Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([N:19]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[N:28]=1)=[O:26])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([N:19]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:34]=2)[N:28]=1)=[O:26])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CN(C)C(=O)N(Cc1ccccc1)C(=O)c1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)N(Cc1ccccc1)C(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 91.7 %

Procedure:
A mixture of methyl thiosalicylate (1.8 g, 10.7 mmol), N-benzyl-N-[(6-cyano-2-pyridyl)carbonyl]-N′,N′-dimethylurea (1.6 g, 5.4 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 8 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (2.2 g, 93%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:22]([O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:22]([O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-L-proline (4.3 g, 15 m mole), L-proline benzyl ester hydrochloride (3.7 g, 15.3 m mole) and HOBt (2.0 g, 15 m mole) were dissolved in methylene dichloride (40 ml). WSC (2.8 ml) was added dropwise to the above mixture while cooling to -15° C. and stirring. The reaction was carried out for 3 hours at a temperature of not more than 0° C., and then overnight at room temperature. The solvent was removed by distillation under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate, and washed with 1N hydrochloric acid, water, 5% sodium bicarbonate and water, in order. The mixture was dried over anhydrous sodium sulfate. The solvent thus obtained solution was distilled under reduced pressure leaving a residue. The residue was crystallized with a mixture of ethyl acetate and n-hexan to give a crystal of N-t-butyloxycarbonyl-L-alanyl-L-prolyl-L-proline benzyl ester (6.3 g, 88.7%) having melting point of 143° to 145° C. and specific rotatory power of [α]D25 =-131.0° (C=1, chloroform).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:33][CH3:34])[CH2:20][CH2:21][N:22]([CH3:32])[C:23]([C:25]1[NH:26][C:27]([CH:30]=O)=[CH:28][CH:29]=1)=[O:24])[CH3:18]>>[CH2:33]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][N:22]([CH3:32])[C:23]([C:25]1[NH:26][C:27]([CH:30]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])=[CH:28][CH:29]=1)=[O:24])[CH3:34]
Reactant: CCN(CC)CCN(C)C(=O)c1ccc(C=O)[nH]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: CCN(CC)CCN(C)C(=O)c1ccc(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)[nH]1
Yield: 63 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (209 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-diethylaminoethyl)methylamide to give 277 mg (63%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([CH3:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([CH3:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)O)c(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 2-[2-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-4-methyl-phenoxy]acetate (260 mg, 0.61 mmol, 1.0 eq) in THF (10 mL) was added NaOH (1M aqueous solution, 5 mL, 5 mmol, 8.2 eq) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The organic solvent was evaporated in vacuo and the mixture that remained poured into water. The pH was adjusted to pH 4-6 with dilute HCl and the precipitate that formed was collected by filtration, washed with water and dried in vacuo to give title compound (I(i)) as a solid (200 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]2[C:20]([CH2:21]O)=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12.N(C(OCC)=O)=NC(OCC)=O>>[Cl:15][C:14]1[C:9]([C:8](=[O:28])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:10]([N:16]2[C:20]([CH2:21][N:52]3[C:51](=[O:53])[C:50]4=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]4[C:48]3=[O:58])=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:27])[CH3:26])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1nc(CN(C)C)n(-c2cccc(Cl)c2C(=O)c2ccc(F)cc2)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2cccc(Cl)c2C(=O)c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 4'-fluoro-6-chloro-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[3-chloro-2-(4-fluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[CH:14][N:13]([CH2:17][C:18](=[O:20])[CH3:19])[C:12]=2[C:11](=[O:21])[NH:10][C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:25]1([CH2:24][N:10]2[C:11](=[O:21])[C:12]3[N:13]([CH2:17][C:18](=[O:20])[CH3:19])[CH:14]=[N:15][C:16]=3[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]2=[O:22])[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CC1)c(=O)n2Cc1ccccc1

Procedure:
18.1 g of 3-benzyl-7-(2-oxopropyl)xanthine were treated with 11.4 ml of bromomethylcyclopropane and 9.2 g of potassium carbonate in 150 ml of DMF for 3 hours at 70° C. The mixture was concentrated, water was added and the product was extracted with ethyl acetate. After concentration of the solution the product crystallised, m.p. 138° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:5]1[C:4]2[CH2:3][N:2]([CH3:1])[CH2:14][CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:27]
Reactant: CN1CCc2c([nH]c3ccccc23)C1
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCCn1c2c(c3ccccc31)CCN(C)C2
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
A round bottom flask fitted with reflux condenser containing 2-methyl-2,3,4,9-tetrahydro-1H-β-carboline (16) (0.20 g, 1.1 mmol), and sodium hydride (60% by wt. in mineral oil, 0.055 g, 1.35 mmol) was vacuum purged and filled with argon, followed by addition of DMF (4 mL). After stirring at 60° C. for 20 min, ethyl 6-bromo-hexanoate (0.24 g, 1.1 mmol) was added and the mixture was stirred at 60° C. for 6 h. The reaction was quenched by addition of water (30 mL), transferred to a separatory funnel and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried (Na2SO4) and concentrated. The product was purified by MPCC (0-10% gradient of MeOH in CH2Cl2), giving 190 mg of 6-(2-methyl-1,2,3,4-tetrahydro-b-carbolin-9-yl)hexanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][N:21]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OC(C)C)CC3)cc1

