Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:21](I)([CH3:23])[CH3:22]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:14][CH:21]([CH3:23])[CH3:22])=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: O=C1NCCc2cc(F)c(O)c(Cl)c21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(F)cc2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.6 %

Procedure:
To a solution of 8-chloro-6-fluoro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (Cpd O, 131 mg, 0.607 mmol) in DMF (3.0 mL) was added cesium carbonate (0.210 g, 0.645 mmol) and iso-propyl iodide (0.0850 mL, 0.850 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc and washed with water (2×) and brine. The organic layer was concentrated under vacuum and the residue was purified by column chromatography (40-100% EtOAc/heptane) to give the title compound (Cpd P, 62 mg, 40%) as a white solid. MS 258 [M+H].
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]1[CH:6]=[C:7]([NH2:21])[C:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])=[CH:9][CH:10]=1>C(O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]2[N:11]([C:12]3[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=3[CH3:18])[C:2]([NH2:1])=[N:21][C:7]=2[CH:6]=1
Reactant: N#CBr
Reactant: Cc1cc(C)c(Nc2ccc(F)cc2N)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(-n2c(N)nc3cc(F)ccc32)c(C)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A solution of cyanogen bromide (2.67 g, 25.2 mmol) in anhydrous ethanol (10 mL) was added at 0° C. to a solution of 4-fluoro-N1-(2,4,6-trimethyl-phenyl)-benzene-1,2-diamine (4.74 g, 19.4 mmol) in anhydrous ethanol (20 mL) under nitrogen. The reaction mixture was warmed up to room temperature for 10 min, then was heated at 155° C. For 40 min with a flow of nitrogen to remove ethanol. Upon cooling to room temperature, the resulting solids were transferred to a separatory funnel via dichloromethane (70 mL), and washed sequentially with 1 N sodium hydroxide (2×35 mL), water and brine. The organic layer was dried over anhydrous sodium sulfate and solvents were removed in vacuo to afford the title compound as a red solid (5.11 g, 98% yield). The purity of this compound was determined to be 95% by LC/MS. 1H NMR (CDCl3, 300 MHz) δ 7.12 (dd, J=9.7, 2.4 Hz, 1H), 7.06 (s, 2H), 6.69 (td, J=9.1, 2.4 Hz, 1H), 6.56 (dd, J=8.5, 4.7 Hz, 1H), 2.38 (s, 3H), 1.98 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 161.0, 157.9, 154.2, 143.3, 139.9, 137.4, 129.8, 128.8, 107.8 (d, J=10.2 Hz), 106.9 (d, J=25.3 Hz), 103.1 (d, J=25.2 Hz)21.1, 17.5; Mass spec.: 270.17 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[CH3:19])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:42])[F:41])[N:32]=[CH:31][C:30]=1[CH:44]([CH3:46])[CH3:45]>CC#N>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:28][C:29]3[N:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([F:42])([F:41])[F:43])[N:32]=[CH:31][C:30]=3[CH:44]([CH3:46])[CH3:45])=[CH:14][C:13]=2[CH3:19])[CH:5]=1
Reactant: COC(=O)c1cccc(C=Cc2ccc(O)cc2C)c1
Reactant: CC(C)c1cnn(-c2ccccc2C(F)(F)F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)cnn3-c3ccccc3C(F)(F)F)cc2C)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of 3-[2-(4-hydroxy-2-methyl-phenyl)-vinyl]-benzoic acid methyl ester (107 mg, 0.4 mmol) and potassium carbonate (138 mg, 1 mmol) in CH3CN (4 mL) is added 5-bromomethyl-4-isopropyl-1-(2-trifluoromethyl-phenyl)-1H-pyrazole in CH3CN (4 mL, approximately 0.1 mmol/mL). The reaction mixture is stirred at 80° C. for 5 hours and filtered through a Celite® pad eluting with EtOAc. The combined filtrate is concentrated and purified by column chromatography (0 to 20% EtOAc in hexanes) to give the desired product, 136 mg (64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:25](Cl)(=[O:27])[CH3:26].O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:25](=[O:27])[CH3:26])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccccc3)cc2)CC1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(C(C)=O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.4 %

