Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[C:5]([NH2:25])=[C:4]([NH2:26])[N:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:32]=O>>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:25]=[C:32]([C:31]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH3:27])[CH:30]=3)[NH:26]2)=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH2:12][CH2:13]2)[N:7]=1
Reactant: Nc1nc(N)c(N)c(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)n1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(-c2nc3c(N4CCN(C(=O)COc5ccc(Cl)cc5)CC4)nc(N)nc3[nH]2)cc1OC
Yield: 57 %

Procedure:
This compound was synthesized from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]pyrimidine and 3,4-dimethoxybenzaldehyde yielding the pure title compound in 57% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:9](=[O:16])[O:8][C:6]=2[CH:7]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:12]2[CH2:13][CH2:14][C:15]3[C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=4[O:8][C:9](=[O:16])[C:10]=3[CH2:11]2)=[CH:20][CH:19]=1
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=Cc1ccc(Cl)cc1
Product: Cc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccc(Cl)cc1)CC3
Yield: 65 %

Procedure:
Prepared by the procedure of Example 3 from 8-methyl-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one* and 4-chlorobenzaldehyde. Yield 65%; mp 147°-149° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:23]([CH3:31])[C:22]=2[CH:32]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I>[CH:28]1([C:26]([C:24]2[N:23]([CH3:31])[C:22]3[CH:32]=[C:18]([N:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]5[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=5)=[CH:9][C:10]4=[O:14])[CH:19]=[CH:20][C:21]=3[N:25]=2)=[O:27])[CH2:30][CH2:29]1
Reactant: Cn1c(C(=O)C2CC2)nc2ccc(Br)cc21
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(C(=O)C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 150 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (236 mg), (6-bromo-1-methyl-1H-benzimidazol-2-yl)(cyclopropyl)methanone (300 mg), N,N′-dimethylethylenediamine (0.115 ml), copper iodide (205 mg) and potassium carbonate (594 mg) in DMSO (3 ml) was stirred at 150° C. for 1 h. The mixture was purified by NH silica gel column chromatography (hexane/EtOAc). The obtained solid was washed with water and IPE to give the title compound (76 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26]OS(C)(=O)=O)[C:20]=4[CH:32]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O.[CH3:38][NH:39][CH3:40]>C1COCC1>[CH3:38][N:39]([CH3:40])[CH2:26][CH2:25][CH2:24][N:21]1[C:20]2[CH:32]=[C:16]([C:9]3[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)=[N:12][N:11]4[CH2:13][CH2:14][CH2:15][C:10]=34)[CH:17]=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCOS(C)(=O)=O)c4c2)CCC3)n1
Reactant: CNC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCN(C)C)c4c2)CCC3)n1
Temperature: 80 °C
Yield: 95 %

Procedure:
Combine methanesulfonic acid methanesulfonic acid 3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propyl ester (Example 57a; 22 mg, 0.048 mmol) with 2M dimethylamine in THF (2 mL). Heat the mixture at 80° C. for 30 min. Cool, evaporate the excess amine, and purify the crude product with FCC to give the title compound (18.5 mg, 95%). MS m/e 401.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH:19]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])=[CH2:20]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:20][CH:19]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: C=CP(=O)(OCC)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C1CC(c2ccc(Cl)cc2)=NO1
Yield: 102.8 %

