Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[C:18]=1[CH:19]=[O:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[Br:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N:10]2[CH:9]=[CH:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[C:11]2=[O:15])[C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1c(Br)cccc1Br
Reactant: CC(C)(C)c1ccc2c(=O)[nH]ccc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(Br)c3C=O)ccc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6-tert-Butyl-2H-isoquinolin-1-one (272 mg, 1.35 mmol), 2,6-Dibromo-benzaldehyde (891 mg, 2.5 eq), xanthphos (35 mg, 0.045 eq) and cesium carbonate (616 mg, 1.4 eq) were taken up in dioxane (2.7 mL). Then nitrogen was bubbled through the solution for 10 minutes before adding bis(dibenzylideneacetone)palladium (23 mg, 0.03 eq). The resulting mixture was stirred at 100° C. overnight. By TLC and LC/MS there was no desired product observed. Next added copper iodide (55 mg, 0.02 eq) and cesium carbonate (320 mg, 0.73 eq) and more dioxane (4 mL). The resulting mixture was heated to 100° C. with stirring for 30 hours and by TLC the reaction was now complete. After cooling to room temperature, ethyl acetate (175 mL) and water (50 mL) were added. The layers were partitioned, and separated. The organice layer was then washed with water (3×50 mL) and finally with brine (1×50 mL) before drying over magnesium sulfate, filtering and concentrating. Purification on silica gel eluting with a step-wise gradient of 5% ethyl acetate to 20% ethyl acetate in hexanes gave the title compound as a light tan powder (215 mg). MS (ESI) 346.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:28]=[CH:27][C:15]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.Cl.[CH3:30][NH:31][CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>>[CH3:30][N:31]([CH3:32])[C:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:16](=[O:17])[C:15]2[CH:27]=[CH:28][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)=[O:25]
Reactant: CNC
Reactant: O=C(O)C1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: CN(C)C(=O)C1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1

Procedure:
In a similar manner to Example 5, Compound 9-2 (27 mg, 5%) was obtained using Compound 50 (500 mg, 1.33 mmol), dimethylamine hydrochloride (230 mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (306 mg, 2.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 2.00 mmol) and N-methylmorpholine (0.439 mL, 4.00 mmol).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:6]=1[CH:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23]>C(O)C>[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:6]=1[CH:16]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)C(C)(C)CCCCC(c1ccccc1)c1c(C)c(OC)c(C)c(C)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(C(CCCCC(C)(C)C(=O)O)c2ccccc2)c1C
Temperature: 90 °C
Reaction time: 15 h
Yield: 98.6 %

Procedure:
3N Sodium hydroxide (9 ml) was added to a solution of 1.20 g (2.73 mmole) of ethyl 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2,2-dimethyl-7-phenylheptanoate in ethanol (12 ml), followed by stirring at 90° C. overnight (15 hours). After cooling by standing at room temperature, the ethanol was distilled off under reduced pressure, and the residue was made acid by adding a 10% aqueous phosphoric acid solution, followed by extraction of the product with isopropyl ether. The isopropyl ether layer was washed with aqueous sodium hydrochloride solution, dried (magnesium sulfate) and evaporated to give 1.11 g (99%) of 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2,2-dimethyl-7-phenylheptanoic acid. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:12][C:13](=[O:14])[NH:1]2
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2c(Cl)cccc2[nH]1
Temperature: 160 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A mixture of 2.0 g (11 mmol) of 2-amino-6-chlorobenzoic acid and 1.4 g (23 mmol) of urea was heated to 160° C. for 2 hrs. and at 180° C. for a further 2 hrs. The resulting brown mass was triturated with 200 ml of methanol, filtered off and dried in a vacuum. 1.2 g (53%) of 5-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione were obtained as white crystals;
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:30][C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: ClCc1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(=O)N1c2ccc(OCc3cccnc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Alkylation of 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 3-picolylchloride.HCl (12 mg), cesium carbonate (63 mg) and tetrabutylammonium bromide (30 mg) acetonitrile (1 ml) was performed according to the method described in example 39.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:21](O)[CH3:22])[CH:20]=1>ClCCl.O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:21]([F:11])[CH3:22])[CH:20]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(O)c1cc(Br)ccc1Cl
Solvent: O
Solvent: ClCCl
Product: CC(F)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
Bis(2-methoxyethyl)aminosulfur trifluoride (4.5 g, 20.34 mmol) was added to a stirred solution of 1-(5-bromo-2-chlorophenyl)ethanol (3.99 g, 16.95 mmol) in dichloromethane (50 mL) at 0° C. The resulting solution was stirred at 0° C. for 3 h. The reaction mixture was quenched with a 5% solution of aqueous sodium bicarbonate (100 mL) and the resulting bubbling biphasic reaction mixture was vigorously stirred at 0° C. for 15 min. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane twice. The combined organic layers were washed with 1M hydrochloric acid, dried and concentrated by rotary evaporation. The product was purified by flash chromatography on silica gel (hexanes) to yield the title compound (2.65 g, 11.16 mmol, 65.8% yield) as a clear oil: 1H NMR (CDCl3) δ 7.65 (d, 1H), 7.37 (m, 1H), 7.20 (m, 1H), 5.88 (dq, 1H), 1.61 (dd, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]([C:13]1[S:17][C:16]([NH:18]C(=O)OC(C)(C)C)=[N:15][C:14]=1[CH3:26])=[O:12]>FC(F)(F)C(O)=O>[NH2:18][C:16]1[S:17][C:13]([C:11]([NH:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:12])=[C:14]([CH3:26])[N:15]=1
Reactant: Cc1cc(C)c(NC(=O)c2sc(NC(=O)OC(C)(C)C)nc2C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(NC(=O)c2sc(N)nc2C)c(C)c1
Yield: 91.4 %