Procedure:
To 1-(biphenyl-4-yl)cyclopropanecarboxylic acid ethyl ester (9 g, 33.8 mmol) in CH2Cl2 (100 mL) was added aluminum chloride (9.4 g, 71 mmol) followed by acetyl chloride (5.5 g, 71 mmol). The solution was stirred at room temperature for 1.5 hours then slowly poured into water. The organic layer was separated and extracted 2 times with water. The organic layer was dried and evaporated to yield 11.3 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[CH:13]=[CH:12][NH:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[S:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:15]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2scc(-c3ccccc3)c12
Product: Clc1ccnc2scc(-c3ccccc3)c12

Procedure:
3-Phenyl-7H-thieno[2,3-b]pyridine-4-one (0.7 g, 4.29 mmol) was added to phosphorous oxychloride (10 ml) and heated to reflux for 4 hr. The solvent was removed to near dryness and the residue dissolved in DCM. The solution was washed with water followed by saturated sodium hydrogen carbonate and dried over magnesium sulfate. The solution was filtered through a pad of silica and solvents removed in vacuo to give 4-chloro-3-phenyl-thieno[2,3-b]pyridine. Yield=0.261g (25%).
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[CH:6]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:8]2.[C:20]([O-])(=[O:22])[CH3:21].[K+]>CN(C=O)C.O>[C:20]([C:6]1[C:5](=[O:19])[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][CH:3]=2)[O:8][C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: O=c1cc(-c2ccccc2)oc2cccc(CBr)c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(-c2ccccc2)oc2ccccc2c1=O
Temperature: 100 °C
Yield: 107.2 %

