Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
To a solution of 4-(pyridin-2-yl)benzoic acid (100 mg, 0.5 mmol) in DCM (5 mL) was added EDCI (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), Et3N (152 mg, 1.5 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (103 mg, 0.5 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (30 mg, Yield 15.5%). 1H NMR (CD3OD, 400 MHz): δ 8.70-8.60 (m, 1H), 8.01-7.84 (m, 6H), 7.45-7.36 (m, 1H), 7.16-6.99 (m, 4H), 4.20-4.10 (m, 1H), 3.79 (s, 2H), 3.62-3.46 (m, 2H), 2.92 (s, 4H), 2.78-2.65 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][Cl:27]>CC(C)=O>[Cl:27][CH2:26][CH2:25][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:8][CH:9]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:17])[N:6]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)Cc1coc(-c2ccc(O)cc2)n1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1coc(-c2ccc(OCCCl)cc2)n1
Yield: 86.7 %

Procedure:
A mixture of methyl[2-(4-hydroxyphenyl)-1,3-oxazol-4-yl]acetate 150 (1 g, 4.29 mmol, 1 eq), potassium carbonate (2.37 g, 17.16 mmol, 4 eq) and 1-bromo-2-chloroethane (1.54 g, 10.7 mmol, 2.5 eq) in acetone (50 ml) is stirred at reflux for 140 h. Potassium carbonate is then filtered off and the solvent is evaporated. The residue is taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 1.1 g of methyl {2-[4-(2-chloroethoxy)phenyl]-1,3-oxazol-4-yl}acetate i51.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:9]=2[CH3:20])=[CH:4][C:3]=1S(N)(=O)=O.BrC(C1C=CC(Cl)=C(S(N)(=O)=O)C=1)C(=O)C.BrC(C1C=CC=C([N+:52]([O-:54])=[O:53])C=1)C(=O)C>>[CH3:20][C:9]1[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][CH:2]=[C:3]([N+:52]([O-:54])=[O:53])[CH:4]=1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CC(=O)C(Br)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)C(Br)c1ccc(Cl)c(S(N)(=O)=O)c1
Product: Cc1nc(Nc2cnccn2)sc1-c1cccc([N+](=O)[O-])c1

Procedure:
The titled compound is prepared by the same procedure described for the preparation of 33c, replacing 5-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (33b) in this procedure with 1-Bromo-1-(3-nitro-phenyl)-propan-2-one (42a)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[NH:6][C:5](=O)[CH:4]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:5]1[CH:4]=[C:3]([CH2:2][Cl:1])[N:8]=[C:7]([S:9][CH3:10])[N:6]=1
Reactant: CSc1nc(CCl)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nc(Cl)cc(CCl)n1

Procedure:
A mixture of 35 g (0.18 mole) of the known compound 6-chloromethyl-2-methylthiopyrimidin-4-one and 300 ml of phosphorous oxychloride was heated at reflux for 3.5 hours, cooled and evaporated. The mixture was poured into 600 ml of an ice-water mixture and the mixture was extracted with four 200 ml portions of chloroform. The combined extracts were washed sequentially with two 200 ml portions of water, 20 ml of saturated aqueous sodium bicarbonate solution and 200 ml of saturated aqueous sodium chloride solution, and were then dried over magnesium sulfate and evaporated. The residue was distilled at reduced pressure to provide 4-chloro-6-chloromethyl-2-methylthiopyrimidine as a yellow liquid, b.p. 90°-95° C./0.15 mm Hg. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [N:1]1C=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.[N:28]1C=CC(C)=CC=1>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:15]=2)=[O:9])=[CH:5][N:28]=1
Reactant: Cc1ccncc1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(Cc1ccnnc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 4-methylpyridazine for 4-picoline provided the title compound. 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=5.4 Hz, 1H), 9.08 (d, J=8.7 Hz, 2.1H), 8.20 (d, J=8.3 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.96 (m, 2H), 7.83 (d, J=7.9 Hz, 1H), 7.76 (m, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.55 (m, 1H) 7.38 (dd, J=5.4, 2.5 Hz, 1H), 7.09 (m, 2H), 5.44 (s, 2H) 4.23 (s, 2H); MS: (M+H m/z=356.2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[CH3:15][O:14][N:12]([CH3:13])[C:10](=[O:11])[CH:9]=[CH:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([S:17][CH3:16])=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CON(C)C(=O)C=Cc1cccc(Br)c1
Reactant: CSc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C=Cc1cccc(-c2ccc(SC)cc2)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 104.6 %

