Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:10][S:11]([C:14]1[CH:27]=[CH:26][C:17]([CH2:18][CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:8][C:7]1[C:2]2[N:1]=[C:23]([CH3:24])[C:19]([CH2:18][C:17]3[CH:16]=[CH:15][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:27][CH:26]=3)=[C:20]([CH3:21])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Reactant: Nc1cc(O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 160 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (0.36 g), 3-(4-methanesulfonylbenzyl)pentane-2,4-dione (0.5 g) and p-toluenesulfonic acid monohydrate (0.05 g) was heated at 160° C. for 2.5 hours. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (50:1 to 2:1 by volume) to afford title compound (7:10 mixture of keto-enol tautomers) as a beige solid, 0.32 g.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(CC)CC>C(Cl)Cl>[CH3:16][C:15]1[CH:17]=[CH:18][C:12]([S:9]([O:6][CH2:5][CH:4]([OH:7])[CH2:3][N:2]([CH3:8])[CH3:1])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CN(C)CC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC(O)CN(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(dimethylamino)propane-1,2-diol (934 mg, 7.84 mmol) in CH2Cl2 (8 mL) were added Bu2SnO (42 mg, 0.16 mmol), tosyl chloride (1.49 g, 7.84 mmol), and Et3N (1.10 mL, 7.92 mmol). The reaction mixture was stirred at rt for 2 hrs. The mixture was quenched with water (30 mL) and extracted with EtOAc (two×30 mL). The combined organic layers were dried over MgSO4 and concentrated to afford 3-dimethylamino-2-hydroxypropyl 4-methylbenzenesulfonate; [m/z (APCI+) 274.10 (M+H)+]. The residue was dissolved in THF (10 mL), then DBU (2.56 mL, 16.6 mmol) and 4-nitro-1H-pyrazole (602 mg, 5.32 mmol) were added and the resulting mixture was stirred at rt for 30 min. The mixture was then quenched with water (30 mL) and extracted with EtOAc (two×30 mL). The combined organic layer were dried over MgSO4 and concentrated to give the title compound as a pale yellow oil (526 mg, 46° A yield) which was used without purification. m/z (APCI+) for C8H14N4O3 215.10 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[S:15])[N:6]([CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[NH2:8].[CH:17](O)=O>>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][N:6]1[C:7]2[N:8]=[CH:17][NH:1][C:2]=2[C:3](=[O:16])[NH:4][C:5]1=[S:15]
Reactant: O=CO
Reactant: Nc1c(N)n(Cc2ccco2)c(=S)[nH]c1=O
Product: O=c1[nH]c(=S)n(Cc2ccco2)c2nc[nH]c12
Temperature: 70 °C

Procedure:
5,6-Diamino-1-(2-furyl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.12 g, 0.51 mmol) in formic acid (0.5 mL) was stirred at ambient temperature for 0.5 h. The excess of formic acid was evaporated off and the resulting solid dissolved in 10% sodium hydroxide solution (3 mL). This solution was heated at 70° C. for 0.5 h. The reaction mixture was neutralized with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried. Yield: (0.047 g, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C.[N:45]1[CH:50]=[C:49]([NH2:51])[CH:48]=[N:47][CH:46]=1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:51][C:49]1[CH:50]=[N:45][CH:46]=[N:47][CH:48]=1)=[O:6]
Reactant: Nc1cncnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cncnc1
Reaction time: 8 h

Procedure:
In a 2 L round bottom flask with mechanical stirring was charged with 2-methyl-5-nitrobenzoic acid (20 g), HATU (38 g) and diisopropylamine (32 mL) in DMF (90 mL). This mixture was stirred for 30 min then pyrimidin-5-amine was added and the reaction was stirred for 18 hr. The LCMS showed complete conversion. DMF was removed under vacuum as much as possible then water was added and a solid precipitated out (use mechanical stirring). The tan solid was filtered and rinsed with water, then taken up in EtOAc, washed with brine, dried over MgSO4, filtered and concentrated down. The crude was taken up in EtOAc and the product 45 precipitated out. This was filtered and the filtrate was concentrated down and taken up in EtOAc/Hex. After standing overnight, more solids were filtered and were combined with the first crop. 2-methyl-5-nitro-N-(pyrimidin-5-yl)benzamide 45 was obtained as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9]([C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([NH:22][C:23]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9]([C:11]([F:16])([F:15])[CH:12]([F:13])[F:14])=[O:10])=[CH:8][C:2]=1[F:1])=[O:24])=[O:21]
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Reactant: Nc1ccc(S(=O)C(F)(F)C(F)F)cc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(S(=O)C(F)(F)C(F)F)cc1F
Yield: 87 %