Procedure:
A solution of [5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-methyl-2-thiazolyl]carbamic acid, 1,1-dimethylethyl ester (10 g, 26.63 mmol) in trifluoroacetic acid (100 mL) was stirred at rt for 3 h. The solution was concentrated under reduced pressure and the residue was diluted with EtOAc (700 mL), washed with 5% aq. KHCO3 solution (400 mL, 2×), water, and brine; dried (MgSO4), filtered and concentrated. The residue was washed with ether (200 mL) and acetonitrile (100 mL) to obtain the title compound (6.7 g, 91%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]([CH3:35])[C:30](=[O:36])[CH:29]=[CH:28]3)[CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:5][N:4]=1.Cl.[OH-].[Na+]>C(O)C>[CH3:35][N:31]1[C:32]2[C:27](=[CH:26][C:25]([O:24][CH2:23][CH2:22][CH2:21][N:13]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3](=[O:2])[NH:4][CH:5]=3)[CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][C:30]1=[O:36]
Reactant: COc1ncc(N(CCCOc2ccc3c(ccc(=O)n3C)c2)Cc2ccncc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(=O)ccc2cc(OCCCN(Cc3ccncc3)c3c[nH]c(=O)c4ccccc34)ccc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
6-{3-[N-(1-Methoxyisoquinolin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one (55 mg) was added to a 1N-hydrogen chloride in ethanol solution (5 ml), and stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature. 1N-Sodium hydroxide aqueous solution (5 ml) was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (20.6 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([CH2:16][CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:16](\[CH3:17])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)c(Cl)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccc(F)c(Cl)c1
Yield: 101.5 %

Procedure:
3-Chloro-4-fluorobenzaldehyde (10 g, 63.1 mmol) was dissolved in 300 mL toluene. (Carboethoxyethylidene)triphenylphosphorane (25 g, 69.4 mmol) was added and the mixture was heated to reflux overnight. The solution was cooled, diluted with hexanes and the solid was filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ether and filtered through a plug of silica using ether as eluent. The solvent was evaporated in vacuo to afford the title compound (15.55 g) as a semi solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.56 (s, 1H), 7.44 (m, 1H), 7.23-7.32 (m, 1H), 7.16 (m, 1H), 4.28 (q, J=7.12 Hz, 2H), 2.09 (d, J=1.36 Hz, 3H), 1.35 (t, J=7.36 Hz, 3H). MS (DCI+) 243 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:37][CH:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)[N:13]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(Nc2nc(-c3ccccc3Cl)c3ccc(=O)n(-c4ccccc4Cl)c3n2)CC1

