Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]3[CH2:13][CH2:14][CH:15]([C:17]([O:19]CC)=[O:18])[CH2:16][C:11]3(N3CCCC3)[O:10][N:9]=2)=[CH:4][CH:3]=1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:17]([OH:19])=[O:18])[CH2:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCC2C(c3ccc(Cl)cc3)=NOC2(N2CCCC2)C1
Agent: Cl
Product: O=C(O)C1CCc2c(-c3ccc(Cl)cc3)noc2C1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A solution of 0.59 g of ethyl 3-(4-chlorophenyl)-3a,4,5,6,7,7a-hexahydro-7a -pyrrolidino-1,2-benzisoxazole-6-carboxylate (mixture of two diastereoisomers) in 25 ml of 2N hydrochloric acid was heated under reflux for 4 hours. After 1 hour, 0.332 g of a crystalline acid separated out. Crystallization from ethyl acetate/toluene gave 0.23 g of 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-6-carboxylic acid of melting point 227°-228° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[O:22])[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[C].[Pt]>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[C:11](=[O:22])[CH2:10]2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C2=CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1([C@@H]2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-3-pyrrolin-2-one (12.1 g, 40.5 mmol) was dissolved in ethyl acetate (120 ml), a 5% platinum carbon catalyst (water content: 50%, 2.4 g) was added thereto, and it was stirred at room temperature for 17 hours under a hydrogen atmosphere at atmospheric pressure. The reaction solution was then filtered through cellite (washed with ethyl acetate) and the filtrate was then concentrated under a reduced pressure. The concentrate was applied to a silica gel chromatography, and 9.00 g (74%) of the compound of the title were obtained as a pale-yellow syrup from an n-hexane:ethyl acetate=3:2 eluate. Further, 2.60 g (21%) of the diastereomer (4-(R)-isomer) of the title compound was obtained as a pale-yellow syrup. The instrumental analysis data for this resulting compound agreed with the data indicated in PCT/JP96/00208.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]1[CH2:28][O:27][C:6]2([CH2:23][CH2:22][C@:21]34[O:24][C@:8]3([CH2:9][C@@H:10]([CH3:26])[C@@H:11]3[C:20]4=[CH:19][CH2:18][C@@:16]4([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]4[OH:25])[CH2:7]2)[O:5]1>C1COCC1.[Cl-].[NH4+].[Cu]Cl>[CH2:4]1[CH2:28][O:27][C:6]2([CH2:23][CH2:22][C:21]3[C@@:8]([OH:24])([CH2:9][C@@H:10]([CH3:26])[C@@H:11]4[C:20]=3[C@@H:19]([CH3:1])[CH2:18][C@@:16]3([CH3:17])[C@H:12]4[CH2:13][CH2:14][C@@H:15]3[OH:25])[CH2:7]2)[O:5]1
Reactant: C[C@@H]1C[C@@]23CC4(CC[C@@]2(O3)C2=CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21)OCCO4
Reactant: C[Mg]Br
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@]2(O)CC3(CCC2=C2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2C)OCCO3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesiumbromide (1.4 M THF/toluene, 210 mL, 295 mmol) was added to THF (150 mL) and copper (I) chloride (2.92 g, 29.5 mmol) was added. After stirring at room temperature for ½ hr, a solution of the epoxide (Compound 5, 16.26 g 46.99 mmol) in THF (450 mL) was added dropwise over 5 min. The mixture was stirred at room temperature for 3 hr. The mixture was diluted with saturated ammonium chloride solution and air was bubbled through the mixture for ½ hr to oxidize Cu(I) to Cu(II). The aqueous mixture was extracted with ether (3×). The ether extracts were washed with water and brine, combined, and dried over sodium sulfate. Evaporation of the solvent gave 16.70 g of a yellow semi-solid. The material was triturated with ether and the solid was filtered to afford 8.86 g of a mixture of Grignard products (7α,11α-dimethyl and 7α,11β-dimethyl, referred to as Compounds 6a and 6b, respectively). Evaporation of the filtrate gave 7.4 g of a stable foam. Total amount was 16.26 g in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[S:13])([CH3:4])([CH3:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([N:14]=[CH:18][N:19]([CH3:21])[CH3:20])=[S:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNC(N)=S