Procedure:
To a solution of 0.7 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfinyl)aniline in 15 ml of toluene was added 0.5 g of 2-fluoro-6-chlorobenzoyl isocyanate. After the reaction was allowed to proceed at room temperature (20° to 25° C.) for 30 minutes, the crystals which separated out were recovered by filtration and washed with toluene to give 1.0 g of N-(2-fluoro-6-chlorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfinyl)phenyl]urea (Compound No. 31), m.p. of 213°-216° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:11](OC)(OC)(OC)[CH3:12]>O>[Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]2[N:6]([C:11]([CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: COC(C)(OC)OC
Reactant: NNc1ncc(Br)nc1Cl
Solvent: O
Product: Cc1nnc2c(Cl)nc(Br)cn12
Temperature: 130 °C

Procedure:
5-bromo-3-chloro-2-hydrazinylpyrazine 11-1 (945 mg; 3.51 mmol) is dissolved in 12 ml trimethyl orthoacetate and heated up to 130° C. for 1 hour. The solution is diluted with water and extracted with EtOAc. The organic phase is then purified with flash chromatography: cHex/EtOAc=70%/30% to 55%/45% within 10 column volumes.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([F:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C>CO.[C].[Pd]>[F:11][C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:2][NH:3][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1c(Cl)[nH]c(-c2ccccc2)c1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1c[nH]c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86784.9 %

Procedure:
Methyl 2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (0.92 mg), 10% palladium carbon (50% containing water, 0.20 g) and triethylamine (0.56 mL) were suspended in methanol (30 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction mixture was filtered through celite, and the insoluble material was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as a colorless solid (yield 0.69 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][N:13]1C(=O)O[C:16](=[O:17])[C:15]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:14]12>>[CH3:12][NH:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([OH:11])=[N:7]1)=[O:17]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: Oc1n[nH]c2cc(Cl)ccc12
Product: CNc1ccccc1C(=O)n1nc(O)c2ccc(Cl)cc21
Yield: 59 %

Procedure:
6-Chloro-1H-indazol-3-ol was reacted with N-methylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 59.0% yield; m.p. 203°-205° C.
Reaction SMILES: Br[C:2]1[S:6][N:5]=[C:4]([CH3:7])[CH:3]=1.CC#N.C(=O)=O.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH:24]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[CH:31][CH:30]=[CH:29]4)[CH3:25])=[N:22][N:23]=2)[N:20]=1>C1COCC1.CN(C)C(=O)C.[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[CH3:7][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([CH:24]([C:26]4[CH:27]=[C:28]5[C:33](=[CH:34][CH:35]=4)[N:32]=[CH:31][CH:30]=[CH:29]5)[CH3:25])=[N:22][N:23]=3)[N:20]=2)[S:6][N:5]=1
Reactant: CC(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Reactant: Cc1cc(Br)sn1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc3nnc(C(C)c4ccc5ncccc5c4)n3n2)sn1
Temperature: -45 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-3-methylisothiazole (1.00 g, 5.6 mmol) in 10 mL of THF at −45° C. (CH3CN/dry ice) was added isopropylmagnesium chloride LiCl complex (7.9 ml, 7.9 mmol) (LiCl complex, 1 M in THF). The mixture was stirred at −45° C. for 20 minutes and to this was added zinc chloride, 0.5 M in THF (17 ml, 8.4 mmol) slowly via a syringe. The mixture was then warmed up to rt and continued to stir for additional 30 minutes. 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (0.5787 g, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.51 g, 0.56 mmol) and Q-Phos (0.65 g) in 15 mL of N,N-dimethyl acetamide was added to the reaction mixture. The reaction was warmed up to 50° C. for 6 hours and was quenched with 50 mL of satd. NH4Cl aq. solution. The mixture was extracted with 150 mL of EtOAc and the organic phase was washed with 60 mL of brine. The aqueous phases were further extracted with 100 mL EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH in EtOAc) to give afford a red solid. MS (ESI pos. ion) m/z: 373 (MH+). Calc'd exact mass for C20H16N6S: 372.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])=[N:14][NH:15][C:7]=12>>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])=[N:14][NH:15][C:7]=12
Reactant: NCCO
Reactant: COc1ccccc1-c1n[nH]c2c(Cl)cc(C)nc12
Product: COc1ccccc1-c1n[nH]c2c(NCCO)cc(C)nc12

