Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:22])[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[CH2:28][CH2:29]2)=[O:34])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Reactant: CN(C(=O)OC(C)(C)C)C1CNCC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)OC(C)(C)C)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound [(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared from [(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 1-cyclopropylmethyl-piperidine-4-carboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a dark brown oil, which was directly used without further characterisation.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[C:9]([CH3:15])=[N:8]1.Cl.[N:17]1[CH:22]=[CH:21][C:20]([C:23](N)=[NH:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[C:11]2=[N:24][C:23]([C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[N:14][C:12](=[O:13])[C:10]2=[C:9]([CH3:15])[NH:8]1
Reactant: N=C(N)c1ccncc1
Reactant: Cc1nn(C2CCCC2O)cc1C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1[nH]n(C2CCCC2O)c2nc(-c3ccncc3)nc(=O)c1-2
Yield: 23.4 %

Procedure:
A mixture of 1-(2-hydroxycyclopentyl)-3-methyl-1H-pyrazole-4-carboxamide (2.4 g, 10 mmol), 4-pyridinecarboxamidine hydrochloride (3.2 g, 20 mmol), potassium carbonate (2.8 g, 20 mmol) and DMF (50 ml) were heated under reflux for 28 hours. The solvent was removed in vacuo, the residue was dissolved in hot water (25 ml) and was filtered. The filtrate was acidified with acetic acid and the resulting white precipitate was collected by filtration and recrystallized from DMF to afford 0.73 g (21%) of 1-(2-hydroxycyclopentyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as white needles, m.p. 281°-283° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:24]([F:23])([F:33])[F:34]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccccc1C(F)(F)F
Temperature: 100 °C
Yield: 34.1 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (120 mg, 0.32 mmol) and 2-(trifluoromethyl)benzyl bromide (200 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with 1:1 water/brine (20 mL), aqueous sodium thiosulfate, water, and brine. The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50-70% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(2-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (52 mg, 34%) as a white solid. APCI(+)-MS (M+H) 463.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc([N+](=O)[O-])cc2)nn1
Yield: 45.6 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (60 mg, 0.17 mmol); 1-azido-4-nitrobenzene (42 mg, 0.26 mmol); CuSO4 (4.4 mg, 0.03 mmol); NaAsc (22 mg, 0.11 mmol); TBTA (20.0 mg, 0.04 mmol); in t-BuOH/EtOH/H2O (2:2:1); afforded the 45 as an orange solid (40 mg, 45.6%). 1H NMR (DMSO-d6, 400 MHz): δ 9.00-8.99 (d, 1H, J=1.8 Hz); 8.77-8.74 (t, 1H); 8.73 (s, 1H); 8.63-8.61 (d, 1H, J=8.17 Hz); 8.47-8.44 (d, 2H, J=9.13 Hz); 8.21-8.19 (d, 2H, J=9.13 Hz); 7.36 (d, 1H, J=1.78 Hz); 4.71-4.65 (q, 1H); 4.42-4.40 (d, 2H, J=5.50 Hz); 4.20-4.09 (m, 2H); 3.66-3.65 (d, 1H, J=1.75 Hz); 3.52-3.53 (d, 1H, J=1.75 Hz); 3.28-3.06 (m, 2H); 1.22-1.17 (t, 3H). 13C NMR (CDCl3, 100 MHz): 170.25, 167.14, 165.00, 153.70, 152.87, 146.77, 146.68, 140.89, 125.70, 121.59, 120.42, 115.86, 61.60, 53.09, 52.61, 51.40, 34.32, 33.12, 13.94.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4](F)=[O:5].[OH2:17]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:17])=[O:5]
Reactant: O
Reactant: O=C(F)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Product: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Reaction time: 24 h

Procedure:
A suspension of crude 2,3-dichloro4-trifluoromethoxybenzoyl fluoride (2 g, containing mixed antimony halides) in water was stirred vigorously for 24 hours. The mixture was extracted with dichloromethane and filtered. The organic layer was washed with hydrochloric acid (2M), aqueous sodium chloride solution and extracted into sodium carbonate solution (2M). The aqueous extract was acidified to pH1 and the solid was filtered off and washed with water to give 2,3-dichloro-4-trifluoromethoxybenzoic acid (0.6 g) as a white solid mp 123°-126° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].CCO>>[CH3:20][CH:16]([O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)[CH:17]([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1cc2c(OC(C)C(C)C)cccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C(C)Oc1cccc2[nH]c(C(=O)O)cc12
Reaction time: 48 h