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=S)NCCCNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 90 %

Procedure:
A mixture of 1.48 g (6.35 mmol) (3-Thioureido-propyl)-carbamic acid tert-butyl ester and 15 ml Dimethylformamide dimethyl acetal was heated to 100° C. for 16 h. The mixture was concentrated and the residue was purified by flash column chromatography on silica eluting with ethyl acetate/n-hexane 1/1 to yield 1.65 g (90%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[C:16]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:10]2[NH:11][C:12](=[S:14])[NH:13][C:9]=2[CH:8]=1.[OH-].[K+].Cl>CCO.O>[Cl:6][C:7]1[C:16]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:10]2[N:11]=[C:12]([S:14][CH2:2][C:3]([OH:5])=[O:4])[NH:13][C:9]=2[CH:8]=1
Reactant: S=c1[nH]c2cc(Cl)c(C#Cc3ccccc3)cc2[nH]1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CSc1nc2cc(C#Cc3ccccc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromoacetic acid (47.8 mg, 0.344 mmol) in EtOH (1 mL) was added dropwise to a 20 mL scintillation vial equipped with a stirring bar and a septum cap containing a solution of compound 1-3 (49.0 mg, 0.172 mmol) in EtOH (1 mL). To this solution, 1M KOH (2 mL) was added dropwise, and the resulting mixture was stirred at rt for 1 h. The reaction mixture was then diluted with water (4 mL) and acidified with 10% aqueous HCl. The solution was extracted with EtOAc (3 mL then twice 1 mL), extracts were combined and evaporated to dryness in vacuo. The resulting oily residue was dissolved in DMSO (1.0 mL), filtered and purified by reverse-phase HPLC to give the title compound as white solid. LR-MS (API-ES): calculated for C17H11ClN2O2S 342.0, observed m/e 343.1 (M+H)+ (Rt 7.71 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.Cl[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38].[I-].[K+].[OH-].[Na+].Cl>C(C(C)=O)C(C)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=[CH:25][C:24]=2[OH:30])[N:10]=1
Reactant: OCCCCCCCl
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(OCCCCCCO)cc3O)n2)c(C)c1
Temperature: 85 °C

Procedure:
A mixture of 2,4-di-(2,4-dimethylphenyl)-6-(2,4-dihydroxyphenyl)-1,3,5-triazine (20g, 0.049 mole), 6-chloro-1-hexanol (7.04 g, 0.05 mole), available from Aldrich Chemicals, Milwaukee, Wis., potassium iodide (0.37g, 0.0022 mole), PEG 400 (1.9 g, 0.005 mole), available from Aldrich Chemicals, Milwaukee, Wis., sodium hydroxide (2.0g, 0.05 mole) in methyl isobutyl ketone was reflux (120°-122° C.) for 16 hrs. After cooling to 85° C., water (50 ml) was added and the reaction mixture was acidified with 37% hydrochloric acid to pH 1, and the resulting aqueous layer was removed. The organic layer was washed twice with warm water (75 ml per each washing) and the volatiles were removed under reduced pressure. The oily residue was dissolved in acetone and decolorized with activated charcoal and filtered. Cooling to 22° C. gave 2,4-di-(2,4-dimethylphenyl)-6-[2-hydroxy-4-(6-hydroxy-1-hexyloxy)phenyl]-1,3,5-triazine (I-E) as a pale yellow solid (10g), m.p. 117°-118° C. The filtrate was concentrated under a reduced pressure to give a second crop of triazine I-E bringing the total weight of product to 21 g (87% yield). It was characterized to be 2,4-di-(2,4,dimethylphenyl)-6-[2-hydroxy-4-(6-hydroxy-1-hexyloxy)phenyl ]-1,3,5-triazine (I-E).