Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[N+:34]([O-])([OH:36])=[O:35]>CC(OC(C)=O)=O>[CH2:27]([O:26][C:12]1[CH:13]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([Cl:17])=[CH:16][C:11]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[C:10]=1[N+:34]([O-:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])O
Reactant: CCNC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CC(=O)OC(C)=O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 72.5 %

Procedure:
A suspension of 5-(2,4-bis-benzyloxy-5-chloro-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 g, 2.2 mmol) in Ac2O (20 ml) was cooled to 0° C. and HNO3 (0.26 ml, 4.3 mmol) was added dropwise under stirring, the temperature being maintained between 0-5° C. After the addition was complete, the mixture was stirred for 70 h at 5-10° C. and then poured into ice and extracted with DCM (3×40 ml). The extract was dried and concentrated under vacuo. The yellow solid obtained was triturated with Et2O and filtered to give 5-[2,4-bis(benzyloxy)-5-chlorophenyl]-N-ethyl-4-nitroisoxazole-3-carboxamide (810 mg, 73%).
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]1[CH:9]([C:10](=[O:22])[CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[S:8][CH2:7][NH:6]1)C.[OH-].[Na+]>C(O)C>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][CH:12]1[CH2:11][C:10]([CH:9]1[S:8][CH2:7][NH:6][C@@H:5]1[C:4]([OH:23])=[O:3])=[O:22]
Reactant: CCOC(=O)[C@H]1NCSC1C(=O)CC1CCc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CC1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 2.0 g of 3-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline ethyl ester prepared in Reference Example 17 in 23 ml of ethanol was added 37 ml of 1 N sodium hydroxide at room temperature, and the mixture was stirred at the same temperature. After 3 hours, ethanol was evaporated under reduced pressure. After the addition of 100 ml of water and washing with benzene, the water layer was acidified with the addition of diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was treated with isopropyl ether to produce 1.5 g of colorless crystals of 3-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline (yield: 82%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:39](=[O:41])=[O:40].Cl>O1CCCC1.C1CCCCC1>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[C:39]([OH:41])=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1ncn2Cc1ccccc1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C(=O)O)n2Cc1ccccc1
Reaction time: 1 h
Yield: 26 %

Procedure:
Compound 35a (3.95 g, 9.90 mmol) obtained in Example 35 was dissolved in tetrahydrofuran (100 mL), to the solution was added a 1.50 mol/L solution (9.9 mL) of lithium diisopropylamide (14.9 mmol, 1.5 equivalents) in cyclohexane at −78° C., and then the mixture was stirred for 1 hour. Into the reaction solution was poured carbon dioxide generated from dry ice and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 1 mol/L aqueous hydrochloric acid and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5 to 10:1). To the residue were added acetone and diethyl ether, and the deposited crystals were collected by filtration to obtain (R)-1,8-dibenzyl-2-carboxy-7,8-dihydro-4-(n-propyl)-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 47a, 1.13 g, 26%). To Compound 47a (740 mg, 1.67 mmol) was added thionyl chloride (10.0 mL, 137 mmol, 82 equivalents) and the mixture was stirred at 60° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and then to the reaction residue was added methanol (3 mL). The mixture was concentrated and the residue was directly purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound (211 mg, 28%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH3:23])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH3:23])=[CH:6][CH:5]=1
Reactant: CN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CN(CCOc1ccc(N)cc1)CCc1ccc(N)cc1
Yield: 88.7 %

Procedure:
A solution of 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane (1.5 g) in ethanol (100 ml) was stirred for 16 hours at room temperature under three atmospheres of hydrogen in the presence of Raney nickel ("Nicat 102"--Trade Mark). The reaction mixture was filtered and evaporated to dryness. The residual oil was re-dissolved in ether, filtered and evaporated to give a yellow solid (1.1 g), which was crystallised from ethyl acetate/60°-80° petroleum ether to give the title compound, (0.9 g), m.p. 73°-74°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](=O)[NH:6][C:7]=1[CH3:8].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>>[Cl:14][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(=O)[nH]c1C
Product: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Temperature: 140 °C
Reaction time: 0.58 h
Yield: 90.2 %