Procedure:
Compound et was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea with isopropyl chloroformate. LC-MS: m/z=+483 (M+H)+.
Reaction SMILES: COC1C=CC=CC=1C[NH:10][C@H:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[C@H:12]1[CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:26]1([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:12]2[C@@H:11]([NH2:10])[CH:16]3[CH2:17][CH2:18][N:13]2[CH2:14][CH2:15]3)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccccc1CN[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: N[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Yield: 95.8 %

Procedure:
(2S,3S)-N-(2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine (4.13 g, 10 mmol) was hydrogenated in methanol (MeOH) (40 ml)/6N HCl (10 ml) by using 20% palladium hydroxide on carbon (0.2 g) at 2.5 kg/cm2 of hydrogen for 60 hours. The filtrate was concentrated and the residue was partitioned between 2N NaOH and CH2Cl2. The organic layer was dried over MgSO4, and concentrated to give the crude product, which was recrystallized from ethanol (EtOH) to afford the pure title compound (2.80 g, 96%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:7][CH:8]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:43])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:43])[NH:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To the suspension of 4-(3-trifluoromethyl-phenyl)-1H-indole (3.37 g, 12.90 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (155 mL) was added pyridinium tribromide (12.38 g, 38.70 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (63 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (2.07 g, 58%) as a tan solid.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)=[S:16])[C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCN1CCNCC1
Reactant: COc1cc2nc(C(C)(C)C)sc2cc1N=C=S
Solvent: CC(C)=O
Product: COc1cc2nc(C(C)(C)C)sc2cc1NC(=S)N1CCN(CCO)CC1
Reaction time: 2 h

Procedure:
21 g (0.076 mole) of 2-tert.-butyl-6-isothiocyano-5-methoxy-benzthiazole are dissolved in 400 ml of acetone and a solution of 12 g (0.092 mole) of N-(2-hydroxyethyl)-piperazine in 40 ml of acetone is added dropwise. The mixture is stirred for 2 hours, cooled to 0° , filtered and washed with acetone, then with ether and finally with petroleum ether. 2-tert.-butyl-5-methoxy-6-{[4-(2-hydroxyethyl)-piperazin-1-yl]-thiocarbonylamino}-benzthiazole having a melting point of 161-162° is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=4)=[O:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:36]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:41]=1>>[CH2:36]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[C:21]3[C:16]([CH2:15][CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:17][CH:18]=2)=[O:23])=[CH:26][C:27]=1[F:34])[CH3:41]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)cc(Cl)c1)CCC2
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CCC3)cc1F

Procedure:
4-{[1-(3,5-Dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 523.18 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 3,5-dichloro-benzenesulfonyl chloride, yielding 4-{[1-(3,5-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].O>C(O)CCC>[CH3:15][O:16][CH2:17][CH2:18][NH:19][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: COCCN
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Solvent: O
Solvent: CCCCO
Product: COCCNc1nnc(-c2ccccc2)cc1C

Procedure:
A mixture of 7 g of 3-chloro 4-methyl 6-phenyl pyridazine and 7 g of 2-methoxy ethylamine in 50 ml of butanol is taken to reflux for 4 days. The hot solution is poured into 200 ml of water and extracted with ethyl acetate. The organic solution is dried over magnesium sulfate then evaporated to dryness.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](O)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:31])[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F.O(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([C:26]3[CH:27]=[CH:28][C:29]([OH:30])=[C:24]([CH3:31])[CH:25]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1cc2cc(OCc3ccccc3)ccc2o1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(OCc3ccccc3)ccc2o1
Yield: 51.3 %

Procedure:
3-(5-Benzyloxy-benzofuran-2-yl)-pentan-3-ol (6.10 g, 19.7 mmol) and o-cresol (2.55 g, 23.6 mmol) and BF3—OEt2 (1.39 g, 9.83 mmol) in CH2Cl2 are reacted analogous to Example 18-C to give the title compound (4.05 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[H-].[Na+].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CN(C)C=O>[CH:36]1([CH2:35][N:13]([C:12]2[C:3]([O:2][CH3:1])=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:38][CH2:37]1
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3OC)CC2)c1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(CC3CC3)c3cc4ccccc4nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
1-[(2-methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(106 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and sodium hydride(6.2 mg, 0.26 mmol) was added and the solution was stirred at room temperature for 15 min. Bromomethylcyclopropane(22 mg, 0.26 mmol) was added to the above solution. The mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=CN=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.Br[C:18]1C=CC(F)=C[N:19]=1>>[N:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[N:8]1[C:16]2[CH:15]=[N:19][CH:18]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Reactant: Fc1ccc(Br)nc1
Product: c1ccc(-n2cnc3ccncc32)nc1