Procedure:
The compound is prepared in analogy to Example 1 from 23.34 g (0.15 mol) of 4-chlorobenzaldoxime, 22 g of N-chlorosuccinimide, 27.1 g of diethyl vinylphosphonate and 22.9 ml of triethylamine, resulting in 49 g of oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-hexane (150 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-hexyl-1H-pyrazole (118 mg, 56%) as a clear oil.
Reaction SMILES: [Br:1][CH:2](Br)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:22])[CH:19](Br)[Br:20])=[CH:14][CH:13]=2)[CH:6]=1)=[O:4].C(N(CC)CC)C.P([O-])(OCC)OCC>O1CCCC1>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:22])[CH2:19][Br:20])=[CH:14][CH:13]=2)[CH:6]=1)=[O:4]
Reactant: O=C(c1ccc(Oc2cccc(C(=O)C(Br)Br)c2)cc1)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(Oc2cccc(C(=O)CBr)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of 2,2-dibromo-1-(3-(4-(2,2-dibromoacetyl)phenoxy)phenyl)ethanone (16 g, 28 mmol) in tetrahydrofuran (300 mL) at 0° C. was added triethylamine (3.6 mL) and diethyl phosphite (10.7 mL, 83.2 mmol). The reaction was warmed gradually to room temperature and the mixture was stirred during 30 minutes and concentrated under reduced pressure. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resultant crude material was purified by flash chromatography (silica gel: EtOAc/heptane: 3/7) to afford 2-bromo-1-(3-(4-(2-bromoacetyl)phenoxy)phenyl)ethanone (10.2 g, 88%) as yellow oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CCNCC1
Product: N#Cc1ccc(N2CCCCC2)cc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and piperidine.
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[C:11]2[CH:17]=[CH:16][N:15]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[N:13][CH:14]=1)=C\C1C=CC=CC=1.[O:28]1CCOCC1>O>[S:18]([N:15]1[C:12]2=[N:13][CH:14]=[C:9]([CH:1]=[O:28])[N:10]=[C:11]2[CH:17]=[CH:16]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=C/c4ccccc4)cnc32)cc1
Reactant: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (72.3 g, 193 mmol) in 1,4-dioxane (1500 mL) and water (300 mL) was added NaIO4 (165 g, 770 mmol) followed by OSO4 (5.00 g, 19.7 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was concentrated under reduced pressure then was partitioned with 10% aqueous Na2S2O3 (1000 mL) and DCM (1000 mL). The organic layer was washed with water (2×500 mL) and the layers were filtered to remove undissolved precipitate and separated. The organic layer was dried over anhydrous Na2SO4, filtered through Celite®, and concentrated. The residue was purified by filtration through a pad of silica gel (1000 g) eluting with 0-5% EtOAc in DCM. The fractions were concentrated and the solid was triturated with heptane. The mixture was filtered and the filter cake was washed with heptane. This procedure was repeated for the collected undissolved precipitate. The collected solid was then dissolved in 2% EtOAc in DCM and passed through a pad of silica gel (100 g) eluting with 2% EtOAc in DCM. The filtrate was concentrated under reduced pressure. The two batches were combined to give 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (39.1 g, 67%) as an off-white solid: LC/MS (Table 2, Method a) Rt=2.17 min; MS m/z: 302 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]=[C:16]=[O:17])[CH:13]=[CH2:14]>C1C=CC=CC=1>[CH2:12]([NH:15][C:16]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCN=C=O
Reactant: CCCCNc1nc(C)co1
Solvent: c1ccccc1
Product: C=CCNC(=O)N(CCCC)c1nc(C)co1

