Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[CH2:20][CH2:21][CH:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>P(=O)(O)(O)O>[CH3:15][O:14][CH2:13][CH2:12][N:8]1[C:7]2[C:2]3[O:29][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:21][CH2:20][C:3]=3[C:4]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][C:6]=2[N:10]=[C:9]1[CH3:11]
Reactant: COCCn1c(C)nc2cc(C(=O)OC)c(CCC(O)c3ccccc3)c(O)c21
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COCCn1c(C)nc2cc(C(=O)OC)c3c(c21)OC(c1ccccc1)CC3
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
A suspension of methyl 7-hydroxy-6-(3-hydroxy-3-phenylpropyl)-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole-5-carboxylate (2.00 g, 5.01 mmol, Step 10) in 85% phosphoric acid (40 mL) was stirred at 80° C. for 20 minutes. After cooling to room temperature, the mixture was poured onto ice-water (300 mL), and the solution was neutralized by 10 N sodium hydroxide aqueous solution. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (gradient elution from ethyl acetate only to 20:1) to afford the title compound as a pale brown solid (1.47 g, 77%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[S:15][C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[N:13][C:12]=1[C:27]([NH2:29])=[O:28].N1C=CC=CC=1>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:10][C:11]1[S:15][C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[N:13][C:12]=1[C:27]([NH2:29])=[O:28])=[O:8]
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: O=C(Cl)CCCCCBr
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A solution of 6-bromohexanoyl chloride (0.82 mL, 5.28 mmol) in THF (4 mL) was added dropwise to a mixture of 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.30 g, 1.06 mmol) and pyridine (4 mL) in THF (20 mL) at 0° C., and the mixture was stirred for 16 hrs at rt. The reaction mixture was quenched with ice-water. The resulting solids were collected by filtration and washed with ether and EtOAc to give 0.45 g (92% yield) of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([S:13]([N:16]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([NH:25][O:26]C4CCCCO4)=[O:24])=[CH:17]3)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3]1.Cl>CO>[OH:26][NH:25][C:23](=[O:24])/[CH:22]=[CH:21]/[C:18]1[CH:19]=[CH:20][N:16]([S:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)(=[O:15])=[O:14])[CH:17]=1
Reactant: Cn1cc(-c2cccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)c2)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2cccc(S(=O)(=O)n3ccc(/C=C/C(=O)NO)c3)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.1 %

Procedure:
A mixture of 0.086 g (E)-3-{1-[3-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 3.0 ml methanol and 7.0 ml 1M aqueous HCl is stirred at ambient temperature for 24 h. The suspension is partly evaporated and the residual mixture is centrifuged. The product is washed with water and diisopropylether and dried in vacuo. By this method 0.045 g of a light pink powder are obtained. Melting point: 155-160° C., sinter is beginning from 85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C@@H:20]([C:22]([OH:24])=O)[CH3:21])=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:22](=[O:24])[C@@H:20]([CH3:21])[NH:19][C:17]3=[O:18])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H](NC(=O)Nc1ccc(Oc2ccc(F)c(Cl)c2)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H]1NC(=O)N(c2ccc(Oc3ccc(F)c(Cl)c3)cc2)C1=O
Temperature: 100 °C
Yield: 12.6 %

Procedure:
A mixture of N-[({4-[(3-chloro-4-fluorophenyl)oxy]phenyl}amino)carbonyl]-D-alanine (Intermediate 9, 352 mg) in 15 mL of 3N HCl was heated at 100° C. for 16 hours. Then sodium carbonate was added and the mixture was adjusted to pH=8. The mixture was extracted with ethyl acetate (3 times 50 mL) and the combined organic phases were washed with brine and dried over magnesium sulphate. Removal of the solvent afforded a residue which was purified by column chromatography (MeOH/DCM=1/50) to give 42 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1.[CH:17]1([Mg]Br)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([CH:17]2[CH2:19][CH2:18]2)([OH:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1
Reactant: O=C(Cn1ccnc1)c1cc(Cl)ccc1O
Reactant: Br[Mg]C1CC1
Product: Oc1ccc(Cl)cc1C(O)(Cn1ccnc1)C1CC1
Yield: 36 %

