Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]/[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH3:22]
Reactant: C/C(=C/C(C)c1ccccc1C)CO
Reactant: CC[Zn]CC
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccccc1[C@H](C)[C@@H]1C[C@]1(C)CO
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 5.4 g, 0.0066 mol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −20° C. Chloroiodomethane (2.33 g, 13.2 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −5 to −15° C. for 20 minutes, and then cooled to −25° C. (Z)-2-Methyl-4-(2-methylphenyl)pent-2-en-1-ol (0.62 g, 3.3 mmol) was added dropwise at −20 to −25° C. over a period of 15 minutes. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 20 minutes. Next, a 20% aqueous sulfuric acid solution (2.5 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1-Methyl-2-((R*)-1-(2-methylphenyl)ethyl)cyclopropyl]methanol (0.47 g, 2.3 mmol, 70% yield) was obtained as the main isomer, and [(1S*,2S*)-1-methyl-2-((S*)-1-(2-methylphenyl)ethyl)cyclopropyl]methanol (0.12 g, 0.59 mmol, 17% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][CH:15]([OH:30])[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:30])[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:28])=[CH:31][CH:32]=1
Reactant: Cc1cccc(C)c1NCCCNCC(O)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1NCCCNCC(O)COc1ccc(O)cc1

Procedure:
2.5 g. 1-(4-Benzyloxyphenoxy)-3-[3-(2,6-dimethylphenylamino)-propylamino]-propan-2-ol are hydrogenated in 200 ml. methanol in the presence of 0.25 g. palladium-charcoal (10%). The colorless oil (2.0 g.) obtained after suction filtration and evaporation of the filtrate is dissolved in ethanol. By adding an ethanolic solution of oxalic acid, the corresponding oxalate is precipitated out and recrystallized twice from ethanol. There is obtained 1.0 g. (45% of theory) of the desired product in the form of colorless crystals; m.p. 198°-199° C.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[N:11]([C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[C:37]([O:39][CH3:40])[C:36](B(O)O)=[CH:35][N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:36]4[C:37]([O:39][CH3:40])=[N:38][C:33]([O:32][CH3:31])=[N:34][CH:35]=4)=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:24][C:25]=1[F:30]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)c(F)c1)N(c1cc(Cl)cn(C)c1=O)C2=O
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)c(F)c2)N(c2cc(Cl)cn(C)c2=O)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-6-(4-chloro-3-fluoro-phenyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate BA) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a white solid. tR: 1.15 min (HPLC 3); ESI-MS: tR=1.13 min, [M+H]+ 572/574/576 (LC-MS 1); TLC: Rf=0.25 (EtOAc).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(C)(C)C.C(N(CC)C(C)C)(C)C.[CH3:44][O:45][CH2:46][CH2:47][NH:48][CH2:49][CH2:50][O:51][CH3:52]>C(Cl)Cl.C(N(CC)CC)C>[CH3:44][O:45][CH2:46][CH2:47][N:48]([CH2:49][CH2:50][O:51][CH3:52])[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:24]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: COCCNCCOC
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(CCOC)C(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (45 ml) and then, triethylamine (0.7 ml) was added and cooled. Pivaloyl chloride (0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at 5° C. for 2 hours. N,N-Diisopropylethylamine (0.8 ml) and bis(2-methoxyethyl)amine (0.6 g) were added in order, the solution was stirred at 0~5° C. for 2 hours and heated slowly to 20~25° C. and stirred for 30 minutes. The reaction mixture was washed with water twice and with aqueous 5% sodium bicarbonate. Then, the solvent was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and further recrystallized using ethyl acetate and ether. The recrystallized product was filtered and dried to give 1.65 g (yield: 84%) of the desired compound. m.p.: 82~83° C.; 1H-NMR(CDCl3), ppm: δ 1.21(d, 6H), 3.08(m, 4H), 3.25(s, 3H), 3.36(m, 5H), 3.52(m, 5H), 3.64(m, 2H), 3.74(m, 2H), 3.90(m, 2H), 4.15(m, 1H), 6.82(m, 1H), 6.91(m, 1H), 7.44(m, 4H), 7.66(m, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11]OS(C)(=O)=O)[CH:5]=[CH:4][N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C>COCCOC>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:11][C:10]2[CH:17]=[CH:18][CH:19]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:29][C@@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCc1cccc(-c2ccnc(Cl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: C[C@H]1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 64 %

