Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C@@H:23]([C@@H:93]([OH:111])/[CH:94]=[CH:95]/[CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108]CC)[CH2:24][O:25][C@@H:26]1[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([O:34][C@@H:35]2[O:40][C@H:39]([CH2:41][OH:42])[C@H:38]([O:43][C@@H:44]3[O:49][C@H:48]([CH2:50][OH:51])[C@H:47]([OH:52])[C@H:46]([O:53][C@@H:54]4[O:59][C@H:58]([CH2:60][OH:61])[C@H:57]([OH:62])[C@H:56]([OH:63])[C@H:55]4[OH:64])[C@H:45]3[NH:65][C:66]([CH3:68])=[O:67])[C@H:37]([O:69][C@@:70]3([C:87]([OH:89])=[O:88])[O:75][C@@H:74]([C@H:76]([OH:81])[C@H:77]([OH:80])[CH2:78][OH:79])[C@H:73]([NH:82][C:83]([CH3:85])=[O:84])[C@@H:72]([OH:86])[CH2:71]3)[C@H:36]2[OH:90])[C@H:28]([OH:91])[C@H:27]1[OH:92])=[O:21].C([O-])([O-])=O.[Na+].[Na+]>>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C@H:23]([C@H:93]([OH:111])/[CH:94]=[CH:95]/[CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH3:108])[CH2:24][O:25][C@@H:26]1[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([O:34][C@@H:35]2[O:40][C@H:39]([CH2:41][OH:42])[C@H:38]([O:43][C@@H:44]3[O:49][C@H:48]([CH2:50][OH:51])[C@H:47]([OH:52])[C@H:46]([O:53][C@@H:54]4[O:59][C@H:58]([CH2:60][OH:61])[C@H:57]([OH:62])[C@H:56]([OH:63])[C@H:55]4[OH:64])[C@H:45]3[NH:65][C:66]([CH3:68])=[O:67])[C@H:37]([O:69][C@@:70]3([C:87]([OH:89])=[O:88])[O:75][C@@H:74]([C@H:76]([OH:81])[C@H:77]([OH:80])[CH2:78][OH:79])[C@H:73]([NH:82][C:83]([CH3:85])=[O:84])[C@@H:72]([OH:86])[CH2:71]3)[C@H:36]2[OH:90])[C@H:28]([OH:91])[C@H:27]1[OH:92])=[O:21]
Reactant: CCCCCCCCCCCCCCC/C=C/[C@H](O)[C@@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC

Procedure:
IR spectroscopic examination on KBr pellets shows the typical band of the ester at 1750 cm-1. Chromatographic analysis of the product carried out in the same way as in Example 1 shows the presence of a unitary compound with an Rf of 0.92 and the absence of GM1 ganglioside and its internal ester (Rf 0.65 and 0.75, respectively). Hydrolysis with Na2CO3 as described in Example 1 produces the ganglioside GM1.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[CH2:8]1[C:12]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:11][CH2:10][NH:9]1.C(O)(=O)C>CC(O)C>[CH2:8]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:4]1[CH2:5][O:1][C:2](=[O:7])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Reactant: O=C1COC(=O)C1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=C1C=C(N2CCC3(CCNCC3)C2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Commercially available furan-2,4(3H,5H)-dione (0.433 g, 4.33 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (commercially available from multiple vendors, acetic acid salt, 0.65 g, 2.2 mmol) in 20 mL i-PrOH was heated in a sealed tube at 110° C. overnight. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in 30 mL DCM and 5 mL TFA and stirred at rt for 1 h. The mixture was concentrated, and the residue was purified by preparative TLC (10% 2N NH3 in methanol-DCM). LCMS: [(M+1)]+=223
Reaction SMILES: O1[C:5]2[NH:6][CH2:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2C=C1.C(N(CC)CC)C.[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O>C(Cl)Cl.C(OCC)(=O)C>[CH:7]1[C:8]2[N:9]([CH:11]=[CH:12][CH:13]=2)[CH2:10][CH:4]=[CH:5][N:6]=1
Reactant: c1cc2n(c1)Cc1ccoc1NC2
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1=CN=Cc2cccn2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml of methylene chloride under argon is added 1.5 mmol of triethylamine followed by ice bath cooling. A solution of 1.1 mmol of 4-nitrobenzoyl chloride in 5 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]4[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][C:23]=34)[O:16][N:15]=2)[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[NH3:30]>>[NH2:30][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]4[CH2:27][C:26]([CH3:28])([CH3:29])[CH2:25][CH2:24][C:23]=34)[O:16][N:15]=2)=[CH:5][C:6]=1[CH3:13]
Reactant: N
Reactant: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1OCC1CO1
Product: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1OCC(O)CN