Procedure:
The general procedure of Example 1 was repeated using 1-(5-chloro-2-hydroxyphenyl)-2-(1H-1-imidazolyl)-1-ethanone [compound (5-1)] and cyclopropylmagnesium bromide, to thereby yield 4-chloro-2-(1-cyclopropyl-1-hydroxy-2-(1H-1-imidazolyl)ethyl)phenol as colorless crystals (yield: 36.0%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.O[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[CH:22]=1
Reactant: Oc1cccnc1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(COc2cccnc2)cc1)c1ccccc1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 3-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.44 (br s, 3H), 5.12 (s, 2H), 7.17 (br s, 2H), 7.27-7.46 (m, 9H), 8.29 (br s, 1H), 8.49 (br s, 1H); HPLC-MS: m/z=335.0 (M+1); Rt=2.74 min.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=3)=[CH:11][NH:10]2)[CH:4]=1.[CH3:27]I>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:19][CH:20]=3)=[CH:11][N:10]2[CH3:27])[CH:4]=1
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1cccc(C(F)(F)F)c1
Reactant: CI
Product: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A 3.5 gram portion of the atropic ester of Example 1 was reacted with 2.7 grams α,α,α-trifluoro-3-tolylhydrazine hydrochloride in the presence of triethylamine to produce 2.4 grams 1,4-bis-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 207°-208° C. A 1.8 gram portion of the above pyrazolinone was alkylated with 2 grams methyl iodide to produce 1.25 grams of the desired product, m.p. 110°-111° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[N:39]1([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][CH2:40]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)[C:32]([N:55]3[CH2:54][CH2:53][CH:52]([N:39]4[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][CH2:40]4)[CH2:57][CH2:56]3)=[O:34])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: CCOC(=O)CCC1CCN(C2CCNCC2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Product: CCOC(=O)CCC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 24 from 500 mg (0.90 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f) and 341 mg (1.00 mmol) ethyl 3-[1,4′]bipiperidinyl-4-yl-propionate (Example A15b).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=1)[C:9]([OH:11])=[O:10].C[O-].[Na+].[CH2:36](I)[CH3:37].CN(C)C=O>CO.CCOCC.[Cl-].[Na+].O>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=1)[C:9]([O:11][CH2:36][CH3:37])=[O:10]
Reactant: CCI
Reactant: O=C(O)C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(NCc1cccc(C(F)(F)F)c1)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred suspension of α-[3-(trifluoromethyl)benzylamino)-1-benzylindole-3-acetic acid (21.9 g, 0.05 mol) in 250 mL of methanol at room temperature was treated with 11.34 g of sodium methoxide (25% in methanol) at once. The resulting solution was stirred for two hours, concentrated directly on a rotary evaporator and finally the resulting white residue was pumped down under high vacuum using a warm water bath at ca 50° C. The dry sodium salt was dissolved in 100 mL of dimethylformamide, charged at once with ethyl iodide (9.36 g, 0.06 mol, 1.20 eq) and stirred in the dark for 48 hours with an additional 50 mL of dimethylformamide being added after 20 hours to facilitate stirring of the gelantinous precipitate which formed. The contents were diluted with ether and poured into 125 mL of ice water plus 125 ml of saturated brine. The aqueous phase was separated from the organic layer and extracted once more with ether. The combined organic extracts were dried with anhydrous Na2SO4 and concentrated at reduced pressure. Flash chromatography with 250 g of silica gel packed and eluted with ethyl acetate-hexane (1:4) gave the title compound as a yellow oil.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH:5]1([NH:10][N:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][CH2:7][CH2:6]1>O>[OH:15][C:13]1[C:12]([C:1](=[O:2])[CH3:3])=[N:11][N:10]([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:14]=1
Reactant: CC(=O)C=NNC1CCCC1
Reactant: O=CC=O
Solvent: O
Product: CC(=O)c1nn(C2CCCC2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A 40% aqueous solution of glyoxal (1.88 mL, 16.4 mmol) was added to 2-oxopropanal cyclopentylhydrazone (2.53 g, 16.4 mmol) in H2O (125 mL). The mixture was then heated at reflux. After 1 hour, the mixture was cooled to room temperature and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 1.68 g (53%) of 1-(4-hydroxy-1-cyclopentyl-1H-pyrazol-3-yl)ethanone as a yellow oil. The crude product was then used in the next step without further purification.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([S:13]([CH2:16]Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1.C(O)(=O)C>O1CCCC1>[CH3:18][O:19][C:20]1[N:21]=[C:22]([CH2:16][S:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:15])=[O:14])[C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COc1ccc([N+](=O)[O-])cn1
Reactant: O=S(=O)(CCl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccccc2)n1
Yield: 80 %

