Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([OH:39])[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:26]=1.N1C=CC=CC=1>ClCCl>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]([O:39][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:30]=1
Reactant: C1=COCCC1
Reactant: COC(=O)CCC[C@H](O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCC[C@H](OC1CCCCO1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.23 ml (45 mmol) of 97% pure 3,4-dihydro-2H-pyran, followed by 762 mg (3.0 mmol) of pyridinium p-toluenesulfonate are added to a solution of 6.80 g (25.8 mmol) of methyl 5-(4-fluorophenyl)-5-(S)-hydroxypentanoate with a purity of 86 area % in 210 ml of dichloromethane in a 2-neck round-bottom flask with magnetic stirrer under nitrogen. The reaction mixture is stirred at room temperature for 24 h. HPLC analysis (system as in Example 5) shows besides pyridine (tret 4.8 min.) and 1.5 area % precursor (tret 9.8 min.), the product in the form of two diastereomers (ratio about 1:1, tret 14.1 and 14.4 min.). The reaction solution is concentrated to 70 ml in vacuo, diluted with 100 ml of diethyl ether and washed with 1×100 ml and 2×50 ml of water. The organic phase was concentrated in vacuo and the residue was dried under HV. 9.70 g of a pale yellowish oil which, according to HPLC, has a purity of 76 area % are obtained. Yield: 23.75 mmol, 92% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:17][CH2:18][CH:19]1[CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH:19]2[CH2:21][O:20]2)[CH2:8][CH2:7]1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Reactant: BrCCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(OC2CCN(CCC3CO3)CC2)cc1Cl
Temperature: 50 °C
Reaction time: 12 h
Yield: 97.3 %

Procedure:
A mixture of 4-(3,4-dichlorophenoxy)piperidine (WO 0058305, WO 0177101) (2.00 g), 2-(2-bromoethyl)oxirane (J. Am. Chem. Soc. 1981, 103, 7520-8) (1.36 g) and potassium carbonate (2.2 g) in acetone (20 ml) was stirred at 50° C. for 12 h. The solvent was removed under vacuum. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate. The mixture was filtered and the solvent was evaporated to afford the subtitle compound as a yellow oil (2.50 g) which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[C:42]([NH:41][C:38]1[CH:39]=[CH:40][C:35]([C:6]2[CH:7]=[C:8]3[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)[NH:11][N:10]=[C:9]3[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:36][CH:37]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(C(=O)OC(C)(C)C)CC4)c3c2)cc1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (55 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.[H-].[Na+].Br[CH:39]([CH3:42])[C:40]#[N:41]>CN(C=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:4]4[N:3]([CH:39]([C:40]#[N:41])[CH3:42])[C:2](=[O:1])[CH2:7][O:6][C:5]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: CC(Br)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)N1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Reaction time: 1 h
Yield: 34.2 %

