Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a degassed mixture of 2-chloro-5-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 equiv) and potassium phosphate tribasic trihydrate (3 equiv) in a 10:1 mixture of 1,4-dioxane and water (0.09 M)) was added palladium 1,1-bis(diphenylphosphion)ferrocene dichloride (0.2 equiv). The mixture was stirred at 110° C. for 2 h. The suspension was cooled to room temperature and filtered. The filtrate was concentrated and the residue obtained was purified by silica gel chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (88% yield). MS (ESI) m/z=464.1 [M+1]+.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=2)[C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2c(C)oc3cc(OC)ccc23)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(6-methoxy-2-methyl-1-benzofuran-3-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (781 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (702 mg, 95%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClC(Cl)C>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[C:11]1[C:10](=[O:20])[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=1[F:28])=[N:7]2
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1)c1ccc(F)cc1F
Temperature: 80 °C

Procedure:
To a solution of 2-amino-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (50 mg, 0.18 mmol) dissolved in dichloroethane (2 mL) was added triethyl amine (0.079 mL, 0.55 mmol) and 2,4-difluorobenzoyl chloride (49 mg, 0.28 mmol). The mixture was heated to 80° C. for 2 hrs until no further progress was observed. Concentrated reaction to an oil and the crude residue was purified via silica gel chromatography (CH2Cl2/MeOH) to yield the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH3:18][C:19]([CH3:23])([CH3:22])[C:20]#[CH:21]>C(NCC)C.C(Cl)CCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:18][C:19]([CH3:23])([CH3:22])[C:20]#[C:21][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: C#CC(C)(C)C
Reactant: CN1Cc2c(Br)ncn2-c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCCl
Product: CN1Cc2c(C#CC(C)(C)C)ncn2-c2ccccc2C1=O

Procedure:
2.92 g (10 mmol) of 3-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 80° in a pressure tube for 24 hours with 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride, 30 mg of copper(I) iodide and 2.5 ml (20 mmol) of 3,3-dimethyl-1-butyne in 30 ml of diethylamine and 10 ml of ethylene chloride. The reaction mixture was evaporated, the residue was taken up in methylene chloride and washed with water. The organic solution was dried over magnesium sulphate and filtered through a silica gel pad. By crystallization from hexane there was obtained 3-(3,3-dimethyl-1-butynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 148°-150°.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)=[O:12])[CH2:3]2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[CH:16][CH:15]=1)=[O:12])[CH2:3]2
Reactant: O=C(CC1CN2CCC1CC2)Nc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(NC(=O)CC3CN4CCC3CC4)cc2)cc1

Procedure:
In accordance with the general method, 60 mg. (0.17 mmol) of 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(4-bromophenyl)acetamide hydrochloride, 25.4 mg (0.17 mmol) of 4-methoxyphenylboronic acid, 0.17 ml of 2M sodium carbonate solution and 6.1 mg (0.01 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of dimethylformamide. 34 mg (50% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 171.7 %

Procedure:
A mixture of 3.4 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.5 g of 2-(dimethylamino)ethyl chloride hydrochloride, 3.23 g of potassium carbonate and 80 ml of acetone is treated in the same manner as described in Example 1. The product thus obtained is converted into its hydrochloride and recrystallized from a mixture of acetone and ethanol. 3.75 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10]C)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:12][NH2:13]>C(O)C>[NH2:12][NH:13][C:8](=[O:10])[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)CN1CCOCC1
Solvent: CCO
Product: NNC(=O)CN1CCOCC1

Procedure:
To a solution of methyl 2-morpholin-4-ylacetate (1.0 g, 6.28 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.305 mL, 6.28 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as a solid in a quantitative yield and was used without further purification: 1H NMR (CDCl3) δ8.11 (br s, 1H), 3.87 (br s, 2H), 3.71 (t, 4H), 3.09 (s, 6H), 2.53 (t, 4H); ES-MS (m/z) 160 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[NH:7][CH2:6][CH2:5]2.B(O)O>>[CH3:12][CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][NH:7]1
Reactant: CC1NCCc2cc(Br)ccc21
Agent: OBO
Product: CC1NCCc2cc(-c3ccncc3)ccc21

Procedure:
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: CC([O:4][C:5]1[C:8](=[O:9])[C:7](=O)[C:6]=1[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])C.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:7]1[C:8](=[O:9])[C:5](=[O:4])[C:6]=1[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH3:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reactant: CCN
Product: CCCC[Sn](CCCC)(CCCC)c1c(NCC)c(=O)c1=O