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Br:32][C:29]1[CH:30]=[CH:31][C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)=[C:24]([CH:28]=1)[C:25]([NH2:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: NC(=O)c1cc(Br)ccc1N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(Br)cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 11.7 mmol) and 2-amino-5-bromobenzamide (7.6 g, 35.2 mmol), 5-bromo-2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide was isolated as a yellow solid (2.1 g, 35% Yield); 1H NMR (400 MHz, DMSO-d6) δppm 2.36 (s, 3 H), 6.70 (d, J=3.66 Hz, 1 H), 7.46 (d, J=8.42 Hz, 2 H), 7.74-7.78 (m, 2 H), 7.88 (s, 1 H), 7.97 (d, J=8.42 Hz, 2 H), 8.00 (d, J=2.20 Hz, 1 H), 8.35 (d, J=8.79 Hz, 1 H), 8.39 (s, 1 H), 12.16 (s, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][O:21][C:17]=2[CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([N:22]3[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[N:7]=[N:6]4)[CH2:24][CH2:23]3)=[N:20][O:21][C:17]=2[CH:16]=1
Reactant: ClCCCn1nnc2ccccc21
Reactant: Fc1ccc2c(N3CCNCC3)noc2c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1ccc2c(N3CCN(CCCn4nnc5ccccc54)CC3)noc2c1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
1-(3-chloropropyl)-1H-benzotriazole (7.02 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 6-fluoro-3-(piperazine-1-yl)benzisoxazole (6.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.9 g compound (I-37) with a yield of 69.3%. ESI-MS [M+H]+: m/z 380.2.
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:6]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34](C4C=CC([N+]([O-])=O)=CC=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:9]2=[N:10][C:11]([CH3:15])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=1)[CH3:5]>CO>[CH2:4]([C:6]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:9]2=[N:10][C:11]([CH3:15])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=1)[CH3:5]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A solution of sodium methoxide in methanol (30% w/v, 4 mL) was added to a solution of 2-ethyl-5,7-dimethyl-3-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridine (A) (1.0 g) in methanol (20 mL) and the mixture was heated under reflux for 18 hours. The mixture was cooled to ambient temperature and solvent was removed by evaporation. The residue was dissolved in water (50 mL) and the solution was extracted with ether (2×50 mL). The aqueous layer was separated and adjusted to pH 5 with 1M citric acid solution. The product was collected by filtration and dried to give 2-ethyl-5,7-dimethyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridine (0.6 g) as a solid, m.p. 175°-177° C. (decomposition); NMR (d6 -acetone): 1.26(t, 3H), 2.50(s, 3H), 2.53(s, 3H), 2.76(q, 2H), 5.49(s, 2H), 6.91(s, 1H), 7.07(d, 2H), 7.14(d, 2H), 7.6(m, 3H), 7.75(dd, 1H); mass spectrum (+ve fast atom bombardment (FAB), DMSO nitrobenzyl alcohol): 410(M+H)+ ; microanalysis, found C, 64.9; H, 5.6; N, 22.0%; C24H23N7.2.0H2O requires: C, 64.7; H, 6.0; N, 22.0%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:16])([F:15])[F:14].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH:12][C:23]([C:22]3[CH:21]=[N:20][C:19]([C:18]([F:29])([F:17])[F:28])=[CH:27][CH:26]=3)=[O:24])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:14])([F:15])[F:16]
Reactant: Cn1c(C(F)(F)F)cc2cc(CN)ccc21
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc2cc(CNC(=O)c3ccc(C(F)(F)F)nc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
[(1-Methyl-2-trifluoromethylindol-5-yl)methyl]amine (Intermediate 11, 150 mg, 0.657 mmol) was dissolved in DCM (10 mL) and 6-(trifluoromethyl)nicotinoyl chloride (ABCR; 165 mg, 0.789 mmol) was added. Et3N (0.183 mL, 1.315 mmol) was added and the reaction mixture was left to stir at room temperature for 2 hrs. The reaction mixture was quenched with methanol (10 mL) and evaporated to dryness. The resulting residues were partitioned between ethyl acetate and a 1M solution of citric acid. The organic layer was collected, dried (MgSO4), filtered and the solvent removed. The resulting residues were then purified by MDAP and evaporated to dryness to give the title compound (100 mg);