Procedure:
The product of Example 47, and 1-methylpiperidin-4-ylamine were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(1-methyl-piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 1.42 (m, 2H), 1.79 (m, 4H), 2.25 (s, 3H), 2.75 (m, 2H), 3.15 (m, 1H), 5.33 (s, 1H), 6.39 (d, 1H, J=9.8 Hz), 7.24-7.59 (m, 9H). LC MS (m/e)=480 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:11]=3[O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]4[N:24]=[CH:25][S:26][CH:27]=4)(=[O:21])=[O:20])=[CH:15][C:14]=3[C:28]#[N:29])=[CH:8][CH:7]=[N:6]2)[CH2:2]1.[CH2:35](N(CC)CC)[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)C>CO.ClCCl>[Cl:34][C:32]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]3[N:24]=[CH:25][S:26][CH:27]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:28]#[N:29])=[C:10]([C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH2:35][CH3:36])[CH2:4]3)[N:6]=[CH:7][CH:8]=2)[CH:33]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1ccc(Cl)cc1-c1ccnn1C1CNC1
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN1CC(n2nccc2-c2cc(Cl)ccc2Oc2ccc(S(=O)(=O)Nc3cscn3)cc2C#N)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide, Example 809 (500 mg, 0.000797 mol) in methanol (4 mL) and dichloromethane (4 mL) was added triethylamine (161 mg, 0.00159 mol) and the reaction cooled to 0° C. in an ice/water bath. To the suspension was added sodium triacetoxyborohydride (422 mg, 0.00199 mol) and the reaction was then stirred at 0° C. for 10 minutes. Acetaldehyde (105 mg, 0.00239 mol) was added dropwise and the reaction stirred at 0° C. for 1.5 hours. The solvent was removed in vacuo to give an orange oil which was partitioned between dichloromethane (25 mL) and water (25 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL) and filtered through a phase separator. The solvent was removed in vacuo to give a pink solid which was triturated in hot ethyl acetate (10.0 mL), allowed to cool to room temperature and then filtered to give the title compound as a white solid, (431 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[C:29]=1[C:30](Cl)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[C:33]([O:37][CH3:38])=[CH:34][CH:35]=[CH:36][C:28]=4[O:27][CH3:26])=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(OC)cccc4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,6-dimethoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: C([Li])CCC.C1([SiH2]C2C=CC=CC=2)C=CC=CC=1.[CH2:19]([N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CCCCCC.[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Ti+2]>[CH2:19]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCN1Cc1ccccc1
Agent: [Ti+2]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(CN2CCCC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Titanocene dichloride (0.28 g, 1.1 mmol) was dissolved in (15 mL) of tetrahydrofuran in a nitrogen atmosphere, and the reaction mixture was cooled to -78° C., and 2.4 mL of a 1.6M solution of n-butyl lithium in hexane was added. The reaction mixture was stirred for 15 min and then 4.5 mL diphenylsilane (24 mmol) was added. After warming the reaction mixture to room temperature, 1.8 g of N-benzylpyrrolidinone (11 mmol) was added to the black solution, which began bubbling and became warm (i.e., about 30° C.) after 1-2 min. The reaction mixture was stirred overnight at room temperature and then heated to 55° C. for 1 hour. The solution was then poured into 50 mL of ethyl ether and extracted with 1 M HCl (3×50 mL). The aqueous layer was washed with ether (2×25 mL) and then neutralized with a 5 M NaOH solution so that the aqueous layer was basic to pH paper. The product was extracted into ether (3×50 mL) and the emulsion that formed was also extracted with ether (50 mL). The combined ether extracts were dried over MgSO4, filtered, and concentrated in vacuo. N-benzylpyrrolidine was isolated as a yellow oil (1.58 g of 95% pure material, 84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:16][CH2:17][CH2:18]OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:18][CH2:17][O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(NCCOCc2ccccc2)cc1
Reaction time: 24 h
Yield: 33.1 %

Procedure:
p-Chloroaniline (8 g), methanesulfonic acid 2-benzyloxyethyl ester (12.29 g) and sodium hydrogen carbonate (hereinafter, reffered to as sodium bicarbonate) (8.97 g) were dissolved in dioxane (35 ml), suspended and the mixture was heated with stirring for 24 hours. After concentrated under reduced pressure, water and ethyl acetate were added to the mixture and the mixture was separated into layers. The organic layer was washed with water 2 times, and concentrated again under reduced pressure, and the resulting rsidue was subjected to column chromatography on silica gel, and eluted with chloroform/n-hexane [2:1 (v/v)] to give 4-chloro-N-(2-benzyloxyethyl)aniline (4.63 g).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][CH:3]1[NH:22]C(=O)OCC1C=CC=CC=1.I[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>>[NH2:22][C@@H:3]1[C:2](=[O:1])[N:8]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1
Reactant: Ic1ccccn1
Reactant: O=C(NC1N=C(c2ccccc2)c2cc3c(cc2NC1=O)OCO3)OCc1ccccc1
Product: N[C@H]1N=C(c2ccccc2)c2cc3c(cc2N(c2ccccn2)C1=O)OCO3

