath. Diisopropyl azodicarboxylate (2.69 g, 13.3 mmol, 2.6 mL) was added dropwise and the mixture was stirred for 10 min. A solution of benzo[b]thiophen-5-ol (1.20 g, 7.99 mmol) and (S)-tert-butyl-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.34 g, 6.66 mmol) dissolved in dichloromethane (20 mL) was added dropwise at 0° C. The cooling bath was removed, triethylamine (1.35 g, 13.3 mmol) was added, and the mixture was stirred for 16 h. The polymer bound triphenylphosphine was removed by filtration and washed with dichloromethane (3×10 mL). The organic layer was separated, dried over sodium sulfate (200 mg), filtered through a coarse frit (to remove the sodium sulfate), and condensed in vacuo to give a white solid (2.3 g). The crude product was purified by flash chromatography (EtOAc/hexane 1:1) to yield the title compound as a white solid (1.95 g, 55%). MS (M+H)+ 334.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3O)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Into 6 ml of N,N-dimethylformamide was dissolved 0.23 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol. After adding 0.22 g of anhydrous potassium carbonate, 0.13 g of methyl 2-bromopropionate was added at room temperature with stirring and then the mixture was stirred at 80° C. for 3 hours. After cooling the reaction solution to room temperature, the reaction solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica-gel column chromatography to give 0.23 g of methyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound A-3].
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[C:11]=[O:12].[N-]=C=O>C1C=CC=CC=1>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([NH:10][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[O:12])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(N)ccc1I
Agent: [N-]=C=O
Solvent: c1ccccc1
Product: Cc1cc(NC(=O)Nc2cccc(C(F)(F)F)c2)ccc1I
Temperature: 90 °C

Procedure:
To a solution of 4-iodo-3-methylaniline (200 mg, 0.86 mmol) in benzene (5 mL) in a sealable tube was added 1-isocyanato-3-(trifluoromethyl)benzene (0.133 mL, 0.94 mL; “E” is an electrophilic group disussed in scheme 3, and here is an isocyanate). The tube was sealed and heated at 90° C. for 4 h. The mixture was allowed to cool to room temperature before filtering. The off white solid was washed with additional benzene (10 mL) and used without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17])[N:11]=[CH:10][NH:9][C:8]2=O)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40].[C:44]([C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49])#[CH:45]>C(O)(C)C>[ClH:40].[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17])[N:11]=[CH:10][N:9]=[C:8]2[NH:49][C:48]1[CH:50]=[CH:51][CH:52]=[C:46]([C:44]#[CH:45])[CH:47]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc2nc[nH]c(=O)c2cc1OC(C)C
Reactant: C#Cc1cccc(N)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OC(C)C)c(OC(C)C)cc23)c1
Product: Cl