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][N:22]=[C:21]([OH:24])[CH:20]=3)=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(OCC)(=O)C>[C:25]([O:24][C:21]1[CH:20]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:18][CH:17]=2)[O:23][N:22]=1)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1cccc(CCOc2ccc(-c3cc(O)no3)cc2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1cc(-c2ccc(OCCc3cccc([N+](=O)[O-])c3)cc2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-(2-(3-nitrophenyl)ethoxy)phenyl)isoxazol-3-ol (117 mg) obtained in Example 37 in chloroform (5 ml), 0.15 ml of triethylamine and 0.052 ml of pivaloyl chloride were added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:1-1:3)) to afford the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:15]3[C@H:11]([CH2:12][N:13]([C:16](=[O:32])[CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24]CC4C=CC=CC=4)[CH2:14]3)[C@:10]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])([OH:33])[CH:9]([OH:42])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[OH-].[Pd+2].C(O)C>[C:43]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C@H:15]3[C@H:11]([CH2:12][N:13]([C:16](=[O:32])[CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[OH:24])[CH2:14]3)[C@:10]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])([OH:33])[C@H:9]([OH:42])[CH2:8]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccccc1[C@@]1(O)C(O)CC(c2ccccc2)(c2ccccc2)[C@@H]2CN(C(=O)Cc3ccccc3OCc3ccccc3)C[C@@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1[C@@]1(O)[C@H](O)CC(c2ccccc2)(c2ccccc2)[C@@H]2CN(C(=O)Cc3ccccc3O)C[C@@H]21
Temperature: 60 °C
Yield: 84.6 %

Procedure:
A mixture of 1.5 g of (3aR,4R, SR,7aR)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-benzyloxyphenyl)acetyl]perhydro-4,5-isoindolediol and 50 cm3 of ethanol is heated to 60° C. with stirring; 0.5 g of 20% palladium hydroxide on charcoal is added and the reaction mixture is then hydrogenated, with stirring, at a temperature of 60° C. and at atmospheric pressure. After reaction for 45 minutes, the theoretical volume of hydrogen has been absorbed; the reaction mixture is filtered, followed by concentration to dryness under reduced pressure (2.7 kPa). The meringue-like product obtained is purified by crystallization in 10 cm3 of isopropyl ether to give 1.09 g of (3aR,4R,5R,7aR)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-hydroxyphenyl)acetyl]perhydro-4,5-isoindolediol, melting at 188° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.Cl.[O:13]=[C:14]1[CH2:19][NH:18][CH2:17][CH2:16][N:15]1[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[S:36][C:35]2[N:37]3[C:28](=[CH:29][N:30]=[C:31]3[CH:32]=[CH:33][CH:34]=2)[CH:27]=1)=[O:25].C(N(CC)CC)C.[I-].[Na+].N12CCCNC1CCCC=C2>C(#N)C>[C:5]1([CH2:4][CH2:3][CH2:2][N:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]3[S:36][C:35]4[N:37]5[C:28](=[CH:29][N:30]=[C:31]5[CH:32]=[CH:33][CH:34]=4)[CH:27]=3)=[O:25])[C:14](=[O:13])[CH2:19]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(NCCCN1CCNCC1=O)C1=Cc2cnc3cccc(n23)S1
Reactant: BrCCCc1ccccc1
Agent: C1=CN2CCCNC2CCC1
Agent: Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(CCCc2ccccc2)CC1=O)C1=Cc2cnc3cccc(n23)S1
Yield: 66.3 %

Procedure:
1-Bromo-3-phenylpropane (210 mg, 1.05 mmol) was added to a stirred solution of N-[3-(2-oxopiperazin-1-yl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (389 mg, 0.904 mmol), triethylamine (459 mg, 4.53 mmol), sodium iodide (163 mg, 1.09 mmol) and 1,8-diazabicyclo[5.4.0]undecene (275 mg, 1.81 mmol) in acetonitrile (10 ml) at room temperature. After refluxing under nitrogen for 2 days, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (15 g) with Ethyl acetate-Methanol (8:1) to give N-[3-[4-(3-phenylpropan-1-yl)-2-oxopiperazin-1-yl]propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as a purple amorphous powder(285 mg, 66%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1>>[OH:28][CH:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:38][CH:37]=2)[CH2:33][CH2:34]1