Procedure:
5,6-Dimethyl-3-nitro-2-pyridone (1-013-04)(841 mg) and phosphorus pentachloride (1.25 g) was heated with stirring in an oil bath at 140° C. under nitrogen atmosphere. After 35 min, the reaction mixture was cooled under ice-cooling, poured into ice-water, extracted with twice with chloroform, and washed once with water and a saturated aqueous solution of sodium bicarbonate. To the extract was added a decolorzing charcoal, and the extract was dried over magnesium sulfate, and evaporated under reduced pressure to give 2-chloro-5,6-dimethyl-3-nitropyridine (1-013-05) (842 mg, 90.2%) as a crystalline residue.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:14][CH3:15])=[O:13]>C(Cl)Cl>[C:8]([C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:20]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([O:14][CH3:15])=[O:13])(=[O:22])=[O:23])=[O:26])[N:7]=1)#[N:9]
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Reactant: COc1cc(C#N)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C#N)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-cyano-6-methoxypyrimidine, 0.1 g, was mixed with 2-carbomethoxythiophene-3-sulfonyl isocyanate, 0.165 g, in 10 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. The reaction mixture was stripped to yield 0.19 g of the title compound as a solid, m.p. 89°-92° C. (dec). NMR (CDCl3): δ6.89 (s, 3H), 4.20 (s, 3H), 6.83 (s, 1H), 7.59 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O-2].[Mg+2]>C(O)(C)C.[Pd]>[N:5]1[C:4]2[S:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:3]=2[CH:2]=[N:7][CH:6]=1
Reactant: COC(=O)c1cc2c(Cl)ncnc2s1
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(C)O
Product: COC(=O)c1cc2cncnc2s1
Yield: 78.5 %

Procedure:
Methyl 4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (intermediate 10) (114 mg), magnesium oxide (40 mg) and Pd/C (12 mg) in isopropanol (10 mL) were stirred under hydrogen for 48 hours. The solution was filtered through diatomaceous earth, washed with DCM (3×10 mL) and then concentrated in vacuo. Purification by flash chromatography on silica eluting with hexane:EtOAc (2:1) afforded the title compound as a white crystalline solid (76 mg, 78%);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]([NH2:17])[CH3:16].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:17][CH2:15][CH3:16])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNC(C)Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 92 %

Procedure:
A solution of 10 g (51.4 mmol) of 3,4-dimethoxyphenylacetone in 50 mL of methanol was cooled to 0° C. and was treated with 50 mL of 2M solution of ethylamine in methanol. To the reaction mixture 11.5 g (0.183 mmol) of sodium cyanoborohydride was added, and the pH of the reaction mixture was adjusted to 6.5-7 by adding glacial acetic acid. The mixture was allowed to stir at room temperature for 4 days. This was concentrated under reduced pressure, and 150 mL of water was added. The pH of the resulting solution was adjusted to 1 using 6 N HCl. This was extracted with 4×150 mL of ether and the organic layers were discarded. The pH of the aqueous layer was adjusted to 14, and the solution was extracted with 6×100 mL of chloroform. The organic layers were combined, dried (Na2SO4) and concentrated to dryness to give 10.6 g (47.4 mmol, 92%) of 2A as a pale yellow oil (M+H, 224).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]1([NH2:19])[CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[C:22](=[O:39])[N:23]([C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=2[CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[C:25]([Br:27])[N:26]=1>>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]1([NH:19][C:21]2[C:22](=[O:39])[N:23]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[C:25]([Br:27])[N:26]=2)[CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: NC1(c2cccc(F)c2OCc2ccccc2)CC1
Product: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC3(c4cccc(F)c4OCc4ccccc4)CC3)c2=O)c1

Procedure:
Prepared using a similar method to Example 252h from 1-(2-(benzyloxy)-3-fluorophenyl)cyclopropanamine (Example 283b) and methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 252g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:29][C:30]4[S:31][C:32]5[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=5[N:34]=4)=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: BrCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (Preparation 1) (200 mg), 2-bromomethylbenzothiazole (147 mg), Cs2CO3 (263 mg) in 3 mL CH3CN and 3 mL DMF was stirred at 60° C. for 4 hours. The mixture was poured onto water, extracted with EtOAc, washed twice with brine, dried (MgSO4), and evaporated. Chromatography of the residue on silica gel eluting with hexane/EtOAc 4:1 provided the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[CH2:12](Br)[CH:13]=[CH2:14].CC(C)([O-])C.[K+]>CS(C)=O>[CH2:14]([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:11])[CH:13]=[CH2:12]
Reactant: COC(=O)c1cccc(O)c1
Reactant: C=CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1cccc(C(=O)OC)c1
Temperature: 0 °C