Procedure:
6,7-Diisopropoxyquinazolin-4-one (55 mg, 0.210 mmol), triphenylphosphine (121 mg, 0.462 mmol) and 3 mL of carbon tetrachloride were refluxed for 16 hours and the reaction mixture was concentrated in vacuo to a residue which was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline (30 mg, 0.257 mmol) and refluxed for 3 hours. The cooled reaction mixture was vacuum evaporated to afford the solid title product which was column chromatographed on silica gel eluted with 5% acetone in methylene chloride containing 0.25% triethylamine. Fractions containing the pure product were concentrated in vacuo to a solid which was dissolved in 2 mL of 1N HCl in methanol, precipitated with ethyl ether, filtered and dried in vacuo at 70° C. to afford the title product; 140 mg (75%); mp 241°-242° C.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1C(OC)=O.[CH3:20][OH:21]>>[CH3:3][C:4]1[CH:5]=[C:6]([C:20]([OH:21])=[O:1])[C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(-c2ccccc2)ccc1C
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: Cc1ccc(-c2ccccc2)c(C(=O)O)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
32% aq. NaOH (74 mL) was added to a rt solution of methyl 4-methyl-[1,1′-biphenyl]-3-carboxylate (15.5 g, 0.068 mol) in MeOH (124 mL). The rxn mixture was stirred at 65° C. for 2 h, then the org. solvent was evaporated, water added, and the aq. layer acidified with conc. HCl. The mixture was stirred at rt for 30 min, and the precipitate was filtered off to give the title compound A-1-14 as a white solid. LC-MS A: tR=0.80 min; [M+H]+=no ionization.
Reaction SMILES: [SH:1][CH2:2][C@H:3]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([C:13]([OH:15])=[O:14])[NH:5][C:4]1=[O:16].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([S:1][CH2:2][C@H:3]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([C:13]([OH:15])=[O:14])[NH:5][C:4]1=[O:16])(=[O:19])[CH3:18]
Reactant: O=C1N[C@@H](C(=O)O)CCCCCC[C@@H]1CS
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans 3-mercaptomethyl-2-oxo-1-azacyclodecane-10-carboxylic acid (0.75 g, 3.06 mmol) is dissolved in pyridine (20 mL). Acetyl chloride (0.26 g, 3.37 mmol) is added, and the reaction is stirred at room temperature overnight. The reaction is quenched by cooling to 0° C., adding concentrated hydrochloric acid (20 mL), diluting with water, and extracting several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated to give trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid, MS:M+1=288.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[CH2:15](OCC)C>CO.[Ni]>[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:12]=[CH:15][N:8]2[CH2:9][CH2:10][OH:11])=[CH:4][N:3]=1
Reactant: CCOCC
Reactant: Nc1ncc([N+](=O)[O-])c(NCCO)n1
Agent: [Ni]
Solvent: CO
Product: Nc1ncc2ncn(CCO)c2n1
Temperature: 35 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
19.92 g (0.1 mole) of 2-amino-4-(2-hydroxyethylamino)-5-nitropyrimidine was suspended in 400 ml of methanol, to which 10 g of wet Raney nickel was then added. The mixture was stirred at a temperature of 30-40° C. for 3 hours. After completion of the reaction, the reaction product was filtered through nitrocellulose, followed by washing. The filtrate was concentrated under reduced pressure. To the remaining concentrate, 100 ml of triethylorthoformate and 10 ml of concentrated hydrochloric acid were added, and the mixture was stirred under reflux for 9 hours at a temperature of 80-90° C. After completion of the reaction, the product was cooled to room temperature, and 200 ml of ethylether was then added thereto. The resulting crystal was filtered, washed and dried, thereby giving 13.44 g (75% yield) of yellowish brown-colored 2-amino-9-(2-hydroxyethyl)purine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.[NH3:18].O>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:18])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: N
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reaction time: 8 h

Procedure:
2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (36.9 g) (for example, as prepared for Intermediate 1) was heated with 2M ammonia in isopropanol (250 mL) at 50° C. for 5 hours. After standing at ambient temperature overnight, a further quantity of 2M ammonia in isopropanol (100 mL) was added to break up the resultant cake and the reaction mixture was heated for a further 9 hours until the reaction was complete. To the reaction mixture was added water (70 mL) and the yellow solid filtered off. The solid was washed with isopropyl alcohol:water (5:1 (v/v), 60 mL) and then air-dried under suction to give a first crop. The filtrate was re-filtered after standing overnight to isolate precipitate and both solids were dried in vacuo. The first crop was pure with the second crop material showing a very minor impurity (isolated broad signal 3.5 ppm not seen in first crop) but was otherwise identical. Solid first crop (28.4 g), solid second crop (3.42 g).
Reaction SMILES: C1(OC(=O)N[C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([CH2:14][CH2:13][NH:12][C:11]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:31][CH2:32]2)=[O:19])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccccc1N1CCNCC1
Product: CCc1cc(CCNC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C[O-].[Na+].CO>C(Cl)Cl.CO>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([S:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:9]=3)[NH:13][CH:12]=2)=[CH:20][CH2:19]1
Reactant: CN1CCC(=O)CC1
Reactant: c1ccc(Sc2ccc3[nH]ccc3c2)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CC=C(c2c[nH]c3ccc(Sc4ccccn4)cc23)CC1