Procedure:
Intermediate 10 was prepared in a manner analogous to Intermediate 1, substituting 2-bromopyridine for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C11H8N4, 196.07; m/z found 197.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[O:8][C:7](C)(C)O[C:5](=[O:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].C=[N:19][C:20]([CH3:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:3]1[O:8][CH2:7][N:19]([C:20]([CH3:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:5](=[O:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: C=NC(C)(C)c1ccccc1
Reactant: CCC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CCC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CO1
Yield: 75 %

Procedure:
Xylene (2 ml) was added to a mixture of 6-ethyl-5-phenyl-2,2-dimethyl-2H,4H-1,3-dioxin-4-one (0.70 g) and N-methylene-1-methyl-1-phenylethylamine (0.44 g), and the resulting mixture was heated at reflux for 20 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.72 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[N:33]([CH3:34])[C:32](=[O:35])[CH:31]=[CH:30][CH:29]=1>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[N:33]([CH3:34])[C:32](=[O:35])[CH:31]=[CH:30][CH:29]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Cn1c(Br)cccc1=O
Product: C[C@@H](c1ccc(-c2cccc(=O)n2C)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 6-bromo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 2 tR=1.088, m/z=447; 1H NMR (CDCl3) 1.38 (m, 1H), 1.56 (d, 3H), 1.70 (m, 1H), 1.95-2.08 (m, 2H), 2.23 (m, 1H), 2.37 (s, 2H), 3.05 (m, 1H), 3.33 (s, 3H), 3.58 (m, 2H), 5.73 (m, 1H), 6.29 (d, 1H), 6.89 (d, 1H), 7.01-7.09 (m, 4H), 7.21-7.39 (m, 5H), 7.53 (t, 1H).
Reaction SMILES: [CH3:1][Mg]I.[C:4]1([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]2[CH2:14][C:13](=[O:15])[CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)C>[C:16]1([CH:10]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:11]2[CH2:14][C:13]([CH3:1])([OH:15])[CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[Mg]I
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCOCC
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl magnesium iodide (3M in diethyl ether, 1.4 mL, 4.2 mmol) was added dropwise to an ice-cold solution of 1-(diphenylmethyl)-3-azetidinone (1 g, 4.20 mmol) in diethyl ether (25 mL) and the mixture was stirred for 1 hour at 0° C. The crude reaction mixture was then purified directly by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 95:5, to afford the title compound the title compound as a pale yellow oil in 68% yield, 730 mg. 1H NMR(CDCl3, 400 MHz) δ: 1.54(s, 3H), 3.02(m, 2H), 3.22(m, 2H), 4.39(s, 1H), 7.20(m, 4H), 7.26 (m, 4H), 7.41(m, 2H); LRMS ESI+ m/z 254 [M+H]+
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13]>>[Cl:3][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C1CCCN1CCO
Product: O=C1CCCN1CCCl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add thionyl chloride (5 mL) to 1-(2-hydroxy-ethyl)-pyrrolidin-2-one (1.12 mL, 10.0 mmol) dropwise then stir at room temperature for 10 min. Remove solvent in vacuo to give the title compound as an orange oil. MS (ES+) m/z: 148 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:30][S:31][CH2:32][CH2:33][NH2:34]>>[CH3:30][S:31][CH2:32][CH2:33][NH:34][C:23]([C:20]1[C:19]2[N:15]([CH:16]=[CH:17][CH:18]=2)[C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:26]([F:27])([F:28])[F:29])[O:13][N:12]=2)=[CH:22][CH:21]=1)=[O:25]
Reactant: CSCCN
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Product: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12

Procedure:
Using a procedure similar to that described in Example 1, except using 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-indolizine-8-carboxylic acid (37 mg, described above in Example 3) and 2-methylthioethylamine, the title compound was isolated as an orange-reddish solid (21.2 mg, 49%). MS (ES): M/Z [M+H]=516. 1H NMR (400 MHz, CHLOROFORM-d): 2.17 (s, 3H), 2.83 (t, J=6.2 Hz, 2H), 3.75 (q, J=6.0 Hz, 2H), 3.91 (d, J=16.6 Hz, 1H), 4.28 (d, J=16.6 Hz, 1H), 6.83 (d, J=7.4 Hz, 1H), 7.02-7.08 (m, 1H), 7.17 (d, J=7.2 Hz, 1H), 7.46 (t, J=1.7 Hz, 1H), 7.55 (s, 2H), 8.73 (d, J=1.6 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −79.8 (s, 3F).