Procedure:
Methyl-3-hydroxy-benzoate (1.09 g, 4.9 mmol), allyl bromide (0.73 g, 6.0 mmol) and potassium tert-butoxide (6.5 g, 5.8 mmol) in DMSO (15 mL) was stirred at room temperature for 16 hours. The mixture was poured into ice water, extracted with ether, washed with brine, dried (Na2SO4), and evaporated to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.55 (m, 1H), 7.45 (m, 2H), 7.24 (m, 1H), 6.12-5.98 (m, 1H), 5.44-5.26 (m, 2H), 4.64 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH:14]([P:16]([CH3:21])(=[O:20])[O:17]CC)[OH:15])=O)C1C=CC=CC=1.[ClH:22]>>[ClH:22].[NH2:11][CH2:12][CH2:13][CH:14]([P:16]([CH3:21])(=[O:17])[OH:20])[OH:15]
Reactant: CCOP(C)(=O)C(O)CCNC(=O)OCc1ccccc1
Agent: Cl
Product: CP(=O)(O)C(O)CCN
Temperature: 25 °C

Procedure:
A solution of 4.0 g of ethyl P-(3-benzyloxycarbonylamino-1-hydroxy-propyl)-P-methyl-phosphinate in 50 ml of 5.0M aqueous hydrochloric acid is heated to reflux for 20 hours under an inert gas atmosphere. Then, the reaction mixture is cooled to room temperature and washed twice with 100 ml each of dichloromethane and once with diethyl ether. The aqueous layer is evaporated to dryness at 50° under reduced pressure. The oily residue is then co-evaporated 5 times with 50 ml each of water and of absolute ethanol. The remaining white solid is dried under reduced pressure at 80° and then re-crystallised to afford P-(3-amino-1-hydroxy-propyl)-P-methyl-phosphinic acid hydrochloride of m.p. 115°-116.5°. This can be converted into the free compound by dissolving in ethanol and treating with propylene oxide yielding, after filtration and drying, P-(3-amino-1-hydroxy-propyl)-P-methyl-phosphinic acid of m.p. 125°-126.5°.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[NH:11]1[CH2:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].N1CCCCC1>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7](/[CH:9]=[C:15]2/[C:14](=[O:16])[NH:13][C:12](=[O:17])[NH:11]/2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C=O)n1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CSc1nccc(/C=C2\NC(=O)NC2=O)n1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A 40 mL round bottomed vial was charged with 2-(methylthio)pyrimidine-4-carbaldehyde (4) (771 mg, 5 mmol), imidazolidine-2,4-dione (500 mg, 5 mmol, 1.0 equiv.), and piperidine (400 μL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80° C. and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol (1×20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)imidazolidine-2,4-dione (5a) as a yellow solid (565 mg, 1.18 mg theoretical, 48%). LC-MS m/z 237 (M+1). The same procedure can be used to prepare 5b or 5c by replacing imidazolidine-2,4-dione with 1-benzylimidazolidine-2,4-dione or 1-methylimidazolidine-2,4-dione respectively.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>>[NH:19]1[C:18]([NH:17][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:13]=2)=[O:16])=[N:22][N:21]=[N:20]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cccc(Oc2ccccc2)n1
Product: O=C(Nc1nnn[nH]1)c1cccc(Oc2ccccc2)n1
Yield: 39.6 %

Procedure:
0.25 g of 6-phenoxy-2-pyridinecarboxylic acid, 0.2 g of N,N'-carbonyldiimidazole and 0.11 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from ethanol, whereby 0.13 g of N-(5-tetrazolyl)-6-phenoxy-2-pyridinecarboxamide is obtained.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([C:29]2[S:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[N:23][C:24]=3Cl)[O:7]1)(=O)C.[NH3:35]>>[NH2:35][C:24]1[N:23]=[C:22]([C:29]2[S:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@H:8]1[C@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:6]([CH2:5][OH:4])[O:7]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(-c4ccc(C)s4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Product: Cc1ccc(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)s1
Temperature: 40 °C