Procedure:
5-(Pyrid-2-ylthio)indole (0.347 g, 1.53 mmol), 1-methylpiperid-4-one (0.347 g, 0.38 mL, 3.06 mmol), sodium methoxide (0.497 g) and some finely ground molecular sieves were heated in refluxing MeOH (20 mL) for 24 hr. After work-up and chromatography (silica gel; CH2Cl2 /MeOH; 0-15%), 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole was obtained as a yellow solid (0.35 g). This was treated with fumaric acid (0.189 g, 1.6 mmol) in MeOH/Et2O to give, as a pale yellow crystalline solid: 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole fumarate, 0.227 g (34%), m.p. 226°-28° C.
Reaction SMILES: [CH:1]12[B:9]([CH2:10][CH:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2>O1CCCC1>[CH2:10]=[C:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1.[CH:5]12[BH:9][CH:1]([CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CCCC(CB2C3CCCC2CCC3)CC1
Solvent: C1CCOC1
Product: B1C2CCCC1CCC2
Product: C=C1CCCN(C(=O)OC(C)(C)C)CC1

Procedure:
For this the compounds of general formula XV are reacted with tert.-butyl 4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)-piperidine-1-carboxylate (obtained from the reaction of tert-butyl 4-methylene-piperidine-1-carboxylate with 9-bora-bicyclo[3.3.1]nonane in tetrahydrofuran at reflux temperature) or tert-butyl 4-(9-bora-bicyclo[3.3.1]non-9-ylmethyl)-azepan-1-carboxylate (obtained from the reaction of tert-butyl 4-methylene-azepan-1-carboxylate with 9-bora-bicyclo[3.3.1]nonane in tetrahydrofuran at reflux temperature) in the presence of a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]-palladium-II-dichloride-dichloromethane complex, bis-tri-tert.-butylphosphine-palladium-(0), bis-tri-cyclohexylphosphine-palladium-(0), [1,2-bis(diphenylphosphino)ethane]palladium-II-dichloride or [1,3-bis(diphenylphosphino)propane]palladium-II-dichloride, but preferably [1,1′-bis(diphenylphosphino)ferrocene]-palladium-II-dichloride-dichloromethane complex, as well as a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl-amine, but preferably potassium carbonate, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile or N,N-dimethylformamide, optionally with the addition of water, at temperatures between 30° C. and 150° C., but preferably between 50° C. and 120° C., to obtain the compounds of general formula IX.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:29])OCC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH2:16][CH:17]=[CH2:18])[CH2:9]1.C([Li])CCC.O1[CH2:37][C@@H:36]1[CH2:38][NH:39][C:40](=[O:42])[CH3:41].C1C[O:46]CC1>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:29][C:20]2=[O:46])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH2:16][CH:17]=[CH2:18])[CH2:9]1
Reactant: C=CCN1CC(c2ccc(NC(=O)OCc3ccccc3)cc2F)CCS1(=O)=O
Reactant: CC(=O)NC[C@H]1CO1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=CCN1CC(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CCS1(=O)=O
Reaction time: 1 h
Yield: 73 %