Procedure:
The diketone compound (2.3 g, 6.92 mmol) was taken into a mixture of HCl (1 mL) and acetic acid (15 mL) and heated at 100° C. for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated to give 1.75 g of the intermediate in 80.6% yield. In a 100 mL dry round-bottomed flask fitted with condenser and magnetic stirrer were placed this intermediate (925 mg, 2.94 mmol) in CH2Cl2 (30 mL). BBr3 (2.21 g, 8.83 mmol, 1M solution in CH2Cl2) was added slowly at 0° C. The reaction mixture was stirred for 16 h at rt under nitrogen. The reaction mixture was quenched by carefully adding methanol. The solvent was removed under reduced pressure and the resulting solid was washed with water and dried to give 1.0 g of crude 3′-fluoro-4′-methoxy-5-bromo methyl flavone in 97% yield. To a solution of 5-bromomethyl flavone (1.0 g, 2.86 mmol) in DMF (20 mL), potassium acetate (845 mg, 8.60 mmol) was added. The mixture was heated at 100° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give crude acetyl flavone (810 mg, 86%). To a solution of the acetyl flavone (810 mg, 2.47 mmol) in methanol (15 mL), K2CO3 (1.02 g, 7.41 mmol) was added and the reaction mixture was stirred for 2 h at rt. The solvent was removed and the product was taken in to water and neutralized by dilute HCl. The solid was separated by filtration, washed with water and dried to give 2-(3-fluoro-4-hydroxyphenyl)-6-(hydroxymethyl)-4H-chromen-4-one in 38% yield. MS (ES) m/z: 286.96 (M); Mp. 256-258° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[OH-].[Na+].[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:29]([CH3:31])([CH2:30][C@@H:13]12)[C@@H:28]1[C@H:19]([C@H:20]2[C@@:24]([CH2:26][C:27]1=[O:32])([CH3:25])[C@@H:23]([C:33]#[N:34])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3.O>C(O)CO>[OH:12][C@@H:14]1[C@@H:13]([N:5]2[CH2:6][CH2:7][O:8][C:3]([CH3:9])([CH3:2])[CH2:4]2)[CH2:30][C@@:29]2([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:24]2([CH3:25])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:33]#[N:34])[CH2:15]1
Reactant: CC1(C)CNCCO1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C#N)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
2,2-Dimethylmorpholine hydrochloride (9.67 g) and sodium hydroxide (2.55 g) were added to a mixture (4:1) of (2α,3α,5α,17β)-2,3-epoxyandrostan-11-one-17-carbonitrile and its 3α,4α-epoxy isomer (5.0 g) (British patent 1,434,919) in 1,2-ethanediol (50 ml) and the mixture was heated in an atmosphere of nitrogen at 120° C. for 19 h and then at 150° C. for 4.5 h. The reaction mixture was poured into water (500 ml) and the precipitated solid was filtered off and dissolved in dichloromethane. After washing the solution with water and drying over sodium sulfate, the solvent was removed under reduced pressure and the residue (6.9 g) was chromatographed on silica gel. The purified product (4.3 g) was sequentially crystallised from ethanol and acetone-diethyl ether to give (2β,3α,5α,17β)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)androstan-11-one-17-carbonitrile (2.37 g). m.p. 206°-210° C.; [α]D +122.9° (c 0.8).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=O)[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[F:27][C:28]([F:36])([F:35])[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([NH:34][C:31]2[S:32][CH:33]=[C:29]([C:28]([F:36])([F:35])[F:27])[N:30]=2)=[O:26])[CH:21]=[CH:20][S:19]3)[CH2:2][CH2:3]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 (200 mg, 0.539 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (100 mg, 0.593 mmol) in the presence of EDCI hydrochloride (206 mg, 1.079 mmol) and DMAP (99 mg, 0.809 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 72 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.24-0.26 (m, 2H), 0.47-0.49 (m, 2H), 1.15-1.18 (m, 1H), 3.75 (d, J=6.9 Hz, 2H), 3.79 (s, 3H), 6.96-6.99 (m, 1H), 7.09 (t, J=7.8 Hz, 1H), 7.30-7.33 (m, 1H), 7.40-7.42 (m, 1H), 7.46 (d, J=15.6 Hz, 1H), 7.87 (d, J=15.6 Hz, 1H), 8.03 (s, 1H), 8.06 (d, J=4.2 Hz, 1H), 12.94 (s, 1H); ESI-MS (m/z) 521.34 (MH)+.
Reaction SMILES: Br.Br.C([NH:10][C@@H:11]1[C@@H:16]2[CH2:17][CH2:18][C@@H:13]([CH2:14][NH:15]2)[CH2:12]1)C1C=CC=CC=1.[CH:19]1([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:33])=[C:29](F)[CH:30]=3)[C:25](=[O:34])[C:24]([C:35]([OH:37])=[O:36])=[CH:23]2)[CH2:21][CH2:20]1.C1CCN2C(=NCCC2)CC1>>[NH2:10][C@@H:11]1[C@@H:16]2[CH2:17][CH2:18][C@@H:13]([CH2:14][N:15]2[C:29]2[CH:30]=[C:31]3[C:26]([C:25](=[O:34])[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]3[CH:19]3[CH2:21][CH2:20]3)=[CH:27][C:28]=2[F:33])[CH2:12]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: c1ccc(CN[C@H]2C[C@H]3CC[C@@H]2NC3)cc1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Product: N[C@H]1C[C@H]2CC[C@@H]1N(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
In a manner similar to that of Example 14, the title compound of Example 12 (0.80 g) was coupled to 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the presence of DBU, and the product was similarly subjected to catalytic hydrogenation to remove the benzyl group, yielding 0.24 g of the title compound, mp 267°-270°, [α]D20 66.3°(DMSO). NMR data was the same as for the racemic compound of Example 22.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][NH2:27])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[C:32]([CH:34]=O)[N:31]=[CH:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][NH:27][CH2:34][C:32]2[N:31]=[CH:30][S:29][CH:33]=2)[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cscn1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CN)n2)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CNCc3cscn3)n2)c(OC)c1
Reaction time: 16 h
Yield: 29.4 %