Procedure:
Compound 12 (50 mg, 0.1 mmol) was dissolved in 5 mL methanolic ammonia (saturated at 0° C.) and the mixture was heated at 40° C. for 24 h. After concentration in vacuo, the residue was purified using prep. TLC (10% MeOHIDCM) to afford 13 1HNMR (CD3OD)δ2.5 (s, 3 H) 3.75 (d, 1 H), 3.85 (d, 1 H), 4.15 (d, 2 H) 4.45 (m, 1 H), 4.85 (m, 1 H), 6.0 (d, 1 H), 6.75 (d, 1 H), 7.7 (d, 1 H), 8.25 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:18]1[CH:23]=[CH:22][C:21]([O:24][C:25](Cl)=[S:26])=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:21]1([O:24][C:25](=[S:26])[O:17][CH:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(C(O)c2cccnc2)cc1F
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(C(OC(=S)Oc2ccccc2)c2cccnc2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-fluoro-4-(hydroxy-pyridin-3-yl-methyl)-benzonitrile (as described in Example 20, Step C) (0.4 g, 1.75 mmol) in CH2Cl2 (25.0 mL) at 0° C. was added phenyl thionochloroformate (0.388 mL, 2.8 mmol) and DMAP (0.471 g, 3.86 mmol). The solution was stirred at 25° C. for 3 hr. The reaction was partitioned with saturated NaHCO3 and CH2Cl2. The CH2Cl2 layer was washed with brine, dried with MgSO4, and evaporated in vacuo to obtain the title compound after chromatography (silica gel, CH2Cl2:MeOH 99:1).
Reaction SMILES: [CH2:1]([C:3]1[N:7](CCC)[N:6]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])=[CH:14][CH:13]=2)[C:4]=1[C:32]([O:34][CH3:35])=[O:33])[CH3:2].[C:36]1(OC)[CH:41]=CC=C[CH:37]=1.CCOC(C)=O>FC(F)(F)C(O)=O>[NH2:27][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:5]2[N:6]([CH2:37][CH2:36][CH3:41])[N:7]=[C:3]([CH2:1][CH3:2])[C:4]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:13][CH:14]=1)(=[O:26])=[O:25]
Reactant: COc1ccccc1
Reactant: CCCn1nc(Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(C(=O)OC)c1CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCn1nc(CC)c(C(=O)OC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of the compound obtained in example 43 (2.65 g, 5.3 mmol) in trifluoroacetic acid (58 mL) was added anisole (1 mL) and the mixture stirred under an argon atmosphere for 18 h. The solvent was concentrated and the residue purified by chromatography on silica-gel (hexane-EtOAc mixtures) to give a 1:1 mixture of regioisomers, from which the title compound was obtained as a white solid by recrystallization from EtOAc (1.34 g, 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1.[CH3:13][N:14]([CH:16]=O)[CH3:15]>CC#N.C(Cl)Cl>[CH3:13][N:14]([CH2:16][C:6]1[C:2]([CH3:1])=[N:3][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=1)[CH3:15]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cn1ccc(C)n1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(CN(C)C)c(C)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(3-methyl-1H-pyrazol-1-yl)acetate (94 mg) and DMF (1.5 mL) in MeCN (3 mL) was added N,N-dimethylmethyleneiminium iodide (390 mg). The reaction mixture was stirred at 90° C. overnight. After cooling down, the reaction mixture was diluted with DCM and washed with sat. NaHCO3 and water. The aq. layers were extracted with DCM, the combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo to afford ethyl 2-(4-((dimethylamino)methyl)-3-methyl-1H-pyrazol-1-yl)acetate (112 mg, brown oil). LC-MS (B): tR=0.39 min; [M+H]+: 226.23.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][O:16][CH3:17])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1([CH3:57])[O:49][C@H:48]([CH2:50][N:51]2[CH:55]=[CH:54][C:53]([NH2:56])=[N:52]2)[CH2:47][O:46]1>ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][O:16][CH3:17])[C:11]([NH:56][C:53]2[CH:54]=[CH:55][N:51]([CH2:50][C@@H:48]3[CH2:47][O:46][C:45]([CH3:57])([CH3:44])[O:49]3)[N:52]=2)=[O:13])[C:7](=[O:18])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: COCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.1 %

Procedure:
In a round bottom flask under argon was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methoxy-butyric acid (62 mg, 0.19 mmol) in dichloromethane (5 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (37 μL, 0.21 mmol) and 1-hydoxybenzotriazole (27 mg, 0.20 mmol) and stirred at 25° C. for 2 h. After this time period, 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 45 mg, 0.23 mmol) was added and stirred for 16 h at 25° C. After this time, the reaction was diluted with dichloromethane (10 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (4 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-4-methoxy-butyramide (26 mg, 27%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[C:10]1([CH3:9])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Nc1cnncc1Cl
Product: Cc1ccccc1-c1cnncc1N

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 5-chloro-pyridazin-4-ylamine (CAS RN 53180-92-0) and 2-methylphenylboronic acid (CAS RN). Light yellow solid (37%). MS (ESI+): m/z=186.103 ([M+H]+).