Procedure:
The title compound was prepared form ethanolamine and 7-chloro-5-methyl-3-(methoxyphenyl)-1H-pyrazolo[4,3-b]pyridine (D13) in an analogous manner to the preparation of Example 2 giving a pale yellow solid, m.p. 193°-194° C. Ratio of meta and para isomer 1:2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11](Br)[CH:12]=[CH2:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
5-Hydroxy-1H-indole (500 mg, 3.76 mmol) and allyl bromide (499.7 mg, 4.13 mmol) were dissolved in DMF (15 mL), then Cs2CO3 (1.468 g, 4.51 mmol), and water (6 drops) were added. The reaction mixture was stirred at rt for 12 h, after which it was concentrated under reduced pressure, diluted with water, and the aqueous layer was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:11) gave 514 mg (79%) of the title compound as a light-yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.59 (d, 2H), 5.29 (d, 1H), 5.45 (d, 1H), 6.12 (m, 1H), 6.48 (d, 1H), 6.90 (d, 1H), 7.11 (s, 1H), 7.19 (s, 1H), 7.28 (m, 1H), 8.04 (br, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]1([C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6])[OH:4].[C:11](Cl)(Cl)=[S:12]>>[O:4]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[O:6][C:11]1=[S:12]
Reactant: Oc1ccccc1O
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: S=c1oc2ccccc2o1

Procedure:
To 200 ml of aqueous sodium hydroxide (16.00 g, 0.400 mol) at 5° was added catechol (22.00 g, 0.200 mole). The resulting dark green solution was stirred magnetically and maintained at 5°-10° while thiophosgene (17 ml, 25.5 g, 0.22 mol) was added dropwise over 2 hours. The green color of the solution was discharged during the addition and an orange-brown precipitate formed. The mixture was filtered through a Buchner funnel into a saturated solution of aqueous sodium hydroxide to destroy any residual thiophosgene. The solid thus collected on the funnel was washed with 1.5 l of water and dried to give 27.41 (90 percent) of the crude 1,3-benzodioxole-2-thione (I): mp 151°-153° (sealed capillary; lit. mp 154°, 158°-158.5°). Sublimation twice at 150° (1 atm) gave white needles in 81 percent overall yield (lit. 25 percent): mp 158°-159.5° sealed capillary).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CN.Cl[P:11]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]3[CH:21]=[CH:22][CH:23]=[C:13]([C:14]=23)[O:12]1.CCCCCC>C1(C)C=CC=CC=1>[CH3:1][NH:3][P:11]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]3[CH:21]=[CH:22][CH:23]=[C:13]([C:14]=23)[O:12]1
Reactant: ClP1Oc2cccc3cccc(c23)O1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CNP1Oc2cccc3cccc(c23)O1
Temperature: 5 °C

Procedure:
Under a nitrogen atmosphere, 0.4 ml triethylamine was added to 1.5 ml methylamine (2 M in THF) in 20 ml dry toluene. To the resulting solution was cooled to 5° C. and 250 mg 2-chloronaphtho[1,8-de][1,3,2]dioxaphosphinine (available from Hansa Fine Chemicals GmbH, Bremen, Germany) was slowly added. After stirring overnight at room temperature 20 ml hexane was added. The precipitate was removed by centrifugation. The solvents were removed under vacuum. The product N-methylnaphtho[1,8-de][1,3,2]dioxaphosphinine-2-amine was isolated as an oil and used as such. 31P-NMR C6D6 δ 121.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.Cl.[CH2:13]1[O:15][CH2:14]1>CO>[OH:15][CH2:14][CH2:13][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][O:6][C:7](=[O:8])[C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)COC(=O)C(C)(C)N1
Reactant: C1CO1
Agent: Cl
Solvent: CO
Product: CC1(C)COC(=O)C(C)(C)N1CCO

Procedure:
45.0 g (0.29 moles) of 3,3,5,5-tetramethyl-2-morpholone are dissolved in 450 ml of methanol. The solution is poured into an autoclave, added with 1 ml of concentrated HCl (37%) (% w/w) and pressurized with ethylene oxide (2 bars).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16](=[O:33])[CH2:17][C@H:18]2[NH:21][C:20](=[O:22])[C@@H:19]2[C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH3:24])[CH2:13][N:12]1[C:34]([O:36][CH2:37][C:38]1C=CC=C[CH:39]=1)=[O:35])=[O:10])[C:2]1C=CC=C[CH:3]=1.Cl>CO.[Pt]=O>[CH2:37]([O:36][C:34]([NH:12][CH2:13][CH:14]([CH2:15][NH:11][C:9]([O:8][CH2:1][CH:2]=[CH2:3])=[O:10])[C:16](=[O:33])[CH2:17][C@H:18]1[NH:21][C:20](=[O:22])[C@@H:19]1[C@H:23]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[CH3:24])=[O:35])[CH:38]=[CH2:39]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)C1CN(C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
To a solution of (3S,4R)-4-[2-{1,2-bis(benzyloxycarbonyl)pyrazolidin-4-yl}-2-oxoethyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (500 mg) and 1N hydrochloric acid (1.64 ml) in methanol (20 ml) was added platinum oxide (50 mg) under nitrogen atmosphere. The suspension was stirred under hydrogen atmosphere for 4 hours at room temperature. After then, the catalyst was filtered off and washed with water. After tetrahydrofuran (50 ml) and water (20 ml) was added, the pH was adjusted to 8.0 with saturated aqueous sodium bicarbonate in an ice bath and allyl chloroformate (348 ml) was added keeping pH at 8.0-8.5. After stirring for an hour at pH 8.0-8.5, the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel to give (3S,4R)-4 -[4-allyloxycarbonylamino-3-(N-allyloxycarbonylaminomethyl)-2-oxobutyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-oxoazetidine (289 mg).
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][C:56]=1[CH3:57])[NH2:53]>C(O)(=O)C>[CH3:49][C:50]1[CH:51]=[C:52]([N:53]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:54]=[CH:55][C:56]=1[CH3:57]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Cc1ccc(N)cc1C
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: Cc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1C
Yield: 50 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (70 mg, 0.30 mmol), triethyl orthoformate (0.57 ml), 3,4-dimethylaniline (67.8 mg, 0.56 mmol), and acetic acid (0.07 ml) were used to give 49.2 mg (0.15 mmol, 50% yield) of the title compound.
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:6][CH:5]([N:7]2[C:11]([CH2:12][CH3:13])=[C:10]([O:14][C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)[C:9]([CH2:23][CH3:24])=[N:8]2)[CH2:4]1>C(O)=O.C(OCC)(=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([Cl:21])[CH:18]=1)[O:14][C:10]1[C:9]([CH2:23][CH3:24])=[N:8][N:7]([CH:5]2[CH2:6][N:3]([CH3:1])[CH2:4]2)[C:11]=1[CH2:12][CH3:13]
Reactant: CCc1nn(C2CNC2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: C=O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCc1nn(C2CN(C)C2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Yield: 72.7 %