Procedure:
To a solution of (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (Example 20, product from Step 3) (422 mg, 1.1 mmol, 1 equiv), 1,3-thiazole-4-carbaldehyde (150 mg, 1.3 mmol, 1.2 equiv.) and acetic acid (32 μL, 2.2 mmol, 2 equiv) in DCE (5 mL) was added sodium triacetoxyborohydride (400 mg, 1.87 mmol, 1.7 equiv) and the reaction mixture was stirred for 16 h. Saturated NaHCO3 was added and the product was extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with dichloromethane—MeOH/NH3 0-10%) to afford (5-amino-6-{[(thiazol-4-ylmethyl)-amino]-methyl}-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (157 mg). MS: [M+H]+=486.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12](CO)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[Br:23]C1C=CC=C(Br)N=1>CS(C)=O>[Br:23][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: Brc1cccc(Br)n1
Solvent: CS(C)=O
Solvent: Oc1ccccc1
Product: Brc1cccc(Oc2ccccc2)n1

Procedure:
The 6-phenoxy-2-pyridinylmethanol may be prepared by first reacting phenol with 2,6-dibromopyridine in dimethyl sulfoxide under basic conditions to give 2-bromo-6-phenoxypyridine. This compound is then reacted at -70° C. with n-butyllithium in diethyl ether and then with dimethylformamide at -30° C. to give 2-formyl-6-phenoxypyridine. This aldehyde is in turn reacted with sodium borohydride in methanol, yielding the corresponding 6-phenoxy-2-pyridinylmethanol.
Reaction SMILES: O=[C:2]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:10][CH:9]=1)[C:4]([O:6]C)=O.[NH2:32][NH2:33].O>C(O)C>[N:29]1[CH:30]=[CH:31][C:26]([C:2]2[NH:33][NH:32][C:4](=[O:6])[C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=[CH:27][CH:28]=1
Reactant: NN
Reactant: COC(=O)C(C(=O)c1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 37 %

Procedure:
To a stirred solution of methyl 3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)propanoate (0.2 g, 0.48 mmol) in ethanol (5 mL), NH2NH2.H2O (0.12 g, 2.42 mmol) and TEA (0.146 g, 1.45 mmol) were added dropwise at RT. The reaction mixture was then refluxed for 16 h and then concentrated in vacuo to obtain crude product. The crude material was washed with water (5 mL) and ether (5 mL) to afford 5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one (70 mg, 37%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 9.12 (bs, 1H), 8.38 (d, J=7.2 Hz, 2H), 8.02-7.96 (m, 3H), 7.76 (t, J=7.6 Hz, 2H), 7.64-7.56 (m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.96 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.21 (s, 1H). MS: M+H: m/z=395.1 and HPLC: 80%, (Condition-C).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH2:16][CH2:17][CH2:18]Cl)[C:12](OC)=[O:13]>C(O)C>[NH2:2][N:3]1[CH2:18][CH2:17][CH2:16][CH:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Br:4])[C:12]1=[O:13]
Reactant: NN
Reactant: COC(=O)C(CCCCl)c1ccccc1Br
Solvent: CCO
Solvent: O
Product: NN1CCCC(c2ccccc2Br)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 2-bromophenylacetate (2.0 g) in DMF (5 mL) was added to a suspension of sodium hydride (containing mineral oil at 40%, 384 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (1.96 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product of methyl 2-(2-bromophenyl)-5-chloropentanoate. Hydrazine monohydrate (4 mL) was added to a solution of the resulting crude methyl 2-(2-bromophenyl)-5-chloropentanoate (2.895 g) in ethanol (20 mL), and the reaction solution was stirred at room temperature for three hours. Hydrazine monohydrate (8 mL) was further added to the reaction solution, and the reaction solution was stirred at room temperature for two days. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.504 g of the crude purified title compound. The property value of the compound is as follows.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][CH3:13].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH2:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH3:11])[C:4]=1[CH2:3][C:2]1[NH:17][CH2:16][CH2:15][N:18]=1)[CH3:13]
Reactant: CCc1cccc(CC)c1C=C(Br)Br
Reactant: NCCN
Product: CCc1cccc(CC)c1CC1=NCCN1

