Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)O1.Br[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[CH3:30][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([N+:27]([O-:29])=[O:28])[C:21]=1[C:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1C1=CC(C)(C)CC(C)(C)C1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane (3.96 g, 15 mmol) produced in Example (4b), 2-bromo-3-nitrotoluene (2.48 g, 11.5 mmol), tetrakis(triphenylphosphine)palladium(0) (1.33 g, 1.15 mmol), tripotassium phosphate (3.66 g, 17.3 mmol), 1,2-dimethoxyethane (30 mL) and water (10 mL) was stirred for 10 hours and 20 minutes at an external temperature of 80° C. under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture, and it was filtered through Celite. The filtrate was then extracted with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (hexane) to give 3.14 g of the title compound as a yellow oil.
Reaction SMILES: C(OC(=O)C)(=O)C.O[CH:9]([C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3>N1C=CC=CC=1>[CH3:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[C:23](=[O:24])[C:10](=[CH:9][C:25]3[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:11][CH2:12][C:13]=12
Reactant: Cc1ncccc1C(O)C1CCc2c(C)c3ccccc3n2C1=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1ncccc1C=C1CCc2c(C)c3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (2.24 g) was added to a solution of 8,9-dihydro-7-[(hydroxy)(2-methylpyridin-3-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.35 g, a mixture of the isomers A and B) in pyridine (20 ml). After being stirred at 60° C. for 2 hours, the solution was evaporated in vacuo. The residue was diluted with chloroform, washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.27 g) were dissolved in toluene (30 ml). The solution was stirred at 60° C. for 2 hours and evaporated in vacuo. The residue was crystallized from ethyl acetate to give 8,9-dihydro-10-methyl-7-[(2-methylpyridin-3-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (0.92 g).
Reaction SMILES: N1CCCCC1.C1(NC(N2C3C(=CC(OC4C=CN=C(N(C(OC5C=CC=CC=5)=O)C(=O)OC5C=CC=CC=5)C=4)=CC=3)C=C2)=O)CC1.[CH:48]1([NH:51][C:52]([N:54]2[C:62]3[C:57](=[CH:58][C:59]([O:63][C:64]4[CH:69]=[CH:68][N:67]=[C:66]([NH:70][C:71]([N:73]5[CH2:78][CH2:77][CH:76](N6CCCC6)[CH2:75][CH2:74]5)=[O:72])[CH:65]=4)=[CH:60][CH:61]=3)[CH:56]=[CH:55]2)=[O:53])[CH2:50][CH2:49]1>CN(C)C=O>[CH:48]1([NH:51][C:52]([N:54]2[C:62]3[C:57](=[CH:58][C:59]([O:63][C:64]4[CH:69]=[CH:68][N:67]=[C:66]([NH:70][C:71]([N:73]5[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]5)=[O:72])[CH:65]=4)=[CH:60][CH:61]=3)[CH:56]=[CH:55]2)=[O:53])[CH2:50][CH2:49]1
Reactant: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Agent: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCCCC1
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and piperidine (0.42 ml, 4.2 mmol) were added to a mixture (467 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate obtained in Example 68; and the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; the obtained solid was washed with a solvent mixture of hexane: diethyl ether 1:1 to yield the title compound as crystals (241 mg, 0.57 mmol).
Reaction SMILES: [CH:1]1([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2C=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=CC=CC=2)CCCCCC1.Cl[CH:30]([O:32]C(Cl)Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]1([C:8]2[CH:9]=[CH:12][C:13]([CH:30]=[O:32])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=Cc1ccccc1C1CCCCCC1
Reactant: ClC(Cl)OC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: c1ccc(C2CCCCCC2)cc1
Solvent: ClCCl
Product: O=Cc1ccc(C2CCCCCC2)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Cycloheptylbenzaldehyde can be manufactured as follows: 200 ml of titanium tetrachloride are added dropwise, whilst stirring, to a solution of 200 g of cycloheptylbenzene in 600 ml of absolute methylene chloride under a nitrogen atmosphere at -10° C, and thereafter 132.5 g of dichloromethyl ether are added similarly at 0° C. The reaction mixture is then stirred for a further 30 minutes at 10° C and poured onto 3 kg of ice, and the whole is extracted twice with 500 ml of methylene chloride. The organic phases are washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. Distillation of the evaporation residue in a high vacuum yields 4-cycloheptyl-benzaldehyde in the fraction boiling at 120°-130° C/0.8 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:44][N:45]([CH3:54])[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>CC(N(C)C)=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([N:51]1[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][N:45]([CH3:54])[CH3:44])[CH2:49][CH2:50]1)=[O:6]
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cc(C)c(N)c(C(=O)O)c3)cc12
Reactant: CN(C)CCN1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC(=O)N(C)C
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(C)c(N)c(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Yield: 30.8 %