Procedure:
A solution of 2-butylamino-4-methyloxazole (12.0 g, 0.078 mol) and allyl isocyanate (6.46 g, 0.078 mol) in dry benzene was heated under reflux for 4 hours, and worked up as described in Example 3. The product was further purified by chromatography on a silica-gel column, eluting with a 1:1 mixture of benzene and ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.C([O:29][C:30](=[O:34])[C@H:31]([CH3:33])[NH2:32])(C)(C)C.F[B-](F)(F)F.Cl.C(C1NC=C[N+]=1C(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[N:7]([CH2:8][CH2:9][O:10][C:4]4[CH:3]=[C:2]([NH:32][C@@H:31]([CH3:33])[C:30]([OH:34])=[O:29])[CH:23]=[CH:22][C:5]=43)[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: CC(C)c1[nH]cc[n+]1C(C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: COCCOC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N[C@@H](C)C(=O)O)cc1OCC2
Yield: 41.8 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 (0.72 g, 1.69 mmol), alanine tert-butyl ester hydrochloride (1.52 g, 8.4 mmol), Rh(COD)2.BF4 (0.07 g, 0.18 mmol), diisopropylimidazolium hydrochloride (0.07 g, 0.35 mmol) and cesium carbonate (4.38 g, 13.4 mmol) in DME (7 mL) was heated at 90° C. under an argon atmosphere for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between DCM and water. The aqueous phase was acidified with 1M HCl, extracted with 10% methanol in DCM and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to give (S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-propionic acid (0.27 g, 33%). LCMS: RT=2.47 min, [M+H]+=383.
Reaction SMILES: [C:1](OC1C=CC2C=C(C)SC=2C=1)(=[O:3])C.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].C[O:26][C:27]1[CH:28]=[CH:29][C:30]2[C:34]([C:35](Cl)=[O:36])=[C:33]([CH3:38])[S:32][C:31]=2[CH:39]=1.C([O-])([O-])=O.[K+].[K+]>CO>[OH:26][C:27]1[CH:28]=[CH:29][C:30]2[C:34]([C:35]([O:3][CH3:1])=[O:36])=[C:33]([CH3:38])[S:32][C:31]=2[CH:39]=1
Reactant: COc1ccc2c(C(=O)Cl)c(C)sc2c1
Reactant: CC(=O)Oc1ccc2cc(C)sc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: CO
Product: COC(=O)c1c(C)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
This material was prepared from 6-acetoxy-2-methylbenzo[b]thiophene 8b (500 mg, 2.42 mmole) by acylation with oxalyl chloride in the presence of AlCl3 as previously described for example 1c. A solution of the crude 6-methoxy-2-methylbenzo[b]thiophene-3-carbonyl chloride in MeOH (24 ml) was cooled to 0° C. prior to the addition of K2CO3 (351 mg, 2.66 mmole). The reaction was warmed to ambient temperature and stirred 3 hours. The solvent was removed, in vacuo, and the resulting residue was diluted with CH2Cl2 (75 ml) and H2O (25 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (50 ml). The combined organics were washed with brine (25 ml), dried (Na2SO4), filtered, and concentrated in vacuo to afford the 468 mg (87%) of a pale brown solid. 1H NMR (300 MHz, DMSO-d6) δ 9.68 (1H, s), 8.06 (1H, d, J=8.9 Hz), 7.23 (1H, d, J=2.3 Hz), 6.91 (1H, dd, J=2.3, 8.9 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][NH:5][C:6]=1[CH2:7][CH2:8][CH2:9]Cl.[OH-].[K+]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([CH3:11])=[N:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: Cc1n[nH]c(CCCCl)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nn2c(c1Br)CCC2
Yield: 49 %

Procedure:
To a solution of 4-bromo-5-(3-chloro-propyl)-3-methyl-1H-pyrazole (2.42 g, 10.2 mmol) in isopropyl alcohol (35 mL) was added KOH (0.86 g, 15.3 mmol) dissolved in water (7 mL). The reaction was heated to reflux for 4 h. After cooling the reaction was partially concentrated, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated to give a light yellow oil as the desired product (1.01 g, 5.0 mmol). MS m/z 203.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[CH3:24])/[C:21]([OH:23])=[O:22])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:17])[CH3:16])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)[C:33]1C=C(O)C=C[CH:38]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[CH3:24])/[C:21]([O:23][CH2:33][CH3:38])=[O:22])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:16])[CH3:17])[CH:10]=1
Reactant: C/C(=C\c1cc(F)c(Oc2cccc(N(C)C)c2)c(F)c1)C(=O)O
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2cccc(N(C)C)c2)c(F)c1

Procedure:
E-3-[3,5-Difluoro-4-(3-dimethylaminophenoxy)phenyl]-2-methyl-propenoic acid guanidide hydrochloride ##STR15## 10 a) The ester from 8 a, 3 eq. of potassium carbonate and 1.1 eq. of 3-dimethylaminophenol were stirred in DMF at 150° C. for 5 hours. After working up and purification, ethyl E-3-[3,5-difluoro-4-(3-dimethylaminophenoxy)phenyl]-2-methyl-propenoate was isolated.
Reaction SMILES: CC(=O)C.O.[NH2:6][NH2:7].C(O[CH:11](OCC)[CH:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=O)C>C(O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:12]1[CH:11]=[N:6][NH:7][C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CCOC(OCC)C(C(=O)c1ccccn1)c1ccccn1
Reactant: NN
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cn[nH]c2-c2ccccn2)nc1