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazole (500 mg, 1.18 mmol) in 2 N methanolic ammonia (7 mL) is heated in a sealed vial to 100° C. for 5 min in a microwave oven (300 W, active cooling during irradiation). The solvent is evaporated and the residue is purified by prep. HPLC (GROM-SIL ODS-4 HE, 75×30 mm ID, 10 μm, 20-95% acetonitrile in water containing 0.5% formic acid) to afford 1-amino-3-{4-[5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (220 mg) as a colourless resin; LC-MS: tR=0.92 min, [M+1]+=428.38.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]([CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:7].C=[CH:13][CH:14]=[CH:15][CH3:16].Cl.Cl[CH2:19]Cl>>[C:6]([C@@H:8]1[C:15]([CH3:16])([CH3:19])[CH2:14][CH:13]=[CH:10][C@H:9]1[CH3:11])(=[O:5])[CH3:7]
Reactant: C=CC=CC
Reactant: CC(=O)C=C(C)C
Reactant: ClCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Reaction time: 0.5 h

Procedure:
To powdered anhydrous aluminum chloride (13.7 g, 0.10 mol) under nitrogen is added dry dichloromethane (30 ml). Mesityl oxide (20.0 g, 0.20 mol) in dichloromethane (75 ml) is then added with stirring over 30 minutes and the mixture is heated under reflux for 1 hour. Penta-1,3-diene (mixture of isomers) (70.0 g, 1.03 mol) in dichloromethane (300 ml) is added dropwise over 6 hours. The mixture is then stirred overnight at room temperature. Liquid paraffin (100 ml) and 10% hydrochloric acid (200 ml) is added and the mixture is steam distilled for 3 hours. The steam distillate is extracted with ether (5×75 ml) and the product worked up as usual. The residue is distilled to give a liquid, b.p. 52°-54° at 1 mm Hg (15.0 g, 0.09 mol, 45%), shown by GLC [column (A), 120° C.] to consist of two components in the proportions ca. 13:87 in order of increasing retention time. These were separated by preparative GLC [column (B), 130° C.]: trans-4-acetyl-3,5,5-trimethylcyclohexene (6) (Found: C, 79.6; H, 10.75. C11H18O requires C, 79.5; H, 10.85%); m/e 166 (M+, 33%), 123 (100), 109 (39), 107 (33), 81 (39), 69 (33), 67 (27), 55 (27), 43 (82) and 41 (50); π9.17-8.86 (9H, 4 overlapping lines, 3- and 5-Me), 8.60-8.04 (2H, m, 6-H2), 7.87 (3H, s, Ac), 7.90-7.30 (2H, m with br s overlapping, 3- and 4-H), and 4.54br (2H, s, 1- and 2-H); νmax. (film) 1 710 (Ac) and 695 cm-1 (cis--CH=CH); cis-4-acetyl-3,5,5-trimethylcyclohexene (5) (Found: C, 79.55; H, 10.8%); m/e 166 (M+, 4%), 138 (39), 123 (95), 109 (11), 107 (23), 81 (12), 69 (8), 67 (9), 55 (12), 53 (11), 43 (100) and 41 (23); π9.18-8.89 (9H, 3 overlapping lines, 3- and 5-Me), 8.68-8.18 (2H, m, 6-H2), 7.97 (3H, s, Ac), 7.70-7.30 (2H, m, 4- and 3-H), and 4.86-4.16 (2H, m, 1- and 2-H); νmax. (film) 1 170 (Ac), and 1 692 and 710 cm-1 (cis--CH=CH).
Reaction SMILES: [ClH:1].N[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.N([O-])=O.[Na+].[S:17](=[O:19])=[O:18]>O>[S:9]([C:6]1[CH:7]=[CH:8][C:3]([S:17]([Cl:1])(=[O:19])=[O:18])=[CH:4][CH:5]=1)(=[O:11])(=[O:10])[NH2:12]
Reactant: Cl
Reactant: O=S=O
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reaction time: 0.25 h