Procedure:
Intermediate 125 Methanesulfonic acid 3-(2-chloro-pyrimidin-4-yl)-benzyl ester (0.70 g) and Intermediate 126 2-(S)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.61 g) with diisopropylethylamine (0.70 mL) in ethylene glycol dimethyl ether (20 mL) was refluxed for 3 hours, cooled to room temperature, evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water (3×), brine, dried over dried over Na2SO4, chromatographed on silica gel (dichloromethane:methanol=98:2) to give 0.60 g of oily product with yield 64%. LC-MS showed the product had the expected M+H+ of 403. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.0 (s, 1H) 7.9 (d, 1H) 7.6 (d, 1H) 7.5 (m, 2H) 4.2 (S, 1 h) 3.8 (d, 1H) 3.4 (m, 2H) 3.0 (m, 1H) 2.7 (d, 1H). 2.6 (d, 1H) 2.1 (m, 2H) 1.5 (s, 9H) 1.2 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Cl:15])=[CH:9][CH:8]=3.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH:30]2[CH2:32][O:31]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH:30]([OH:31])[CH2:32][N:6]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=3)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CO2)CC1
Reactant: Clc1ccc2[nH]c3ccc(Cl)cc3c2c1
Product: CC(C)(C)OC(=O)N1CCN(CC(O)Cn2c3ccc(Cl)cc3c3cc(Cl)ccc32)CC1
Yield: 74 %

Procedure:
The same method as employed in the preparation of Example 1 but starting from 3,6-dichloro-9H-carbazole and (±)-4-oxiranylmethyl-piperazine-1-carboxylic acid tert-butyl ester gives after flash chromatography the title compound as a white foam in a 74% yield.
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[O:41][C:42]([CH3:45])=[N:43][N:44]=1)=[C:22]2[C:26]([O:28]CC1C=CC([N+]([O-])=O)=CC=1)=[O:27])([O:4]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].C(O)C.P([O-])([O-])(O)=O.[K+:54].[K+]>O.O1CCOCC1.O.[Pt](=O)=O>[OH:4][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[O:41][C:42]([CH3:45])=[N:43][N:44]=1)=[C:22]2[C:26]([O-:28])=[O:27])([CH3:3])[CH3:1].[K+:54]
Reactant: Cc1nnc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@@H](C(C)(C)OC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@H]3C2)o1
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nnc(SC2=C(C(=O)[O-])N3C(=O)[C@@H](C(C)(C)O)[C@H]3C2)o1
Temperature: 25 °C

Procedure:
A mixture of 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 mg), platinum (IV) oxide monohydrate (50 mg), ethanol (0.5 ml) and 0.1M aqueous solution of dipotassium hydrogen phosphate (2.35 ml) in a mixture of water (2.5 ml) and dioxane (6 ml) was shaken under a hydrogen atmosphere (40 psi) at ambient temperature for an hour. After the catalyst was filtered off, the filtrate was evaporated to half of the original volume. The resultant aqueous solution was washed three times with diethyl ether and then evaporated in vacuo. The residue was dissolved in water (25 ml) and the resultant aqueous solution was chromatographed on nonionic adsorption resin "Diaion HP-20AG" eluting with water (100 ml) and 10% aqueous isopropyl alcohol (100 ml). The fractions, whose UV spectra showed λmax 292 nm, were combined and lyophilized to give potassium (5R, 6R)-6-(1-hydroxy-1-methylethyl)-3-(5-methyl-1,3,4-oxadiazol-2-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (14.3 mg) as powder.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42](O)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:45][CH2:46][CH3:47])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:48][CH:49]([CH2:52][OH:53])[CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]([NH:51][CH2:50][CH:49]([OH:48])[CH2:52][OH:53])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:45][CH2:46][CH3:47])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCC(O)CO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NCC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NCC(=O)NCC(O)CO)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-ylamino}-acetic acid (example 229) was reacted with N-(2,3-dihydroxy-propyl)-amine (Aldrich) to give the title compound as a mixture of diasteromers. HR-MS (ES, m/z) calculated for C39H51Cl2N6O5 [(M+H)+] 753.3293, observed 753.3293.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Ni]
Product: COc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1

Procedure:
Prepared from (2′-methoxy-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example C1) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white solid (169 mg).
Reaction SMILES: [C:1]1([P:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[N:13]=[C:12]([C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH3:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:34]O>ClCCl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([C:12]1[N:13]=[C:8]([P:7](=[O:34])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:9]=[CH:10][CH:11]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:15]
Reactant: CC(c1ccccn1)(c1ccccn1)c1cccc(P(c2ccccc2)c2ccccc2)n1
Reactant: OO
Solvent: ClCCl
Product: CC(c1ccccn1)(c1ccccn1)c1cccc(P(=O)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.7 g of 2,2′-(1-(6-(diphenylphosphino)pyridin-2-yl)ethane-1,1-diyl)dipyridine were dissolved in 25 ml of dichloromethane and ice-bath cooled. 1.8 ml of hydrogen peroxide (35 wt % in water) were added drop wise and the mixture was stirred overnight at room temperature. The reaction was quenched with 20 ml of saturated ammonium chloride solution and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and dried with magnesium sulphate. The solvent was removed under reduced pressure until the residue starts to foam. The residue crystallised from diethyl ether. After drying in high vacuum 5.1 g (74%) of an off-white solid were obtained. The compound was further purified by gradient sublimation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](OC(N1CCC2(CNC2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:10]2([CH2:13][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:11]2)[CH2:9][CH2:33]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1nc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (46.4 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([OH:16])[CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[K+].Cl>C1COCC1.CN(C=O)C.O>[CH2:12]([O:16][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCO
Reactant: O=C(O)c1cc(F)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOc1ccc(Cl)c(C(=O)O)c1