Procedure:
The propanone was dissolved in 1 L of ethanol, 5.8 mL (0.12 mol) of hydrazine hydrate was added, and the mixture was heated to reflux for 1 hr. The ethanol was stripped off in vacuo, and the residue was put through a 600 g silica gel column eluting with 1:1 hexane-acetone to yield about 4 g of 4,5-bis(2-pyridinyl)-1H-pyrazole as a light tan solid after removal of solvent.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCCN(C)C1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.47 g (6.0 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-one dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are deprotonated at -70° C. with 11.73 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (75 min) with 0.713 ml (6.0 mmol) of benzyl bromide in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate 4:1→2:1) and crystallisation from ether/hexane yields the pure title compound: TLC Rf (D)=0.36.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:30]=[C:25]([OH:24])[CH:26]=[CH:27][CH:28]=2)[CH:3]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(F)(F)F)cc2F)n1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(O)c2)n1
Reaction time: 15 h
Yield: 116.9 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [1.47 g, 4.2 mmol, see Example 52, step 1], (3-hydroxy-phenyl)-boronic acid, (637 mg, 4.62 mmol), and Cs2CO3 (3.4 g, 10.5 mmol) in ethylene glycol dimethyl ether (20 mL) and water (4 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (243 mg, 0.21 mmol) at room temperature. After 15 h at 85° C., the mixture is diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The extracts are dried (MgSO4), filtered through a pad of SiO2, and concentrated to afford 3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol (2 g). LCMS: RT=2.32 minutes; MS: 408 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:28](OCC)=[O:29].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[C:9]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:28]=[O:29])=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: Cn1nnnc1C=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -80 °C
Reaction time: 0.67 h
Yield: 71.5 %

Procedure:
To a finely divided suspension of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (1.0 g, 3.3 mmoles) [prepared in Step B] in tetrahydrofuran (10 mL) at -80° C. was added n-butyl lithium (1.54 mL of 2.14M solution), 3.3 mmoles) with the formation of a dark violet color. After stirring for 40 minutes at -80° C., ethyl formate (0.32 g, 4.3 mmoles) was added and the mixture stirred for 2.5 hours at -80° C. The mixture was hydrolyzed with 1N hydrochloric acid and extracted with methylene chloride. The extracts were dried (MgSO4) and evaporated in vacuo. The residue was triturated with diethyl ether to give 0.77 g of yellow solid, m.p. 128°-131° C. The solid was crystallized from isopropyl acetate-hexane to give 0.55 g of the title compound; m.p.=130°-132° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)[C:5]([F:8])([F:7])[F:6].Br[C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]3[N:31]=[C:30]([CH:32]4[CH2:34][CH2:33]4)[N:29]([CH3:35])[C:28]=3[CH:36]=2)[C:20](=[O:37])[CH:19]=1>CC(N(C)C)=O>[CH:32]1([C:30]2[N:29]([CH3:35])[C:28]3[CH:36]=[C:24]([N:21]4[CH:22]=[CH:23][C:18]([O:15][CH2:14][C:12]5[N:13]=[C:9]([C:4]([F:3])([F:16])[C:5]([F:8])([F:7])[F:6])[S:10][CH:11]=5)=[CH:19][C:20]4=[O:37])[CH:25]=[CH:26][C:27]=3[N:31]=2)[CH2:33][CH2:34]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Reactant: OCc1csc(C(F)(F)C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)C(F)(F)F)n4)cc3=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
NaH (60% in oil, 51.5 mg) was added to a solution of (2-(perfluoroethyl)thiazol-4-yl)methanol (300 mg) in DMA (5 ml) at 0° C. After being stirred at 0° C. for 30 min, 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)-one (295 mg) was added to the reaction mixture. The mixture was stirred at 120° C. under N2 atmosphere for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by crystallization from EtOH-water to give the title compound (25 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCC1CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (2.0 g, 10.4 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (3.83 g, 20.8 mmol), sodium iodide (779 mg, 5.20 mmol) and potassium carbonate (8.63 g, 62.4 mmol) in dimethylformamide (15 mL) was stirred at room temperature overnight. After this time, the mixture was diluted with water (15 mL) then extracted with ethyl acetate (3×75 mL). The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give an orange oil which solidified upon drying under reduced pressure (2.32 g, 73.7%). 1H-NMR (CDCl3) δ: 8.13 (dd, J=2.7, 9 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 4.15-4.05 (m, 1H), 3.97-3.87 (m, 1H), 3.05-3.01 (m, 4H), 2.72-2.70 (m, 2H), 2.28 (s, 3H), 2.17-1.60 (m, 7H).