Procedure:
To a mixed solution of 80 ml water and 50 ml of concentrated hydrochloric acid was added 25.0 g (145 mmol) of 4-aminobenzenesulfonamide followed by stirring. An aqueous solution (20 ml) of 10.5 g (152 mmol) of sodiumnitrite was added dropwise thereinto at −13° C. to −10° C. during 15 min. After 10 min, the reaction solution was added to a mixed solution saturated with sulfur dioxide (prepared by saturating sulfur dioxide in a mixed solution of 150 ml of acetic acid and 12.5 ml of concentrated hydrochloric acid followed by adding 3.7 g of cuprous chloride) at −30° C. under stirring. After 1 hr, 500 ml of ice water was added to the reaction solution, and the resulting precipitates were collected by filtration. The precipitates were dissolved in a mixed solution of 450 ml of toluene and 150 ml of ethyl acetate. After the resulting insoluble matters were filtered off, the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and brine successively, and dried over magnesium sulfate. The solvent was evaporated, 100 ml of toluene was added to the resulting residue and the crystals were collected by filtration to give 20.9 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[Li]CCCC.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>C1COCC1>[F:18][C:19]1[CH:20]=[C:21]([CH:22]([OH:23])[C:11]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:7]([NH:9][CH3:10])=[O:8])[CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CNC(=O)c1ccc(OC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(OC)cc1C(O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a −78 C solution of 4-methoxy-N-methylbenzamide (2.0 g) in THF was added n-BuLi (10 mL, 2.5 M in hexanes). The reaction was stirred for 10 min at −78 C, warmed to 0 C, then cooled back to −78 C. 3-fluorobenzaldehyde (1.90 mL) was added as a solution in THF via cannula. The reaction was warmed to room temp, then quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, concentrated, and purified by flash chromatography (5% MeOH in CH2Cl2) to give 2-[(3-fluorophenyl) (hydroxy)methyl]-4-methoxy-N-methylbenzamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[C:17](=[O:24])[NH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[C:17]([O:24][CH3:25])=[N:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[C:25](=[O:28])[N:16]2[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]n(-c2ccc(OCc3ccccc3)cc2)c2ncccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1nn(-c2ccc(OCc3ccccc3)cc2)c2ncccc12
Product: Cn1c(=O)c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[4-(benzyloxy)phenyl]-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (1.4 g) in DMF (50 ml) were added potassium carbonate (0.73 g) and iodomethane (0.75 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 1-[4-(benzyloxy)phenyl]-3-methoxy-1H-pyrazolo[3,4-b]pyridine (1.1 g) and 1-[4-(benzyloxy)phenyl]-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (0.28 g).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:48]([NH:55][C@@H:56]([CH3:64])[CH:57]([O:61][CH2:62][CH3:63])[O:58][CH2:59][CH3:60])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C>[CH2:62]([O:61][CH:57]([O:58][CH2:59][CH3:60])[C@@H:56]([N:55]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:23])[CH3:64])[CH3:63]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(OCC)[C@H](C)NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)N(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid 68 mg (0.22 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate 84 mg (0.22 mmol) in dichloromethane 1 ml, a solution of (S)—N-benzyl-1,1-diethoxypropan-2-amine (Compound IV-15) 47 mg (0.2 mmol) and N,N′-diisopropylethylamine 38 ml (0.22 mmol) in dichloromethane 1 ml was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated aqueous sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 7:3) to obtain the title compound 48 mg (45%).
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14](O)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:62][C@H:63]([C:71]([NH2:73])=[O:72])[CH2:64][CH2:65][CH2:66][NH:67][C:68](=[NH:70])[NH2:69].CN1CCOCC1>CN(C=O)C.CC(O)=O>[C:20]([NH:1][C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([NH:62][C@H:63]([C:71]([NH2:73])=[O:72])[CH2:64][CH2:65][CH2:66][NH:67][C:68](=[NH:69])[NH2:70])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21]
Reactant: N=C(N)NCCC[C@H](N)C(N)=O
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.45 g of Fmoc-D-Phe-Pro (3 mmol) and 405 mg of HOBt were dissolved in 40 ml of DMF and, at 0oC, 630 mg of DCC were added, and then the mixture was stirred at 0oC for 30 minutes and at room temperature for 30 min. Then 880 mg of Arg-NH2 × 2 CH3COOH and 630 pl of NMM were added. After 12 hours, insolubles were filtered off, the DMF was evaporated off, and the oily residue was taken up chloroform. The organic phase was extracted by shaking three times with saturated sodium bicarbonate solution and three times with saturated sodium chloride solution, and was dried over sodium sulfate. After the chloroform had been evaporated off, a pure product was obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:26]1[CH2:29][CH2:28][CH2:27]1.CN(C=O)C>CCOC(C)=O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([N:26]4[CH2:29][CH2:28][CH2:27]4)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: C1CNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1c(Cc2ccc(-n3cccn3)cc2)c(N2CCC2)nc2ccc(Br)cc12
Temperature: 100 °C

Procedure:
3-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (2.50 g, 5.77 mmol, Intermediate 4: step c), azetidine (988 mg, 17.3 mmol), and DMF (30 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The vessel was then cooled and contents were transferred to a separatory funnel with EtOAc dilution, then extracted three times with deionized water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-20% hexane/ethyl acetate) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:5]/[C:4]2[CH:3]=[C:2]([F:1])[C:9]([F:10])=[C:8]([F:11])[CH:7]=2)/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc(F)c(F)c(F)c2)cc1OC
Yield: 18.8 %