Procedure:
3-(3-Bromo-phenyl)-N-methoxy-N-methylacrylamide (14.5 g, 53.7 mmol) prepared in Step 1, 4-(methylthio)phenylboronic acid (18.0 g, 107.4 mmol), Pd(PPh3)4 (3.1 g, 2.7 mmol) and sodium carbonate (17.1 g, 161.1 mmol) were added to a mixed solvent of N,N-dimethylformamide (100.0 mL) and distilled water (10.0 mL). The reaction mixture was stirred at 80° C. for 20 hours, quenched with a saturated solution of ammonium chloride, and then extracted with diethyl ether three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 17.6 g of the titled compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[N:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)OC)cc(Cl)n1
Temperature: 25 °C
Yield: 70 %

Procedure:
Add methyl 2,6-dichloro-isonicotinate (3.8 g, 18.4 mmol), tetrakis(triphenylphosphine)palladium (0) (1.15 g, 0.99 mmol), triphenyhlphosphine (524 mg, 2 mmol) in toluene (40 mL) to a previously nitrogen-filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(vinyl)tin (6.98 mL, 24.0 mmol) and heat the sealed mixture at 95° C. overnight. Cool to room temperature, dilute with diethyl ether and filter through a filtering agent. Wash the organic filtrate with saturated ammonium chloride, saturated sodium bicarbonate and saturated aqueous sodium chloride. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (70%).
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[N:5]=[N:6][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:8][N:9]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:12][CH:10]([C:7]1[N:6]=[N:5][C:4]([S:3][CH3:2])=[N:9][CH:8]=1)[CH3:11])=[O:18]
Reactant: CSc1ncc(C(C)N)nn1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ncc(C(C)NC(=O)c2cccc(Br)c2)nn1
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a stirred solution of 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethanamine hydrochloride (Intermediate 4) (10 g, 49 mmol) in N,N-dimethylformamide (100 mL) was added 3-bromobenzoic acid (11 g, 54 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospahte (20 g, 52 mmol) and triethylamine (24 mL, 170 mmol). After stirring for 18 hours the solution was concentrated under reduced pressure to approximately 50 mL. The solution was diluted with ethyl acetate (200 mL) and washed with 0.1N HCl (2×100 mL) and saturated sodium bicarbonate solution (100 mL). The solution was dried with magnesium sulfate and filtered, and silica gel (25 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (0:100) to ethyl acetate:hexanes (40:60) using a RediSep silica gel cartridge (120 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 3-bromo-N-{1-[3-(methylthio)-1,2,4-triazin-6-yl]ethyl}benzamide (14.5 g) as a white solid. 1H NMR (CDCl3): δ8.47(s, 1H), 7.95 (dd, J=1.8, 1.7 Hz, 1H), 7.72 (ddd, J=7.9, 1.6, 1.1 Hz, 1H), 7.64 (ddd, J=7.9, 2.0, 1.1 Hz, 1H), 7.32 (dd, J=8.0, 7.7 Hz, 1H), 7.20 (d, J=7.2 Hz, 1H), 5.47 (dq, J=7.2, 7.0 Hz, 1H), 2.68 (s, 3H), 1.70 (d, J=7.0 Hz, 3H). MS m/z 353, 355 (M+1, M+3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:22]#[C:23][CH3:24])[CH2:18][C:19](O)=[O:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.C1COCC1.[NH2:42][C:43]1[S:44][CH:45]=[CH:46][N:47]=1>O>[S:44]1[CH:45]=[CH:46][N:47]=[C:43]1[NH:42][C:19](=[O:20])[CH2:18][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)[C:22]#[C:23][CH3:24]
Reactant: Nc1nccs1
Reactant: CC#CC(CC(=O)O)c1ccc(OCc2ccc(OC)cc2)cc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: C1CCOC1
Product: CC#CC(CC(=O)Nc1nccs1)c1ccc(OCc2ccc(OC)cc2)cc1
Yield: 1.6 %