Procedure:
4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid ethyl ester 89 (2.4 g, 8.72 mmol) is mixed with a 1M-solution of KOH in EtOH (43.6 ml, 87.2 mmol) and stirred for 48 hours. The solvent is then evaporated and the residue is partitioned between water and ether. The water layer is acidified with HCl and extracted twice with ether. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a beige powder.
Reaction SMILES: CO[C:3](=O)[N:4]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:3][N:4]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To an ice-cold, stirred solution of trans-N-[4-(4-hydroxyphenyl) cyclohexyl]-N-(3-phenylpropyl)carbamic acid methyl ester (0.30 g, 0.82 mmol) in anhydrous THF (20 mL), under a N2 atmosphere, was added LiAlH4 (95% powder, 0.034 g, 0.89 mmol). The reaction mixture was stirred at room temperature for 6 hours. LAH (95% powder, 0.07 mg, 1.8 mmol) was added, and stirring was continued for 14 hours. The reaction mixture was then quenched by the slow addition of H2O (2 mL). The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1 MeOH:CH2Cl2) gave trans-4-{4-[methyl(3-phenylpropyl)amino]cyclohexyl}phenol (0.19 g, 70%) as an off-white solid: IR (thin film): 2931, 1613, 1515 cm−1; 5 1H NMR (300 MHz, CD3OD) δ 7.30-7.11 (m, 5H), 7.00 (d, J=8 Hz, 2H), 6.67 (d, J=8 Hz, 2H), 2.69-2.49 (m, 5H), 2.41-2.31 (m, 1H), 2.30 (s, 3H), 2.00-1.78 (m, 6H), 1.55-1.34 (m, 4H); CI-MS (methane) (m/z): 324 [M+H]+; HRMS-API (m/z): [M+H]+ Calcd for C22H29NO, 324.2327. found: 324.2333. HPLC: method A, 7.82 minutes (99.8%); method B, 13.89 minutes (99.7%); Anal. Calcd for C22H29NO.0.25 H2O: C, 80.57; H, 9.07; N, 4.27. Found: C, 80.51; H, 8.83; N, 4.27.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[C:22][CH2:23][CH3:24].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:23]([C:22]1[CH:21]=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1)[CH3:24]
Reactant: CCC#Cc1cccc[n+]1N
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1cc2ccccn2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 6.1 g portion of the obtained N-amino-2-(1-butynyl)pyridinium mesitylenesulfonate was dissolved in tetrahydrofuran (600 mL), potassium tert-butoxide (3.55 g) was added at room temperature, and the mixture was vigorously stirred for 30 minutes. After adding ice water to the reaction mixture, extraction was performed with ethyl acetate. The aqueous layer was again extracted with ethyl acetate, the insoluble portion was filtered with a celite filter, and the organic layers were combined and washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (0.63 g) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a light yellow oil.
Reaction SMILES: [Cl:1][CH:2]([Cl:15])[CH:3]([C@H:5]1[C@H:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]1([CH3:14])[CH3:13])[OH:4].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH2:11]([O:10][C:8]([C@H:7]1[C@H:5]([CH:3]([O:4][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:2]([Cl:15])[Cl:1])[C:6]1([CH3:14])[CH3:13])=[O:9])[CH3:12]
Reactant: CCOC(=O)[C@H]1[C@H](C(O)C(Cl)Cl)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1[C@H](C(OS(=O)(=O)c2ccc(C)cc2)C(Cl)Cl)C1(C)C
Temperature: 40 °C
Reaction time: 72 h