Procedure:
3,4,5-Trifluorobenzaldehyde (160 mg) and 3,4-dimethoxybenzyl cyanide (177 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (60 mg, yield: 19%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])=[C:8]([Cl:20])[CH:7]=1)[CH3:5].B.[Na].O>CO>[CH3:1][O:2][C:3](=[O:21])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[OH:19])=[C:8]([Cl:20])[CH:7]=1)[CH3:5].[CH3:1][O:2][C:3](=[O:21])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[OH:19])=[C:8]([Cl:20])[CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc(CC2CCCCC2=O)c(Cl)c1
Agent: B
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)C(C)c1ccc(C[C@@H]2CCCC[C@@H]2O)c(Cl)c1
Product: COC(=O)C(C)c1ccc(C[C@@H]2CCCC[C@H]2O)c(Cl)c1
Yield: 50 %
Yield: 30 %

Procedure:
6 g of methyl-2-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]propionate were dissolved in 30 ml of methanol and then incorporated with 0.75 g of sodium boron hydride under agitation at room temperature, agitated at room temperature for 30 minutes, incorporated with 100 ml of water and then extracted with 100 ml of ethyl acetate. The extract obtained was washed with water, dried and then freed of the solvent at a reduced pressure to obtain a mixture of trans-form and cis-form bodies. The thus obtained mixture was absorbed onto a silica gel-packed column and then separated with ethyl acetate-hexane (1:3) to obtain 1.8 g (yield 30%) of methyl-2-[3-chloro-4-(cis-2-hydroxycyclohexane-1-yl methyl)phenyl]propionate and 3.0 g (yield 50%) of methyl-2-[3-chloro-4-(trans-2-hydroxycyclohexane-1-yl methyl) phenyl]propionate.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]1=[O:12])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH:16]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:16]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH3:20])=[O:18])[C:7](=[O:11])[C:6]1=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCNC(=O)C1=O
Reactant: COC(=O)C(Br)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CCN(C(CCc2ccccc2)C(=O)OC)C(=O)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-butylpiperazine-2,3-dione (Intermediate D, 500 mg, 2.9 mmol) in 4 mL DMF, cooled to 0° C., was added sodium hydride (60% dispersion in mineral oil, 128 mg, 3.2 mmol). The reaction was stirred at rt for 30 min, recooled to 0° C. and a solution of methyl 2-bromo-4-phenylbutanoate (Intermediate C, 820 mg, 3.2 mmol) in 1 mL DMF was added dropwise. The mixture was stirred at rt for 1 h, quenched with brine and extracted with EtOAc. Drying, solvent evaporation and flash chromatography (silica gel, 35-90% EtOAc/hexanes) gave methyl 2-(4-butyl-2,3-dioxopiperazin-1-yl)-4-phenylbutanoate. 1H NMR (CDCl3) δ 7.29 (m, 2H), 7.18 (m, 3H), 5.27 (X of ABX, 1H, J=10.8 Hz, J=4.6 Hz), 3.72 (s, 3H), 3.63 (m, 1H), 3.54 (m, 1H), 3.47 (m, 2H), 3.38 (m, 1H), 3.28 (m, 1H), 2.67 (m, 2H), 2.36 (m, 1H), 2.03 (m, 2H), 1.57 (m, 2H), 1.35 (m, 2H), 0.95 (t, 3H, J=7.3 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:31][C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35](O)=[O:36])[C:23]3=[O:41])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:31][C:32]4[CH:40]=[CH:39][CH:38]=[C:34]([C:35]([N:10]5[CH2:9][CH2:8][N:7]([C:4]6[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=6)[CH2:12][CH2:11]5)=[O:36])[CH:33]=4)[C:23]3=[O:41])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Product: O=C(c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCN(c2ccncc2)CC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 1-(pyridin-4-yl)piperazine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C33H29ClN4O2: 548, observed (M+H)+: 549.1 1H NMR (400 MHz, MeOD-d4) δppm 2.20-2.29 (m, 2 H) 3.26-3.31 (m, 1 H) 3.58 (br. s., 4 H) 3.88 (br. s., 4 H) 5.08-5.25 (m, 2 H) 6.14 (d, J=7.58 Hz, 1 H) 6.77 (t, J=7.58 Hz, 1 H) 6.92 (d, J=7.83 Hz, 1 H) 7.12 (t, J=7.20 Hz, 3 H) 7.21-7.32 (m, 4 H) 7.41 (s, 1 H) 7.45 (d, J=7.33 Hz, 1 H) 7.50-7.61 (m, 2 H) 8.19 (d, J=7.58 Hz, 2 H).