Procedure:
A pear-shaped flask was charged with a stir bar, compound 12 (50 mg, 0.154 mmol), carbonyl diimidazole (25 mg, 0.154 mmol) and THF (4 mL). The mixture was refluxed for 1 hour, and 2-amino thiazole (16 mg, 0.154 mmol) was then added. The reaction was refluxed for 48 hours, poured into water and extracted with ethyl acetate. The organic layer was concentrated and the resulting residue was purified via HPLC to yield 1.0 mg (2%) of 3-[4-(4-Methoxy-benzyloxy)-phenyl]-hex-4-ynoic acid thiazol-2-ylamide (24) as a film. 1H NMR (400 MHz) (acetone-d6) δ 7.39 (4H, m), 7.11 (1H, s), 6.95 (3H, m), 5.03 (2H, s), 3.82 (3H, s), 2.95 (2H, m), 1.79 (3H, s).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].N1C=CC=CC=1.[CH2:12]([C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:19][CH3:20])[C:16](Cl)=[O:17])[CH:13]=[CH2:14]>C1C=CC=CC=1>[CH2:12]([C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:19][CH3:20])[C:16]([O:5][CH2:1][CH2:2][C:3]#[CH:4])=[O:17])[CH:13]=[CH2:14]
Reactant: C#CCCO
Reactant: C=CCC(OC)(C(=O)Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C#CCCOC(=O)C(CC=C)(OC)c1ccccc1
Yield: 89.2 %

Procedure:
Into a solution of 1.4 g of 3-butyn-1-ol and 20 g of pyridine in 20 cc of benzene, was added a solution of 4.5 g of α-allyl-α-methoxyphenyl acetic chloride in 10 cc of benzene while being cooled with ice, whereby white precipitates were deposited immediately. The reaction mixture was washed with a diluted hydrochloric acid, 5% aqueous solution of sodium carbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of benzene gave 4.6 g of oily 3-butynyl α-allyl-α -methoxyphenylacetate, nD25 1.5137.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:23]([CH2:24][CH3:25])=[CH:22][N:13]([C@@H:14]2[O:21][C@H:18]([CH2:19]O)[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:26])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:46]=[N+:47]=[N-:48].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:46]([CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[C:23]([CH2:24][CH3:25])[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]2=[O:26])[CH2:15][C@@H:16]1[OH:17])=[N+:47]=[N-:48]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)nc1NC(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)nc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.1 %

Procedure:
A mixture of 1.436 g of N-benzoyl-2'-deoxy-5-ethylcytidine, 1.072 g of triphenylphosphine, 1.304 g of sodium azide and 1.360 g of carbon tetrabromide in 16 ml of dimethylformamide was stirred at room temperature for 20 hours. 8 ml of methanol were added, the mixture was stirred for 30 minutes and then evaporated. The residue was suspended in 80 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed with water and evaporated. The residue was subjected to flash chromatography on a column of silica gel using ethyl acetate for the elution, there being obtained 1 g of 5'-azido-4-N-benzoyl-2',5'-dideoxy-5-ethylcytidine in the form of a white crystalline solid of melting point 125°-126° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O.ClCCCl>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:12][CH:11]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 66 %

Procedure:
525 ml of 1,2-dichloroethane and 209 g of aluminium chloride are added to a round flask which is fitted with a stirrer, thermometer, condenser and dropping funnel. The mixture is cooled to 0° C. and 127 g of propionic acid chloride are allowed to drop in at 0°-5° C. within 75 minutes. After the addition, the temperature is allowed to rise to 18° C. and then 141.6 g of anisole are added within 2 hours and at 20° C. The mixture is left to stand for 12 hours and then the product is poured into a mixture of 800 g of ice, 130 ml of water and 130 ml of concentrated hydrochloric acid. The aqueous phase is separated and extracted with two 250 ml portions of 1,2-dichloroethane. The combined organic phases are washed with three 200 ml portions of 2% sodium hydroxide and with 250 ml of water. The solvent is removed by evaporation under a vacuum and the residue (198 g) is distilled over a 25 cm column. There are obtained 142 g of p-methoxy-propiophenone (yield: 66.4% of theory). B.p.=90° C./0.4 mmHg; melting point 26° C.; nD20 =1.5451; d420 =0.9645.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][N:20]([CH2:30][CH2:31][OH:32])[C:21]1[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:20]([CH2:30][CH2:31][OH:32])[CH2:19][CH2:18][OH:17])=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:20]([CH2:19][CH2:18][OH:17])[CH2:30][CH2:31][OH:32])=[CH:22][CH:23]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C([O-])c1ccc(N(CCO)CCO)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N(CCO)CCO)cc3)cc2)cc1)c1ccc(N(CCO)CCO)cc1