Procedure:
In a 50 ml round bottom flask was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol) in DMF (Volume: 4 ml) to give a brown solution. sodium hydride (10.18 mg, 0.254 mmol) and 2-bromopropanenitrile (17.05 mg, 0.127 mmol) were added. The reaction mixture was stirred at 50 degree for 1 h then room temperature overnight. The reaction mixture was partitioned between DCM (20 ml) and water (20 ml). The organic phase was separated and concentrated. The residue was purified by column (biotage, 25 g) eluted with ethyl acetate/cyclohexane (0-50%) to give product (19 mg). LCMS (Method A): RT=7.14 min, M+H+=525.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19](=O)[CH:20]([CH3:22])[CH3:21])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[OH:18])=[O:10])=[CH:4][CH:3]=1.Cl.[OH-].[NH4+].C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:18][C:19]=2[CH:20]([CH3:21])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)C(C(=O)c1ccc(F)cc1O)c1ccc(Cl)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1oc2cc(F)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chlorophenyl)-1-(4-fluoro-2-hydroxy-phenyl)-4-methyl-pentane-1,3-dione (16.4 g, 49 mmol) in glacial acetic acid (150 ml) is added concentrated HCl (20 ml). The reaction mixture is stirred at 140° C. for 2 h, allowed to cool and then poured into a mixture of 880 ml of ammonium hydroxide and ice (200 ml). Ethyl acetate (300 ml) is added with vigorous stirring. The phases are separated, and the aqueous phase is washed with ethyl acetate (200 ml). The organic phases are combined, washed with water and brine and dried (MgSO4). The solvent is removed in vacuo, and the crude product is purified by flash chromatography on silica gel using iso-hexane:ethyl acetate (25:1 to 15:1) as the eluent. The resulting oil is crystallised from iso-hexane (150 ml) to give the title compound.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:19]=[C:20]([Si:24]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Br:43])[CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:43][C:39]1[CH:38]=[C:37]([Si:24]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([C:4]3[C:5]4[O:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:36]=2)([C:20]2[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Reactant: OB(O)c1cccc2c1oc1ccccc12
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3cccc4c3oc3ccccc34)c2)c1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
A mixture solution of dibenzo[b,d]furan-4-yl boronic acid (2.5 g, 11.79 mmol), bis(3-bromo-phenyl)diphenylsilane (14.57 g, 29.5 mmol), Pd(PPh3)4 (0.136 g, 0.118 mmol) and K2CO3 (3.26 g, 23.58 mmol) in 150 mL of toluene and 50 mL water was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was separated and evaporated to dryness. The residue was purified by column chromatography on silica gel with hexane:DCM (9.5:0.5, v/v) as eluent to yield (3-bromophenyl)(3-(dibenzo[b,d]furan-4-yl)phenyl)diphenylsilane (4.4 g, 64%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[P:30](Cl)(=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>CC(OC)(C)C>[CH2:32]([O:31][P:30]([O:1][C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O:34][CH2:35][CH3:36])=[O:37])[CH3:33]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CCOC(=O)C1=C(OP(=O)(OCC)OCC)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 1-tert-butyl 3-ethyl 4-oxopiperidine-1,3-dicarboxylate (11.50 g, 42.4 mmol, ASDI) in MTBE (500 mL) at about −78° C. was added NaHMDS (1 M in THF, 53.0 mL, 53.0 mmol). After about 1 h, diethyl phosphorochloridate (7.62 mL, 53.0 mmol) was added to the reaction mixture. After about 30 min, the reaction mixture was allowed to warm to ambient temperature and stirred for about 16 h. The reaction mixture was partitioned between saturated aqueous NH4Cl (100 mL) and EtOAc (50 mL). The layers were separated. The aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to yield 1-tert-butyl 3-ethyl 4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (8.55 g, 49%) as a yellow oil: LC/MS (Table 1, Method b) Rt=2.35 min; MS m/z: 408 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:9])=[CH:6][CH:5]=1>ClCCl>[Br:1][CH:10]([C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCCCC(=O)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CCOC(=O)CCCCC(Br)C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Bromine(21.1 g) was added dropwise to a dichloromethane solution (200 ml) of ethyl 6-(4-chlorobenzoyl)hexanoate (37.3 g) at room temperature. After stirring for 30 minutes, the reaction mixture was washed with sodium hydrogensulfite, saturated sodium bicarbonate and water in turn. The dichloromethane layer was dried(MgSO4). The solvent was evaporated to give ethyl 6-bromo-6-(4-chlorobenzoyl)hexanoate(47.6 g, quant.) as an oily substance.
Reaction SMILES: Cl.[N:2]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH:13]C(=O)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)CO.[OH-].[K+]>O>[N:2]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:13])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1N1CCCC1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: N[C@@H]1CCCC[C@@H]1N1CCCC1