Procedure:
A 1M KOt-Bu solution in tetrahydrofuran (50 mL, 50 mmol) is cooled to −40° C., treated portion-wise with a solution of chloromethyl phenyl sulfone (4.39 g, 23.0 mmol) and then with a solution of 2-methoxy-5-nitropyridine (3.55 g, 23.0 mmol) in tetrahydrofuran, stirred for 45 min at −40° C., treated with glacial acetic acid (3.0 g, 50 mmol) and filtered. The filtercake is air-dried to give the title compound as a tan solid, 5.70 g (80% yield), mp 147–149° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:25])[CH2:23]Cl)[N:3]=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28].[I-].[Na+]>CC(C)=O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:25])[CH2:23][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])[N:3]=1
Reactant: CCCNCCC
Reactant: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CCl)nc2N)cc1I
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCN(CCC)CC(=O)Nc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Temperature: 55 °C
Reaction time: 22 h
Yield: 32.7 %

Procedure:
N-[4-Amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-chloro-acetamide (0.31 g, 0.65 mmol), N,N-di-n-propylamine (0.33 g, 3.25 mmol) and sodium iodide (20 mg) were added to 20 mL acetone. The reaction mixture was stirred at 55° C. under nitrogen atmosphere for 22 hours, then cooled and concentrated under reduced pressure. The residue was diluted with water and extracted with methylene chloride. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (methylene chloride/MeOH 100:1) to give 115 mg (33%) of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-dipropylamino-acetamide, m.p.=129-131° C., MS (M+H)=542.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C1(CN)CC1.[Cl:19][C:20]1[CH:57]=[CH:56][C:23]([C:24]2[C:29]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:40]5[N:44](CC)[C:43]6C=C[C:49](C(O)=O)=[CH:50][C:42]=6N=5)[CH:36]=4)[N:31]=3)=[CH:28][C:27]([O:54][CH3:55])=[CH:26][CH:25]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:57]=[CH:56][C:23]([C:24]2[C:29]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:40]5[N:44]([CH2:43][CH:42]6[CH2:50][CH2:49]6)[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:36]=4)[N:31]=3)=[CH:28][C:27]([O:54][CH3:55])=[CH:26][CH:25]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Agent: NCC1CC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4CC4CC4)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and cyclopropylmethylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=O)=[N:9]2)=[CH:4][CH:3]=1.ClC(OCC)=O.[Li].[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28]>C1COCC1.CCOCC.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([NH:30][S:27]([CH3:26])(=[O:29])=[O:28])=[O:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Agent: CCOC(=O)Cl
Agent: [Li]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(=O)c(C(=O)NS(C)(=O)=O)nn1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a mixture of 1.3 g of 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid and 0.73 ml of triethylamine in 50 ml of THF was added at -40° C., 0.53 ml of ethyl chloroformate, and the resulting mixture was allowed to reach room temperature over 2 hours with continued stirring. The mixture was then cooled to -78° C., and the monolithium salt of methanesulfonamide (prepared from 18 mmole of lithiodiisopropylamide and 15 mmole (1.42 g) of methanesulfonamide) in 25 ml of THF was added dropwise at -65° C. The resulting slurry was allowed to reach room temperature with continual stirring. After an additional hour of stirring the reaction mixture was diluted with 200 ml of ether and washed with 1N hydrochloric acid. The ether layer was then extracted with 5% sodium bicarbonate and the aqueous phase was acidified to pH2. The resulting precipitate was collected by filtration and recrystallized from methanol to yield 1.206 g of product, m.p. 225°-227°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:13][O:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(C)cc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
To a solution of methyl 2-hydroxy-4-methylbenzoate (3 g; 18.2 mmol) in DMF (36 mL) was added potassium carbonate (5 g; 36.4 mmol) and methyl iodide (3.35 mL; 182 mmol) dropwise. The reaction mixture was stirred at room temperature for 24 hours. The insoluble's were filtered, washed with ethyl acetate and the volatiles were removed under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate (1 to 30%) in heptane to furnish 2.78 g of the methyl 2-methoxy-4-methylbenzoate (85%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N+:15]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:15][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: CC(C)n1c(=O)oc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)n1c(=O)oc2cc(N)cc(F)c21