Procedure:
Paraformaldehyde (30 mg, 0.330 mmol) was added in one portion to a stirred solution of the pyrazole of Example 51 (120 mg, 0.330 mmol) in formic acid (2 ml) at room temperature. The mixture was heated at 100° C. for 5 hours, cooled to room temperature and concentrated under reduced pressure to leave a colourless oil. The oil was dissolved in ethyl acetate (50 ml) and the resulting solution was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (85 mg) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]#[N:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH2:14][NH2:15]>CCO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([NH2:12])[NH:14][N:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: NN
Reactant: Cc1cc(C)cc(C(=O)CC#N)c1
Solvent: CCO
Product: Cc1cc(C)cc(-c2cc(N)[nH]n2)c1

Procedure:
3-(3,5-Dimethyl-phenyl)-3-oxo-propionitrile (2.0175 gms.) is then suspended in 55 mL of anhydrous EtOH. This suspension is treated with 0.73 mL of anhydrous hydrazine and subsequently heated to refluxing temperature for 1 day. The reaction mixture is concentrated in vacuo. The residue is then triturated with isopropanol to precipitate out the 5-(3,5-dimethyl-phenyl)-2H-pyrazol-3-ylamine as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.N[CH:31](C1C=CC(C(OC)=O)=CC=1)[CH2:32]C>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH:19]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[CH2:31][CH3:32])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CCC(N)c1ccc(C(=O)OC)cc1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Product: CCC(NC(=O)c1cc(F)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-(1-aminopropyl)benzoate: 1H-NMR (CDCl3) δ 8.33–8.26 (2H, m), 8.05–7.99 (3H, m), 7.39 (2H, d, J=8.4 Hz), 7.20–7.15 (4H, m), 5.15 (1H, q, J=7.3 Hz), 3.90 (3H, s), 1.92 (2H, dq, J=7.3, 7.3 Hz), 0.95 (3H, t, J=7.3 Hz); MS (ESI) m/z 427 (M+H)+, 425 (M−H)−.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 58 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-hexyl chloroformate. Yield: 58% of theory, C35H43N7O5 (641.2); Rf value: 0.42 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=642; (M+H+Na)++=332.7.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@:12]2([CH3:26])[O:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:13]2)=O)=CC=1)([O-])=O.[N+](C1C=CC(C(OC[C@H]2OC(=O)N(C3C=CC(OC)=CC=3)[C@H]2C)=O)=CC=1)([O-])=O>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[CH2:13][C@@:12]([CH2:11][OH:10])([CH3:26])[O:16][C:15]2=[O:17])=[CH:23][CH:22]=1
Reactant: COc1ccc(N2C[C@](C)(COC(=O)c3ccc([N+](=O)[O-])cc3)OC2=O)cc1
Agent: COc1ccc(N2C(=O)O[C@H](COC(=O)c3ccc([N+](=O)[O-])cc3)[C@@H]2C)cc1
Product: COc1ccc(N2C[C@](C)(CO)OC2=O)cc1
Yield: 90 %

Procedure:
The reaction was conducted in a similar manner to Referential Example 9 except that Compound [77] obtained in Referential Example 7 was used instead of Compound [76], whereby the title compound was obtained in a yield of 90%.