Procedure:
45 mg (0.12 mmol) of 2-amino-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methyl-benzoic acid and 40 mg (0.16 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride were dissolved in 2 mL of dimethyl acetamide. 45 μL (approx. 0.2 mmol; density unknown) of 1-(2-dimethylaminoethyl)-piperazine was added and the mixture irradiated in a Personal Chemistry® Optimizer to 120° C. for 30 min. The resulting crude was directly purified by mass-triggered reverse-phase HPLC to afford 19 mg (37 μmol, 31%) of {2-amino-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methyl-phenyl}-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanone as an ivory solid. 1H NMR (500 MHz, DMSO-d6) δ 13.71 (s, br., 1H), 8.75 (d, 1H), 8.16 (d, 1H), 7.63 (dd, 1H), 7.46 (dd(d), 1H), 7.44 (m, 1H), 7.22 (m, 1H), 7.21 (m, 1H), 7.09 (dd(d, 1H), 5.01 (s, 2H), 3.84 (s, 3H), 3.48 (m, br., 4H), 2.45-2.30 (m, 6H), 2.19 (s, 3H), 2.13 (s, 6H), MS: m/z 514.2 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH2:7].[C:9](Cl)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].CCOCC>ClCCl>[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH:7][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCNC(C)=O
Reaction time: 48 h

Procedure:
A 10.0 g portion of β-alanine methyl ester hydrochloride was slurried in 200 ml of dichloromethane. A 20 ml portion of acetyl chloride and 20 g of anhydrous potassium carbonate were added and the mixture was stirred vigorously for 48 hours. The mixture was poured into 400 ml of ether, 20 g of fresh anhydrous potassium carbonate added and the solids allowed to settle for 15 minutes. Suction filtration through celite and concentration gave an oil. This oil was concentrated four times from 50 ml portions of toluene, giving 4.73 g of the desired compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@H](C)[C@H](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)C(O)=O)C1C=CC=CC=1.N[C@@H]([C@H](C1C=CC=CC=1)C)C(NC1C=CC(I)=CC=1F)=O.[NH2:54][C@@H:55]([C@H:72]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[CH3:73])[C:56]([NH:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]#[C:66][Si](C)(C)C)=[CH:61][C:60]=1[F:71])=[O:57].[NH2:80][C@H:81]([C:105]1[CH:110]=[CH:109][C:108]([O:111][CH2:112][C@H:113]([OH:116])CO)=[CH:107][CH:106]=1)[C:82](N[C@@H]([C@H](C1C=CC=CC=1)C)C(NC1C=CC(I)=CC=1Cl)=O)=[O:83]>>[C:65]([C:62]1[CH:63]=[CH:64][C:59]([NH:58][C:56](=[O:57])[CH:55]([N:54]2[C:82](=[O:83])[C@@H:81]([C:105]3[CH:106]=[CH:107][C:108]([O:111][CH2:112][CH2:113][OH:116])=[CH:109][CH:110]=3)[NH:80][C:1]2=[O:8])[C@H:72]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[CH3:73])=[C:60]([F:71])[CH:61]=1)#[CH:66]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@H](O)CO)cc1)C(=O)Nc1ccc(I)cc1Cl
Reactant: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(C#C[Si](C)(C)C)cc1F
Agent: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(I)cc1F
Product: C#Cc1ccc(NC(=O)C([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCCO)cc3)C2=O)c(F)c1

Procedure:
Prepared by the same method as described in example 48 except that (i) after step 3, and prior to step 4, (2S,3S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide was converted to (2S,3S)-2-amino-N-(2-fluoro-4-trimethylsilanylethynyl-phenyl)-3-phenyl-butyramide under the conditions described below, and (ii) after initial purification in step 6 the product was subjected to chiral HPLC separation as described below. The trimethylsilyl group introduced in step 3 was subsequently removed during step 5 of the synthesis, concomitant with removal of the tert-butyloxycarbonyl protecting group.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OO)(=O)C.P(Cl)(Cl)([Cl:29])=O>C(O)(=O)C>[Cl:29][C:15]1[CH:14]=[CH:13][C:12]2[C:11]([C:9]([NH:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:10])=[C:20]([CH3:21])[CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: Cc1ccc2ncccc2c1C(=O)NCC1CCCCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: Cc1ccc2nc(Cl)ccc2c1C(=O)NCC1CCCCC1