Procedure:
Prepared from 4-fluoro-3-isopropyl-6-nitro-1,3-benzoxazol-2(3H)-one (Step 1, 0.87 g, 3.64 mmol), ammonium chloride (1.95 g, 36.4 mmol) and iron powder (0.81 g, 14.6 mmol) in ethanol (30 ml) and water (15 ml) according to the method of EXAMPLE 86, Step 7 (0.77 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:9][CH:10]=[C:5]2[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[Li+].[OH-].Cl>C1COCC1.C(OCC)C>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=[C:5]2[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1
Reactant: CCOC(=O)COc1ccc2c(-c3ccccc3)nn(C)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)c2ccc(OCC(=O)O)nc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A mixture of Ethyl 2-(1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetate (0.33 g, 1.059 mmol) and aqueous LiOH (0.446 g, 10.599 mmol in 3.0 mL H2O) in THF (3.0 mL) was stirred at rt for 6 h. The reaction mixture was neutralized with diluted HCl and diluted with diethyl ether. The organic layer was extracted with water and brine and dried over anhydrous Na2SO4. Concentration of the organic layer furnished the crude product as a white solid. The crude product was purified by column chromatography (eluent: 75% EtOAc in hexane) to yield the title compound as a white solid (0.291 g, 97%). [1H-NMR (CDCl3, 300 MHz) δ 8.21 (d, 1H), 7.92-7.84 (m, 2H), 7.52-7.35 (m, 3H), 6.77 (d, 1H), 5.05 (s, 2H), 4.02 (s, 3H); HPLC RtA=4.315 min (97%); LCMS RtC=0.389 min; [M+H]+=283.9]
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(N(CC)CC)C.[C:31]1([CH:37]([CH3:40])[CH:38]=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[C:31]1([CH:37]([C:40]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C=O)c1ccccc1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(c1ccccc1)c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Yield: 9.5 %

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (0.5 g, 1.7 mmol) in ethanol (20 mL) was added triethylamine (1 mL) and 2-phenylpropanal (0.25 g, 1.9 mmol). The reaction mixture was heated at reflux for 12 h. The mixture was then concentrated under reduced pressure, diluted with ice cold water and extracted with ethyl acetate. The organic layers were dried, filtered and concentrated, and the resulting residue was purified by preparative TLC to afford the title compound (65 mg, 9%). MS (ES+APCI) (M+H) 404.2; LCMS retention time 2.206 min (Method Y).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(O)(=O)=O)C=CC=CC=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([OH:39])=[O:38]>C(Cl)Cl.CCOC(C)=O>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([OH:39])=[O:38].[CH2:1]([NH:8][CH2:9][CH2:10][O:11][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][O:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: OCCNCc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1ccc(CNCCOC2CCCCO2)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
100 g of 2-(benzylamino)-1-ethanol are added at ambient temperature to a mixture of 110 g of benzenesulfonic acid in 1.8 liters of DCM, the temperature at the end of the addition being 34.4° C. and the pH=2. The reaction mixture is cooled to 20° C. and 105 ml of 3,4-dihydro-2H-pyran are added dropwise, the reaction mixture turning yellow, then pink and finally purple in color at the end of the addition. The mixture is poured onto 2 liters of a 10% aqueous K2CO3 solution, then, after separating by settling, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The oil obtained is dissolved in 200 ml of AcOEt, a hot solution of 72.7 g of maleic acid in 655 ml of AcOEt is added and the mixture is left stirring overnight at ambient temperature. The precipitate formed is filtered off, washed with 3×100 ml of AcOEt and dried under vacuum at ambient temperature. 207 g of the expected product are obtained in the maleate form.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:42][CH:41]=4)[C:38]([CH3:53])=[C:37]([OH:54])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:41]=[CH:42][C:43]([O:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:44][CH:45]=4)[C:38]([CH3:53])=[C:37]([O:54][CH3:3])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(OC2CCCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: OCCO
Solvent: CCOCC
Product: COC1=C(C)C(c2ccc(OC3CCCCC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(4-(cyclohexyloxy)phenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (0.500 g, 1.24 mmol, 1 eq) and MeOH (10 ml); yield: 0.050 g (10%); MS m/z: 418.2 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 7.90 (s, 1H), 7.78 (s, 1H), 7.5 (s, 1H), 7.26 (s, 2H), 7.06 (d, 2H), 6.76 (d, 2H), 5.24 (s,1H), 4.07 (d, 4H), 1.80 (d, 2H), 1.76 (d, 5H), 1.45 (d, 3H), 1.30 (d, 4H); HPLC (METHOD [A]): rt 15.23 min (100%)