Procedure:
(±)-cis-2-(1-Pyrrolidinyl)-N-benzoylcyclohexylamine hydrochloride (10 gm) was combined with ethylene glycol (50 ml) and potassium hydroxide (10 gm) and the solution was heated to reflux for 48 hours. The solution was diluted with water (200 ml) and extracted with ether. The ether was removed on a rotary evaporator and the residue was distilled (94° C. at 0.05 mm Hg) to provide the product.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:11])[C:6]=2[C:5]([OH:12])=[C:4]([CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])\[CH3:16])[C:3]=1[O:23][CH3:24].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:35][CH2:36][CH:37]=[CH:38][CH2:39]Br>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[CH:18]([CH2:39][CH:38]=[CH:37][CH2:36][Br:35])[CH2:17][C:15]([CH3:16])=[CH:14][CH2:13][C:4]1[C:5]([OH:12])=[C:6]2[C:7](=[C:2]([CH3:1])[C:3]=1[O:23][CH3:24])[CH2:8][O:9][C:10]2=[O:11]
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: BrCC=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC=CCBr)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a cooled (−78° C.) solution of mycophenolic acid methyl ester 4A (138 mg, 0.41 mmol) in THF (2.5 mL) was added a THF solution of sodium bis(trimethysilyl)amide (1.0 M, 0.98 mL). After stirring for 30 minutes, a solution of 1,4-dibromo-2-butene (950 mg, 4.1 mmol) in THF (2.5 mL) was added and stirring was continued for 10 minutes. The resulting mixture was warmed to −30° C. and stored at this temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate to give, after evaporation of the solvent, a residue that was purified by chromatography on silica gel eluting with ethyl acetate (0% to 40%)/hexanes, affording 2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4B (150 mg, 78%) as an oil; 1H NMR (300 MHz, CDCl3) δ 1.75 (s, 3H), 2.0-2.4 (m, 8H), 2.62 (m, 1H), 3.37 (d, J=6.6 Hz, 2H), 3.58 (s, 3H), 3.76 (s, 3H), 3.88 (d, J=4.8 Hz, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H), 7.67 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH2:36].C[Al](C)C>C1(C)C=CC=CC=1>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1nc2ccccc2[nH]1
Yield: 32.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 1H-benzo[d]imidazol-2-amine (0.046 g, 0.34 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.040 g of desired product. 1HNMR (DMSO-d6): δ 4.01 (s, 3H), 7.11 (m, 2H), 7.48-7.76 (m, 6H), 7.81 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 11.16 (br s, 1H), 12.28 (br s, 1H), 12.76 (br s, 1H); MS (m/z): 478.90 [M]+
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([O:13]CC)=O)[NH:2]1.[N:16](CCCCCC)=[C:17]=[O:18]>>[C:11]1(=[O:13])[CH:3]2[N:2]([CH2:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4]2)[C:17](=[O:18])[NH:16]1
Reactant: CCOC(=O)C1Cc2ccccc2CN1
Reactant: CCCCCCN=C=O
Product: O=C1NC(=O)N2Cc3ccccc3CC12

Procedure:
10,10a-Dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione was prepared from ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate in analogy to example 23 (yield: 85%) and then 1.48 mmol were reacted as described in example 23 with isocyanatohexane. Yield: 61 mg (12%), M+H+:330.20.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:11]([C:18]1[C:23]([I:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:29][C@H:28]([O:30][CH3:31])[C@@H:27](OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:26]2)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O>[CH2:11]([C:18]1[C:23]([I:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:29][C@H:28]([O:30][CH3:31])[C@@H:27]([O:3][C:1](=[O:4])[CH3:2])[CH2:26]2)[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1OS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1OC(C)=O
Reaction time: 6 h