Procedure:
To 20 ml ethylene diamine were added at 0° C. 3.20 g (10 mmol) 2-(2,2-dibromo-vinyl)-1,3-diethyl-benzene and the mixture stirred at ambient temperature for 16 hours. The reaction was quenched by addition of aqueous 2N ammonia, extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in ethyl acetate and crystallization at −10° C. provided 2.85 g 2-(2,6-diethyl-benzyl)-4,5-dihydro-1H-imidazole as colourless solid: MS (ISP): 217.1 ((M+H)+.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].P([O-])([O-])([O-])=O>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:4][C@@H:5]1[N:8]([Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 24 h

Procedure:
To a solution of 1.5 g of (3S,4S)-4-acetoxy-3-phenylacetamido-azetidin-2-one in 100 ml of dichloromethane, at room temperature and under inert atmosphere, 0.069 g (0.56 moles) of 4-dimethylamino pyridine and 0.5 ml of pyridine are added. To this mixture 0.907 g (6 mmoles) of tert-butyldimethylchlorosilane dissolved in 10 ml of anhydrous dichloromethane are slowly added. The mixture is let under stirring for about 24 hours, then a phosphate buffer at pH 7.5 is added. The organic phase is extracted with dichloromethane and the dichloromethane phase is washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under vacuum. Thus, essentially pure (3S,4S)-4-acetoxy-3-phenylacetamido-1-tert-butyldimethylsilyl-azetidin-2-one (III, R=TBDMS) is obtained in quantitative yield.
Reaction SMILES: O[C:2]1[NH:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.P(Cl)(Cl)([Cl:14])=O.N>O>[Cl:14][C:2]1[NH:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2nc(O)[nH]c12
Agent: N
Solvent: O
Product: Cc1cccc2nc(Cl)[nH]c12
Yield: 93 %

Procedure:
2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 mL of phosphoryl chloride are introduced into a 250 mL two-necked flask under an argon atmosphere, with magnetic stirring. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 mL), neutralized to pH=8 with 28% aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3×250 mL). After the usual work-up, the title product is obtained in a yield of 93% (6.23 g). 1H NMR (300 MHz, δ ppm) DMSO D6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14][CH2:13]2)Cl.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>ClC1C=CC=CC=1Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14][CH2:13]2
Reactant: c1c[nH]cn1
Reactant: Clc1ccccc1C(Cl)c1ccc2c(c1)CCCC2
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: Clc1ccccc1C(c1ccc2c(c1)CCCC2)n1ccnc1
Temperature: 180 °C
Yield: 55.3 %

Procedure:
44 g (0.15 mol) of 2-chlorophenyl-1,2,3,4-tetrahydronaphth-6-yl-chloromethane, dissolved in 50 ml of 1,2-dichlorobenzene, are added dropwise to a suspension of 51 g (0.75 mol) of imidazole in 100 ml of 1,2-dichlorobenzene at 180° C. The reaction mixture is heated to 180° C. for 2 hours and, after cooling, is poured onto water and the organic phase is diluted with methylene chloride and washed with water. After drying the solution over sodium sulphate, it is evaporated in vacuo. 26.8 g (55% of theory) of 2-chlorophenyl-imidazol-1-yl-1,2,3,4-tetrahydronaphth-6-yl-methane of refractive index nD20 =1.6000 are obtained.