Procedure:
Using the procedure described in Example 37 treatment of 4-(2-propoxy)-3-(tri-n-butylstannyl)cyclobut-3-ene-1,2-dione with anhydrous monoethyl amine afforded the title compound as a dark viscous oil which crystallized.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:61])([CH3:60])[CH2:48][NH:49]C(OCC1C=CC=CC=1)=O.Cl.NCC(N)=O>>[NH2:49][CH2:48][C:47]([NH:46][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:32][CH:33]=1)=[O:42])([CH3:61])[CH3:60]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)(N)CNC(=O)OCc1ccccc1
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)CN)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-1-benzyloxycarbonylamino-2-(methyl)propane instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: FC1C=C2C(=CC=1)NC=C2C1CCC(=O)CC1.C1O[C:21]2([CH2:26][CH2:25][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([F:36])=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[O:20]C1>>[F:36][C:32]1[CH:31]=[C:30]2[C:35]([C:27]([CH:24]3[CH2:23][CH2:22][C:21](=[O:20])[CH2:26][CH2:25]3)=[CH:28][NH:29]2)=[CH:34][CH:33]=1
Reactant: Fc1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Agent: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Product: O=C1CCC(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
This compound was prepared in the manner as described above for (3a) by replacing 4-(5-fluoro-1H-3-indolyl)-cyclohexanone ethylene ketal with 4-(6-fluoro-1H-3-indolyl)-cyclohexanone ethylene ketal (5.4 g) in 99% (19.3 g) yield as a white solid: mp 102-105° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH2:15][CH2:14]2)[N:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[C:24]([C:28]1[CH:29]=[CH:30][C:31]([CH3:35])=[C:32]([CH:34]=1)[NH2:33])([CH3:27])([CH3:26])[CH3:25].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)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]>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([CH3:35])=[C:32]([NH:33][C:2]2[CH:3]=[C:4]([CH:10]=[C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[CH:23]=[CH:22][N:21]=[CH:20]4)[CH2:15][CH2:14]3)[N:12]=2)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[CH:34]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(C)C(=O)c1cc(Cl)nc(N2CCC(n3ccnc3)CC2)c1
Reactant: Cc1ccc(C(C)(C)C)cc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: Cc1ccc(C(C)(C)C)cc1Nc1cc(C(=O)N(C)C)cc(N2CCC(n3ccnc3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-chloro-6-[4-(1H-imidazol-1-yl)piperidin-1-yl]-N,N-dimethylisonicotinamide (250 mg, 0.749 mmol), 5-tert-butyl-2-methylaniline (132 mg, 0.809 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (187 mg, 0.392 mmol), Pd2(dba)3 (70 mg, 0.076 mmol) and potassium carbonate (119 mg, 0.861 mmol) were combined in a vial, sealed, and put under an atmosphere of N2. Degassed t-amyl alcohol (3 ml) was added. The mixture was stirred at 100° C. overnight.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15]OCC>>[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]1[C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: CCOC=C(C(=O)OC)[N+](=O)[O-]
Reactant: Cc1ccc2cc[nH]c2c1
Product: COC(=O)C(=Cc1c[nH]c2cc(C)ccc12)[N+](=O)[O-]

Procedure:
A mixture of 32.5 g (0.25 mol) of 6-methylindole and 52.5 g (0.30 mol) of α-nitro-β-ethoxyacrylic acid methylester was let stand in a large crystallization dish at room temperature for 20 hours. The brown-orange solid was triturated with ether-hexane 1:1, the crystalline material collected by filtration, washed with ether and dried to afford 44.5 g. (69%) of product as orange crystals, m.p. 167°-169°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].NC1C=CC([S-])=CC=1.[K+].Cl[C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=2)[N:22]=1>CS(C)=O.O>[Cl:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH:30]=[N:29]2
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: Nc1ccc([S-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Sc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.7 %