Procedure:
Prepared according to the method of example 43(a), using N-(cyclohexylmethyl)-6-methyl-5-quinolinecarboxamide (Example 57) (3 g), peracetic acid (3.3 g, 45% in acetic acid), glacial acetic acid (20 mL) and subsequently phosphorous oxychloride (20 mL) to afford the sub-titled compound (1.5 g).
Reaction SMILES: FC(F)(F)S(O[CH:7]1[CH:11]=[C:10]([O:12][CH3:13])[C:9](=[CH:14][C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:8]1)(=O)=O.C(OC([N:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[CH3:13][O:12][CH:10]1[C:9](=[CH:14][C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:8][C:7]([C:34]2[NH:33][CH:37]=[CH:36][CH:35]=2)=[CH:11]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COC1=CC(OS(=O)(=O)C(F)(F)F)NC1=Cc1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC1C=C(c2ccc[nH]2)NC1=Cc1cc2ccccc2[nH]1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The crude triflate 78 was mixed with about 3 equivalent of boronic acid 8, 8 equivalents of potassium carbonate and about 0.1 equivalent of tetrakistriphenylphosphine palladium under argon. Anhydrous 1,4-dioxane (10 mL) was added to the reaction mixture, and it was heated at 90° C. in a sand bath. After three hours, the mixture was cooled and added to ethyl acetate (100 mL). The organic layer was washed with brine (3×100 mL) and was then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude mixture was passed through a short column of neutral alumina using 50/50 hexanes/ethyl acetate as an eluent. The relevant fractions were combined and concentrated, and the resulting crude product was purified using a preparative plate of neutral alumina and eluted using 80/20 hexanes/ethyl acetate. The alumina band containing Compound 79 was washed with ethyl acetate and concentrated to provide the Compound 79 as a red dark solid (2 mg, 20%). (500 MHz, CD3OD) : δ (ppm), 7.55 (m, 2H); 7.20 (t, 1H); 7.13 (s, 1H); 7.03 (t, 1H); 6.90 (s, 1H), 6.88 (s, 1H); 6.85 (s, 1H); 6.32 (s, 1H), 6.17 (s, 1H); 3.97 (s, 3H). MS (M+H): 290.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4](O)=[O:5].Cl>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: OCc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
The required [2,6-dichloro-4-(trifluoromethyl)-phenyl]nethanol was prepared as follows: To a solution of 1,3-dichloro-5-(trifluoromethyl)benzene (4.73 g; 22 mmol) in THF (40 mL) was added n-BuLi in hexanes (8 mL; 2.50 mol/1; 20 mmol), at −78° C. The resulting mixture was stirred for 15 minutes and poured onto dry ice in THF. The reaction mixture was acified to pH=3 (with 5 M aqueous HCl solution) and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 8:2) to afford 2,6-dichloro-4-(trifluoromethyl)benzoic acid (1.2 g). To a solution of this 2,6-dichloro-4-(trifluoromethyl)benzoic acid (1.7 g; 6.6 mmol) in THF (20 mL) was added dropwise a solution of borane-THF complex in THF (1 mol/1, 13.3 mL; 13.3 mmol). Subsequently, the resulting mixture was stirred overnight at 60° C. To the reaction mixture was added 1 M aqueous HCl (30 mL), at 0° C., and the resulting mixture was stirred at RT for 10 minutes. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% aqueous NaHCO3-solution. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:3 followed by Et2O:hexanes 1:1) to afford [2,6-dichloro-4-(trifluoromethyl)phenyl]-methanol (1.3 g), which was used as such in the next step.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)(C)(C)C.Cl.[NH2:14][CH2:15][CH2:16][NH:17][C:18]1[C:19]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=3)[C:26](=[O:36])[O:25][N:24]=2)=[N:20][O:21][N:22]=1.C(N(CC)CC)C>ClCCl.Cl>[Cl:35][C:30]1[CH:29]=[C:28]([N:27]2[C:26](=[O:36])[O:25][N:24]=[C:23]2[C:19]2[C:18]([NH:17][CH2:16][CH2:15][NH:14][S:2]([NH2:5])(=[O:4])=[O:3])=[N:22][O:21][N:20]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of chlorosulfonyl isocyanate (2.0 mL, 23 mmol) in dichloromethane (70 mL) was treated with t-butyl alcohol (2.2 mL, 23 mmol) at 0° C. and stirred at 25° C. for 1 h. This mixture was added to a suspension of 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (4.3 g, 11 mmol) in dichloromethane (70 mL). The reaction mixture was treated with a solution of triethylamine (6.3 mL, 45 mmol) in dichloromethane (20 mL) at 0° C. and stirred at 25° C. for 3 h. The reaction mixture was diluted with 0.1N HCl and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a white solid. The white solid was diluted with dichloromethane (100 mL), treated with trifluoroacetic acid (20 mL), and stirred at 25° C. for 3 h. The reaction mixture was concentrated to a crude residue that was purified by silica gel chromatography to give the desired product (3.7 g, 78%) as a white solid. LCMS for C12H12ClFN7O5S (M+H)+: m/z=420.0. 1H NMR (300 MHz, DMSO-d6): δ 7.98 (dd, J=6.4, 2.1 Hz, 1 H), 7.70-7.60 (m, 2 H), 6.66 (t, J=5.9 Hz, 1 H), 6.57 (s, 2 H), 6.52 (t, J=5.9 Hz, 1 H), 3.42-3.35 (m, 2 H), 3.13-3.06 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=O)CCC.[H-].[Na+].[CH2:17]([O:21][C:22]1[C:26](S(C)(=O)=O)=[N:25][S:24][N:23]=1)[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH2:17]([O:21][C:22]1[C:26]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[N:25][S:24][N:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC(=O)N1CCC[C@H]1CO
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC[C@@H]1CCCN1
Reaction time: 1 h