Procedure:
Compound 327 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-bis(2-hydroxylethyl)aminobenzoate. [M+H]+ calcd for C35H38N4O7: 627.28; found: 627.06.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:10]=1[C:11]#[N:12])=[O:5])C.[H-].[Na+].Br[CH2:21][C:22]1[CH:26]=[C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[O:24][N:23]=1.[OH-].[Na+]>CN(C=O)C>[Cl:32][C:29]1[S:28][C:27]([C:25]2[O:24][N:23]=[C:22]([CH2:21][N:7]3[C:6]([C:4]([OH:3])=[O:5])=[C:10]([C:11]#[N:12])[C:9]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[N:8]3)[CH:26]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1[nH]nc(-c2cccs2)c1C#N
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2cccs2)nn(Cc2cc(-c3ccc(Cl)s3)on2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
287 mg (1.2 mmol) of 4-Cyano-5-thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester was dissolved in 2 ml of DMF and 51.1 mg (1.3 mmol) of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature the solution was cooled to −70° C. and 355 mg (1.3 mmol) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added. The reaction was stirred at room temperature for 3 h. The reaction solution was treated with 1 ml of 2N aqueous NaOH for 16h at room temperature. The product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained asia white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=3[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[NH:10][C:9]=2[C:8]([O:29][CH3:30])=[CH:7][CH:6]=1)=O.[Cl:31][C:32]1[N:33]=[CH:34][N:35]([CH2:38][CH2:39][CH2:40][NH2:41])[C:36]=1[Cl:37].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.O.CN(C1C=CN=CC=1)C>[Cl:31][C:32]1[N:33]=[CH:34][N:35]([CH2:38][CH2:39][CH2:40][NH:41][C:3]([C:5]2[C:13]3[N:12]=[C:11]([C:14]4[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=4[CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[NH:10][C:9]=3[C:8]([O:29][CH3:30])=[CH:7][CH:6]=2)=[O:2])[C:36]=1[Cl:37]
Reactant: NCCCn1cnc(Cl)c1Cl
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(N)cc3CCN3CCOCC3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCCCn2cnc(Cl)c2Cl)c2nc(-c3ccc(N)cc3CCN3CCOCC3)[nH]c12
Temperature: 25 °C
Yield: 60 %

Procedure:
2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (22 mg, 0.05 mmol) was dissolved in THF/H2O, LiOHH2O (6.7 mg, 0.16 mmol) was added thereto and stirred at room temperature. The resulting solution was filtered to remove residual LiOHH2O, and the solvent was removed. The residue was dried and dissolved in DMF. Added thereto were 4,5-dichloro-1-(3-aminopropyl)imidazole (12.5 mg, 0.06 mmol), EDCI (30.9 mg, 0.16 mmol), DMAP (65.6 mg, 0.54 mmol) and HOBt (21.8 mg, 0.16 mmol), followed by stirring at room temperature. The resulting solution was extracted with ethyl acetate and concentrated under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (19 mg, 0.03 mmol) in a yield of 63%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].Cl.[OH-].[Na+].O>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ccc3c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCN3)nc1
Yield: 92.9 %

Procedure:
5-(5-Nitropyridin-2-yloxy)-1H-indole (3.00 g, 11.8 mmol) was dissolved in 1,4-dioxane (30 mL). To the solution were added boran-trimethylamine complex (3.43 g, 47.0 mmol) and hydrochloric acid (1.96 mL, 23.5 mmol) and the resulting solution was refluxed for 1 hour. After cooling for 30 minutes, 6 M hydrochloric acid (9.40 mL, 56.4 mmol) was added to the solution, and the mixture was refluxed again. Thirty minutes later, the reaction mixture was cooled with ice and the pH of the solution was adjusted to 8 by dropwise addition of concentrated aqueous sodium hydroxide. Water (150 mL) was added to the solution, and the mixture was extracted with ethyl acetate (150 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated to yield 2.82 g of the title compound as reddish orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[OH:21])[C:7]=2[C:6]=1[CH3:23])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:31]1[CH2:34][CH2:33][CH2:32]1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:7]=2[C:6]=1[CH3:23])=[O:4]
Reactant: BrC1CCC1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC3)c2c1C
Temperature: 60 °C

Procedure:
A mixture of 4-(4-fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (200 mg), potassium carbonate (166 mg) and bromocyclobutane (113 μl) in DMF (3 ml) was stirred at 60° C. over the weekend. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was concentrated and the residue was triturated with diethyl ether to give the desired compound.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][C:44]([OH:47])([CH3:45])[CH3:46])[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(CC(C)(C)O)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75. Mass spectrum (ESI+): m/z=519 [M+H]+.