Procedure:
5.7 g (0.045 mol) of p-aminothiophenol together with 3 g (0.045 mol) of 86% potassium hydroxide and 2 ml of water in 80 ml of dimethylsulfoxide was heated under stirring at 80°-90° C. for 5 hours to make the potassium p-aminothiophenolate. The water generated was removed off by azeotropic distillation under reduced pressure. To this solution which was allowed to be cooled to room temperature was added a solution of 9 g (0.045 mol) of 2,6-dichloroquinoxaline dissolved in 100 ml of dimethylsulfoxide. The mixture was subjected to the reaction, while stirring, at 80°-90° C. for 8 hours. After the reaction mixture was cooled to the room temperature, it was poured into a great deal of water and stirred. The precipitating solid was filtered off, washed with 5% aqueous solution of sodium hydroxide and then washed with water, followed by drying. The crude crystals thus obtained were recrystallized from a mixed solution of ethanol-benzene to produce 6.7 g (yield 52%) of the intended compound (Compound No. 10) as light-yellow crystals, m.p. 144°-147° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Br:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[N:21]([C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)[CH:27]=[C:26]([CH3:37])[N:25]=1)[CH2:22][CH3:23].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[CH:15]=[CH:14][C:13]=1[N:21]([C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][C:33]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)([OH:36])[CH2:32][CH2:31]2)[CH:27]=[C:26]([CH3:37])[N:25]=1)[CH2:22][CH3:23]
Reactant: CCN(c1nc(C)cc(N2CCC(=O)CC2)n1)c1ccc(C(C)C)cc1Br
Reactant: c1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(N2CCC(O)(c3ccco3)CC2)n1)c1ccc(C(C)C)cc1Br
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
To a solution of 136 mg of furan in 1 ml of tetrahydrofuran was added dropwise 0.9 ml of a 1.63M n-hexane solution of n-butyl lithium under cooling at −15° C. over 10 minutes, followed by stirring at 5° C. for 20 minutes. To the reaction mixture was added dropwise a solution of 432 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-6-methyl-4-(4-oxopiperidin-1-yl)pyrimidine in 2 ml of tetrahydrofuran over 10 minutes while cooling to −15° C., followed by stirring at −15° to 0° C. for 30 minutes. After stirring at room temperature for 1 hour, a saturated aqueous solution of ammonium chloride was added thereto dropwise under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give 279 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(furan-2-yl)-4-hydroxypiperidin-1-yl]-6-methylpyrimidine.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:8](Cl)=[O:9])([CH3:4])[CH3:3].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:36][C:37](=[O:39])[CH3:38].[H-].[Na+]>O1CCCC1>[C:37]([N:36]([CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:6]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1C(C)(C)C
Yield: 51.9 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 9.7 g of product from Example 33, 3.74 g of product from Example 12, 1.2 g of washed 50% sodium hydride and 100 ml of tetrahydrofuran. The residue is purified by column chromatography (silica gel:30% ethyl acetate/hexane) to give 6.43 g of the desired product as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[S:12][CH2:13][CH3:14].C([Li])CCC.CN(C)[CH:22]=[O:23]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:13]([S:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[O:23])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)[CH3:14]
Reactant: CCSc1ccnc2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCSc1ccnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 6-bromo-4-ethylsulfanyl-quinoline (1.48 g, 5.5 mmol) in THF (60 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (2.42 mL, 6.07 mmol, 1.1 equiv.) at −70° C. During the addition, the color of the solution was turned into a dark brown and this solution was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (0.848 mL, 11 mmol) in THF (5 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the yellow solid which was dissolved in ethyl acetate (−10 mL) at hot condition and diluted with hexanes (−20 mL). After cooling in the refrigerator overnight, the solids were collected by filtration and washed with 10% ethyl acetate in hexanes. After drying in air, 0.614 g (51% yield) of 4-ethylsulfanyl-quinoline-6-carbaldehyde was isolated as a yellow solid: EI-HRMS m/e calcd for C12H11NOS (M+) 217.0561, found 217.0554.
Reaction SMILES: [OH:1][CH:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3](OCCCl)=[O:4].[C:16]([O:20][CH:21]([CH3:23])[CH3:22])(=[O:19])[CH2:17][OH:18].C(C1C=CC=CC=1)(C)(C)C>C(OCC)C>[OH:1][CH:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:18][CH2:17][C:16]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: O=C(OCCCl)C(O)Cc1ccccc1
Reactant: CC(C)OC(=O)CO
Solvent: CCOCC
Solvent: CC(C)(C)c1ccccc1
Product: CC(C)OC(=O)COC(=O)C(O)Cc1ccccc1

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25M 2-chloroethyl 2-hydroxy-3-phenylpropionate, 0.25M isopropyl glycolate, and 1.0% tert-butylbenzene was added to 0.43 g Lipase AK. After mixing for 2 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-3-phenylpropionate to the title compound was estimated (by GC, Method B) to be approximately 28%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C13H14O5Tms (M-CH3) 323. 1314, obsd 323. 1290. In identical reactions substituting Lipase P30, Lipase G, Lipase MAP10, porcine pancreatic lipase, Lipase AP12 or Protease M for Lipase AK, the relative values for conversions at 2 d (Lipase AK=100) were 88, 85, 76, 51, 7, and 7%, respectively.
Reaction SMILES: C(O)C.Cl.[N+:5]([C:8]1[N:9]=[C:10]2[N:15]([CH:16]=1)[CH2:14][CH2:13][C@H:12]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][CH:32]([O:44]C4CCCCO4)[C:33]4[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=4)[CH2:27][CH2:26]3)=[CH:21][CH:20]=1)[O:11]2)([O-:7])=[O:6].C(=O)([O-])O.[Na+]>>[N+:5]([C:8]1[N:9]=[C:10]2[N:15]([CH:16]=1)[CH2:14][CH2:13][C@H:12]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][CH:32]([C:33]4[CH:34]=[CH:35][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:37][CH:38]=4)[OH:44])[CH2:27][CH2:26]3)=[CH:23][CH:24]=1)[O:11]2)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(CC(OC4CCCCO4)c4ccc(OC(F)(F)F)cc4)CC3)cc1)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(CC(O)c4ccc(OC(F)(F)F)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A 1 N HCl ethanol solution (6 ml) was added to (R)-2-nitro-7-(4-{4-[2-(tetrahydropyran-2-yloxy)-2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.20 g), and the mixture was stirred at room temperature for 3 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the residue obtained by distilling the solvent off, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The crystal thus obtained was washed with methylene chloride-ether and dried to afford the title compound as a white powder (0.16 g).