Procedure:
4.2 ml of acetic acid was added to a mixture of 7.9 g of cesium carbonate and 15 ml of dimethyl sulfoxide. After foaming stopped, a mixture of 14.4 g of 2-benzyl-3-iodo-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidine-1-yl]pyridine and 35 ml of dimethyl sulfoxide was added thereto, followed by heating under stirring for 6 hours in an oil bath kept at 70° C. in a nitrogen atmosphere. The reaction solution was cooled and then subjected to extraction with ethyl acetate-water. The organic phase was washed with water and brine brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 10-15% ethyl acetate/hexane, to give 7.5 g of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4].[N:37]1([CH2:43][CH2:44][CH2:45][NH2:46])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH:46][CH2:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4]
Reactant: NCCCN1CCOCC1
Reactant: COC(=O)c1c(-c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(C(=O)NCCCN3CCOCC3)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2 ml) of 4-(4-carboxyphenyl)-6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-morpholin-4-ylpropylamine (31 μl) in acetonitrile were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg) and 4-hydroxybenzotriazole monohydrate (38 mg) at room temperature with stirring, and the mixture was stirred at room temperature for 12 hrs. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried and concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1) to give the title compound (93 mg) as colorless crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[S:7](=[O:11])(=[O:10])[CH2:8][CH2:9][C:5]=2[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[S:7](=[O:11])(=[O:10])[CH2:8][CH2:9][C:5]=2[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=S1(=O)CCc2cc(CO)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S1(=O)CCc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.8 %

Procedure:
To a solution of 5-hydroxymethyl-2,3-dihydro-benzo[b]thiophene 1,1-dioxide (185 mg, 0.93 mmol) in CH2Cl2 (6 mL) was added triphenylphosphine (294 mg, 1.12 mmol) and carbon tetrabromide (371 mg, 1.12 mmol). After stirring for 14 h at rt, all volatiles were removed under reduced pressure. 5-Bromomethyl-2,3-dihydro-benzo[b]thiophene 1,1-dioxide (218 mg, 90%) was isolated by chromatography (33-50% ethyl acetate in hexanes).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24]CC)=[O:23].O>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]([OH:24])=[O:23])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
2-n-Butyl benzimidazole (3.00 g, 17.22 mmol) was mixed with powdered potassium carbonate (2.62 g, 19 mmol) and diluted with 25 mL dimethylformamide. To this was added ethyl bromoacetate (18.94 mmol). The reaction mixture was stirred at ambient temperature overnight and poured into 150 mL of water. The resulting crystals were filtered, and recrystallized from hexane to give 2.26 g (50%) of a solid; mp 70°-71° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:30][CH2:31][N:27]([CH3:26])[C:28]5=[O:32])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CN1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)nc2)CC1
Yield: 61 %

Procedure:
Using (6-bromopyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (241 mg) described in Preparation Example 144 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (154 mg) was obtained.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.Cl[CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl>>[C:4]1([C@@H:7]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12]2)[CH2:8][OH:9])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: ClC/C=C\CCl
Reactant: N[C@@H](CO)c1ccccc1
Product: OC[C@@H](c1ccccc1)N1CC=CC1
Yield: 58 %

Procedure:
This was prepared from R-(−)-2-phenylglycinol and cis-1,4-dichloro-2-butene in 58% yield according to the procedures similar to those described in Preparation 1,
Reaction SMILES: [CH2:1]([C:3]1([CH3:13])[CH:8]([CH3:9])[CH2:7][CH2:6][C:5]([CH2:11][CH3:12])([CH3:10])[NH:4]1)[CH3:2].Cl.[CH2:15]1[O:17][CH2:16]1>CO>[OH:17][CH2:16][CH2:15][N:4]1[C:5]([CH2:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:13]
Reactant: C1CO1
Reactant: CCC1(C)CCC(C)C(C)(CC)N1
Agent: Cl
Solvent: CO
Product: CCC1(C)CCC(C)C(C)(CC)N1CCO
Temperature: 100 °C

Procedure:
An autoclave is filled with 36.6 g 2,6-diethyl-2,3,6-trimethylpiperidine, 150 ml of methanol and 1 ml conc. hydrochloric acid. 11 g of ethylene oxide are added under a pressure of 2 atmospheres and the autoclave is heated to 100° C. for 24 hours. The methanol is distilled off and the residue is purified by fractional distillation which yields 1-(2-hydroxyethyl)-2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 8) boiling at 106° C./0.1 mm Hg.