Procedure:
To a solution of 2-chloro-5-fluorobenzoic acid (50 mg) and 1-butanol (263 μL) in THF (0.5 mL) and DMF (3 mL) was added potassium t-butoxide (329 mg) and the solution was reacted at 120° C. for 10 minutes in a microwave synthesizer (Biotage, Initiator). The reaction mixture was cooled and acidified by addition of water and 2M hydrochloric acid, extracted with diethyl ether, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified on column chromatography to obtain the titled compound (17 mg) as white powder.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].COCCO[AlH2-]OCCOC.[Na+].[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]([C:37]#[C:38][CH2:39][OH:40])[CH:28]=1.[NH4+].[OH-]>C1(C)C=CC=CC=1.C1COCC1>[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29](/[CH:37]=[CH:38]/[CH2:39][OH:40])[CH:28]=1
Reactant: OCC#Cc1cnc2ccccc2c1
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC/C=C/c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dry 250-mL three-necked jacketed round-bottom flask was charged sodium bis(2-methoxyethoxy)aluminum hydride. (Red-Al, 70% wt. solution in toluene, 11.0 g, 38.1 mmol, 1.39 equiv) and anhydrous THF (20 mL). To this precooled (0-2° C.) and magnetically stirred solution was added a THF (50 mL) solution of the 3-(3-quinolyl)-2-propyn-1-ol (5.0 g, 27.32 mmol) via a pressure equalizing dropping funnel. The temperature was not allowed to rise above 15° C. After the addition was complete (20 minutes) the mixture was allowed to warm up to room temperature and stirred for one hour. The solution was then cooled back to 0° C. and quenched by the addition of aqueous 10% sulfuric acid (20 mL) such that the internal temperature did not rise above 15° C. The biphasic reaction mixture was then basified to pH 9-10 with aq. conc. NH4OH and the aqueous layer was back extracted with ethyl acetate (2×125 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give exclusively 3-(3-quinolyl) trans-2-propen-1-ol as a solid: 4.1 g, 81%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([N:13]2[C:17]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:16](=[O:23])[NH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:25][C:26]([NH:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH:38]([CH3:40])[CH3:39])=[O:27]>C(C(C)=O)C>[CH:38]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH:35]([CH3:36])[CH3:37])[C:29]=1[NH:28][C:26](=[O:27])[CH2:25][N:15]1[C:16](=[O:23])[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)([CH3:39])[CH3:40]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reactant: O=C1NCN(c2ccccc2)C12CCCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CN(c2ccccc2)C2(CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
72 mg (0.52 mmol) of potassium carbonate are added to a solution of 120 mg (0.52 mmol) of 1-phenyl-1,3-diazaspiro[4.5]decan-4-one and 132 mg (0.52 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide (described in Example 1 a) in 20 ml of methyl ethyl ketone. The reaction medium is stirred at room temperature for 12 hours and then for 6 h at reflux. The medium is then filtered and then the residue is chromatographed on silica gel (heptane then heptane/ethyl acetate 50/50, v/v). 135 mg of N-(2,6-diisopropylphenyl)-2-(4-oxo-1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetamide are obtained in the form of a white solid. Yield=58%, m.p.=251-3° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)C.O.[OH-].[Na+]>CCO>[CH:25]1([O:24][C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([CH2:5][C:4]([OH:30])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CC1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(CC(=O)O)Cc3ccccc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of the 2-(2-cyclobutyloxy-3-methylbenzoylamino)indan-2-acetic acid ethyl ester (288) (400 mg-1 mmol) in EtOH (15 mL)/water (1 mL) is treated with NaOH pellets (800 mg-20 mmol) and stirred at RT for 24 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with HCl to pH 2-3. The product is extracted into EtOAc (3×20 mL) and the combined extracts washed with water (2×10 mL) and brine (2×15 mL). The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is triturated with heptane and the pure product isolated by filtration to give white solid (350 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:22]([CH3:23])[C:21]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=3[N:19]=2)=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])[CH3:2].[ClH:30]>O1CCOCC1>[ClH:30].[CH2:1]([O:3][CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[N:22]([CH3:23])[C:21]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=3[N:19]=2)=[CH:14][CH:15]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(Cc1ccc(OCc2nc3ccc(OC)cc3n2C)cc1)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(Cc1ccc(OCc2nc3ccc(OC)cc3n2C)cc1)C(=O)O

Procedure:
A mixture of methyl 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionate (0.17 g), concentrated hydrochloric acid (2 ml) and dioxane (2 ml) was heated at reflux for 1.5 hours. The reaction mixture was concentrated and the water of the residue was removed by azeotropic distillation in dioxane and the crystals were isolated by filtration to afford the title compound (0.16 g, mp 143-146° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:13][C:12]1=[O:18]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (85 mg, 72%)