Procedure:
A solution of (S)-1-butyloxycarbonyl-2-pyrrolidinemethanol (1.21, 0.006 mol) in THF (5 mL) was added to a suspension of 60% NaH in oil (0.24 g, 0.006 mol) in THF (30 mL). After 1 h, the mixture was heated to gentle reflux for 1 h. To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1 g, 0.0042 mol) and the reaction heated to reflux overnight. The solvent was evaporated, the residue treated with cold H2O, and the mixture extracted with EtOAc. The extracts were dried and treated with a stream of dry HCl for 3 min. After another hour, the solvent was evaporated, the residue treated with cold H2O, and the mixture extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) crystallized from EtOAc, m.p. 99°-100° C. (Compound 32).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].CI.[C:28](O)(=O)C>COCCOC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:28])[C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl
Reaction time: 1 h

Procedure:
A solution of 50.2 g of ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate in 300 ml of absolute 1,2-dimethoxyethane is added dropwise while stirring at 20° C. during 10 minutes to a suspension of 3.6 g of sodium hydride in 100 ml of absolute 1,2-dimethoxyethane. The reaction mixture is stirred for 1 hour, treated with 21.3 g of methyl iodide and stirred for a further 2 hours. The mixture is subsequently rendered neutral with 0.5 ml of acetic acid and evaporated to dryness under reduced pressure. The residue is dissolved in 500 ml of ethyl acetate, the solution shaken three times with 250 ml of water, and the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of hot methylene chloride, seeded, and treated with diethyl ether. There is obtained ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d] pyrimidin-3-yl)-benzoate, m.p. 141°-143° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[N+:15]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O)([O-:17])=[O:16]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][CH:28]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc([N+](=O)[O-])c3)nc2n(CC)c1=O
Yield: 44.9 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.68 g (13.9 mmol) of 3-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.01 g (yield 30%) of Compound 159 as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9](=[O:16])[CH:10]=[C:11]([CH2:14][OH:15])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][Si](C=[N+]=[N-])(C)C>CO.CN(C)C=O.CCCCCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([O:16][CH3:19])=[CH:10][C:11]([CH2:14][OH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=c1cc(CO)[nH]cc1OCc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(CO)ncc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Chloro-benzyloxy)-2-hydroxymethyl-1H-pyridin-4-one (639, 1.06 g, 3.99 mmol) was dissolved in methanol (8.5 mL) and N,N-dimethylformamide (46 mL). Trimethylsilyldiazomethane in hexane (2.00 M, 3.99 mL) was added. The reaction was stirred at room temperature overnight, then additional trimethylsilyldiazomethane in hexane (2.00 M, 3.99 mL) was added. The reaction was stirred at room temperature for 2 days. The mixture was adsorbed onto silica and purified by silica gel chromatography, methanol:dichloromethane to provide the compound (640, 798 mg, 72%). MS (ESI) [M+H+]+=280.4, 282.4.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:11][N:6]1[CH:5]=[C:4]2[C:8]([CH:9]=[CH:10][C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:3]2[CH:12]2[CH2:14][CH:13]2[CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[N:7]1
Reactant: CC(=O)NCC1CC1c1c(Br)ccc2nn(C)cc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)NCC1CC1c1c(-c2ccccc2)ccc2nn(C)cc12
Temperature: 80 °C
Yield: 99.9 %

Procedure:
N-{[2-(5-Bromo-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (100 mg, 0.310 mmol) obtained in Example 29, phenylboronic acid (94.6 mg, 0.776 mmol), 2 M aqueous sodium carbonate solution (3 mL) and tetrakis(triphenylphosphine)palladium(0) (35.8 mg, 0.031 mmol) were added to a mixed solution of ethanol (1.5 mL) and toluene (1.5 mL), and the mixture was stirred under nitrogen atmosphere with heating at 80° C. for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (98.9 mg, yield 99%).