Reactant: Nc1ccc(CN2CCC(O)CC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCC(O)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((4-hydroxy-piperidin-1-yl)-methyl)-aniline Rf value: 0.1 (silica gel, methylene chloride/methanol=10:1) C29H29N3O3
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]2[CH2:20][CH2:19][Si:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[F:30][C:31]([F:41])([F:40])[O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>CN(C)C=O>[F:30][C:31]([F:40])([F:41])[O:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]3[CH2:20][CH2:19][Si:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:37][CH:38]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](CBr)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](COc3ccc(OC(F)(F)F)cc3)CC2)CC1

Procedure:
8.3 g (60 mmols) of potassium carbonate was added to a mixture of 7.9 g (20 mmols) of 4-(trans-4-bromomethylcyclohexyl)-1-phenyl-1-n-propyl-1-silacyclohexane, 3.6 g (20 mmols) of 4-trifluoromethoxyphenol and 50 ml of dimethylformamide, followed by heating under reflux for 10 hours. The reaction mixture was after-treated by a usual manner and purified through chromatography to obtain 7.0 g (yield: 71%) of 4-(trans-4-(4-trifluoromethoxyphenyloxymethyl)cyclohexyl)-1-phenyl-1-n-propyl-1-silacyclohexane. The results of IR and NMR analyses are shown below.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][C:6](=[O:17])[CH:5]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+].O>CN(C)C=O>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:2][CH2:3][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=4)[NH:7][C:6](=[O:17])[CH:5]=3)[CH2:19][CH2:20]2)=[CH:25]1
Reactant: O=c1cc(CCBr)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 50 °C
Reaction time: 30 h
Yield: 51.2 %

Procedure:
A suspension of 4-(2-bromoethyl)-6-nitro-2(1H)-quinolinone (II-9) (891 mg, 3.0 mmol), 3-(4-piperidinyl)-1H-indol (600 mg, 3.0 mmol) and sodium hydrogen carbonate (378 mg, 4.5 mmol) in dimethylformamide (9 ml) was stirred at 50 ° C. for 30 hours. Then the reaction mixture was poured into water. The precipitated solid was filtered, washed with water, dried and recrystallized from a mixed solvent consisting of methanol, tetrahydrofuran and water to give the desired compound (III-19) (640 mg, yield 51.2%) as pale yellow crystals, mp 251°-253 ° C. (recrystallized from a mixture of methanol, tetrahydrofuran and water).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:17][CH2:16]2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>C(O)C>[NH2:8][C@@H:12]([CH2:13][CH2:14][C:15]1([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:17][CH2:16]1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCC2(c3ccc(Cl)cc3)CC2)COC1(C)C
Agent: Cl
Solvent: CCO
Product: N[C@H](CO)CCC1(c2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To (S)-4-{2-[1-(4-chloro-phenyl)-cyclopropyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.5 g) was added under an argon atmosphere 5.5 M HCl solution in ethanol (2 ml). The mixture was stirred for 16 h. The mixture was concentrated. The residue was dissolved in dichloromethane and an excess of ammonia in methanol and some silica gel was added. The solvents were evaporated and the crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: dichloromethane/methanol=90:10) to give (S)-2-amino-4-[1-(4-chloro-phenyl)-cyclopropyl]-butan-1-ol (0.27 g) as a white solid. MS (ISP): 240.2 ([M+H]+)).