Procedure:
Intermediate 3E was prepared from Intermediate 3D and 2-iodopyridine according to the procedure described for Example 1. The racemate was purified by preparative SFC chromatography (Berger SFC MGII, OD-H 250×30 mm ID, 5 μm, 73/17 CO2/MeOH, 85 mL/min) to give Intermediate 4E. RT=1.668 min (H2O/CH3OH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=3 min, wavelength=220 and 254 nm); MS(ES):m/z=373.2 [M+H+].
Reaction SMILES: C(O)(=O)C[CH2:3][C:4]([OH:6])=[O:5].O[CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([NH2:18])=[NH:17].C(OC(=O)C)(=O)C.C([O-])(=O)C>C(N(CC)CC)C>[C:4]([O:6][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([NH2:18])=[NH:17])(=[O:5])[CH3:3]
Reactant: O=C(O)CCC(=O)O
Reactant: N=C(N)NCCOCCO
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCOCCNC(=N)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
2.06 g (9.99 mmol) of 2-(2-hydroxyethoxy)ethylguanidine succinate, 8 ml of triethylamine, 0.122 mg (1.0 mmol) of 4-N,N-dimethylaminopyridine and 1.02 g (9.99 mmol) of acetic anhydride were placed in a 50 ml two neck flask and were stirred for 1 hour at room temperature. After the upper phase was removed by decantation, the obtained crude product was washed five times with 50 ml of diethylether. The product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid) to obtain 1.00 g of the title compound (starch syrup-like, 4.0 mmol, 40.0% in yield) in the form of acetate. Results of the analysis of this compound are as follows.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:6][NH:7][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: CN(CCc1ccccc1OCCCO)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCc1ccccc1OCCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
{2-[2-(3-Hydroxypropoxy)phenyl]ethyl}N-methylcarbamic acid tert-butyl ester (0.587 g, 1.90 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0° C. Trifluoroacetic acid (5 ml) was added. The reaction mixture was stirred for 30 min at 0° C. Dichloromethane (50 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (50 ml) was added dropwise. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous solution was extracted with dichloromethane (3×70 ml). The aqueous phase was made basic to pH 14 with a 20% aqueous sodium hydroxide solution. It was extracted with tert-butyl methyl ether (3×100 ml). The tert-butyl methyl ether extracts were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 227 mg of crude 342-(2-methylaminoethyl)phenoxy]propan-1-ol. The crude product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([CH:32]=2)[NH2:31])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([NH:31][C:2]3[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:32]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COc1ccc(C2CCCCC2)cc1N
Product: COCCN1C(=O)C(Nc2cc(C3CCCCC3)ccc2OC)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 5-cyclohexyl-2-methoxyaniline in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 0.92-1.05 (m, 2H), 1.08-1.33 (m, 3H), 1.41-1.49 (m, 2H), 1.62-1.76 (m, 3H), 2.05-2.15 (m, 1H), 3.38 (s, 3H), 3.70-3.75 (m, 5H), 3.91 (t, 2H), 6.41 (d, 1H), 6.70 (d, 1H), 6.79-6.83 (m, 1H), 7.12-7.22 (m, 4H), 7.24-7.30 (m, 1H), 7.55 (bs, 1H); Mass Spectrum: M+H+ 471.
Reaction SMILES: [Cl:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([CH:10]([OH:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1>O=[Mn]=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1
Reactant: CC(O)c1cc2cc(Cl)sc2nc1Cl
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cc(Cl)sc2nc1Cl
Temperature: 25 °C

Procedure:
To a solution of 1-(2,6-dichlorothieno[2,3-b]pyridin-5-yl)ethanol (5 g, 20.15 mmol) in 200 ml, of anhydrous toluene was added MnO2 (14 g, 161 mmol). The reaction was heated to reflux overnight, cooled to rt, filtered through Celite™ and rinsed with ethyl acetate. Concentration and purification by column chromatography afforded 1-(2,6-dichlorothieno[2,3-b]pyridin-5-yl)ethanone. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.19 (s, 1H), 2.75 (s, 3H) ppm.