Procedure:
Phenylmethyl [3-fluoro-4-[tetrahydro-1,1-dioxido-2-(2-propenyl)-2H-1,2-thiazin-4-yl]phenyl]carbamate (1.70 g, 4.07 mmol) is dissolved in dry THF (18 ml) under nitrogen and cooled to −78°. A 1.6 M solution of n-butyl lithium (2.7 ml, 4.32 mmol) in hexane is added and stirred for 1 hr. A solution of N-[(2S)oxiranylmethyl]acetamide 11 (960 mg, 8.35 mmol) in dry THF (6.5 ml) is added and the stirred mixture allowed to come to 25° overnight. Solvent is evaporated and the residue partitioned between chloroform (100 ml) and ammonium chloride solution (50 ml). The organic layer is washed with brine (40 ml), dried (MgSO4) and evaporated. The residue is chromatographed over silica gel (150 g) eluting with 2-4% methanol-chloroform to afford the oxazolidinone as a white foam (1.275 g, 73%). HRMS(FAB) calcd for m+H=426.1499: Found; 426.1506.
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:18]([OH:20])=O)[C:7]([C:21]#[N:22])=[C:6]([CH3:23])[NH:5][C:4]=1[CH3:24])#[N:2].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]([CH3:61])[CH2:58][CH2:59][NH2:60]>CN(C=O)C>[C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:18]([NH:60][CH2:59][CH2:58][N:57]([CH3:61])[CH3:56])=[O:20])[C:7]([C:21]#[N:22])=[C:6]([CH3:23])[NH:5][C:4]=1[CH3:24])#[N:2]
Reactant: CN(C)CCN
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C(=O)O)c3c2)C(C#N)=C(C)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C(=O)NCCN(C)C)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-3-carboxylic acid (300 mg, 0.94 mmol), from Synthetic Example 3, in DMF (5 mL) was added Et3N (476 mg, 4.7 mmol) and HATU (430 mg, 1.13 mmol). The mixture was stirred at rt for 30 min, then N,N-dimethylethylenediamine (167.2 mg, 1.9 mmol) was added. The mixture was kept at rt overnight, and then quenched with water. The reaction mixture was extracted with CH2Cl2, dried, and concentrated. The residue was purified by flash chromatography followed by HPLC to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-N-[2-(dimethylamino)ethyl]-1H-indazole-3-carboxamide (121 mg, 33.7%) (Cpd. No. 103.2, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=8.16 (s, 1H), 7.63 (d, 1H), 7.41 (d, 1H), 4.55 (s, 1H), 3.82 (t, 2H), 3.43 (t, 2H), 3.01 (s, 6H), 2.14 (s, 6H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>ClCCl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccccc2)c1
Reaction time: 16 h
Yield: 43.4 %

Procedure:
To a solution of 3-nitrobenzenesulfonyl chloride (3.08 g, 13.9 mmol) in 28 mL of dichloromethane was added triethylamine (3.88 mL, 27.8 mmol) and aniline (1.39 mL. 15.3 mmol). After 16 hours, the reaction was poured into ethyl acetate and 10% HCl solution, then washed with brine, dried (MgSO4) and concentrated in vacuo to provide the crude product. Purification by chromatography on silica gel (25-50% CH2Cl2 /hexane, then 5% MeOH/CH2Cl2) provided 1.68 g of the desired product as an off-white solid.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCCCCCN
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCNC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 0 °C

Procedure:
A solution of 72 mg (0.18 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxa-diazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2), 30 mg (0.15 mmol) of methyl 7-amino-heptanoate hydrochloride, 87 mg (0.23 mmol) of HATU and 0.8 ml of pyridine in 3.2 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was poured into ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and, after filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative RP-HPLC. This gave 13 mg (0.02 mmol, 13% of theory) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[CH3:1][C:2]1[N:3]([C:7]2[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc(-n3ccnc3C)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nccn1-c1ccc(COc2ccc(C(=O)O)cc2)cc1

Procedure:
To a solution of ethyl 4-{[4-(2-methyl-1H-imidazol-1-yl)benzyl]oxy}benzoate (Preparation 30, 507 mg, 1.9 mmol) in THF/MeOH/Water (3:3:1, 7 mL) was added lithium hydroxide monohydrate (198 mg, 4.9 mmol) the resulting reaction mixture was heated under reflux for 72 hours. Lithium hydroxide monohydrate (100 mg, 2.5 mmol) was added and the reaction mixture heated at reflux for further 3 hours. The solvent was reduced in vacuo and the residue diluted with water. The resulting aqueous mixture was acidified with 0.2 M aqueous hydrochloric acid to pH 6.5 and the solid precipitate was collected, washed with water and diethyl ether and dried under reduced pressure at 50° C. to yield the title compound as a white solid, which was carried through to the next step without further purification.