Procedure:
A solution of (±) trans ethyl 3-(β,β-dichloro-α-hydroxyethyl)-2,2-dimethylcyclopropane-1-carboxylate (28.0 g, 0.11 M) in pyridine (168 ml) was added dropwise to a solution of tosyl chloride (44.2 g, 0.23 M) in pyridine (224 ml) maintained at 40° C. After the addition the mixture was stored for 3 days at 4° C. The majority of the pyridine was removed under vacuum at 40° C. and the residue was poured into ice/water (200 ml). After acidification with concentrated hydrochloric acid, this mixture was extracted with ether (3×100 ml), the ether layers combined, dried and evaporated to a pale yellow oil, which crystallised on standing. The tosylate was recrystallised from cyclohexane, m.p. 71° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]2[C:12](=[O:22])[O:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[OH:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12](=[O:22])[C:11]=1[CH:8]([C:4]1[CH:3]=[C:2]([NH:1][S:32]([CH:31]=[CH2:30])(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=1)[CH2:9][CH3:10]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCC(c1cccc(N)c1)c1c(O)c2ccccc2oc1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1cccc(C(CC)c2c(O)c3ccccc3oc2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 14.7 mg of 3-[1-(3-aminophenyl)propyl]4 hydroxy-coumarin is added 1 ml of methylene chloride and 8.1 microliters of pyridine. 5.71 microliters of chloroethylsulfonyl chloride is added at room temperature and protection from moisture. The reaction mixture is allowed to stir at room temperature for 3 hours. 5 ml of methylene chloride is added and the solution is washed twice with 5 ml of water. The organic solution is dried over anhydrous sodium sulfate, filtered and dried to give crude title product. Chromatography over 15 g of silica gel using 5% methanol in chloroform and collecting material with Rf =0.3 gives 6.3 mg of the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CO.CN(C)C=O>[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:27]
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1cccc(F)c1
Yield: 41.8 %

Procedure:
Preparation of example 35 from the title compound of Example 7 (0.025 g, 0.09 mmol), 3-Fluoro-benzoic acid (0.015 g, 0.11 mmol), triethylamine (0.05 mL, 0.4 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38 mg, 0.1 mmol) and N,N-dimethylformamide (0.05 M, 1.8 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol), also in an analogous manner, afforded the title compound (15 mg) as a yellow powder in 42% yield.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:13])=[NH:12])[CH2:6][CH2:5][CH2:4][CH2:3]1.CC[O-].[Na+].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:32]([NH:34]N)=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.CCOCC>C(O)C>[ClH:1].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:32]2[NH:34][N:13]=[C:11]([C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[CH:9]=3)[N:12]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)NN)cc1OCc1ccccc1
Reactant: N=C(N)c1cccc(CN2CCCC2)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2nc(-c3cccc(CN4CCCC4)c3)n[nH]2)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a stirred ethanolic suspension of 3-pyrrolidin-1-ylmethyl-benzamidine hydrochloride salt (1:2) (414 mg, 1.5 mmol, 1.5 eq.) in ethanol (15 ml) was added 1.2N NaOEt in ethanol (3.4 ml, 4 eq.) over 3 min. and stirring was then continued for 30 min. at r.t. 3-Benzyloxy-4-methoxy-benzoic acid hydrazide (272 mg, 1 mmol) in ethanol was added at 20° C. and the resulting mixture was heated to reflux for 50 hrs. Upon cooling, the product mixture was filtered, the solvent was evaporated and the residue chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 96:4 affording a solid. This material was dissolved in ethanol at r.t. and an excess 2N HCl/ether solution (1.0 ml, 2 mmol) was added. After 30 min. the solvent was evaporated and the residue dried under high vacuum at 30° C. overnight affording the title compound (326 mg, 89% yield) as a yellow solid. MS: m/e=441.6 (M+H+)
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[K+].[CH3:15][C@:16]12[CH2:33][C:32](=[O:34])[C@H:31]3[C@@H:21]([CH2:22][CH2:23][CH:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:35])[CH2:25]4)[C@@H:20]1[CH2:19][CH2:18][C:17]2=[O:36]>C1COCC1.C(OCC)(=O)C>[OH:35][C@H:26]1[CH2:27][CH2:28][C@@:29]2([CH3:30])[CH:24]([CH2:23][CH2:22][C@@H:21]3[C@@H:31]2[C:32](=[O:34])[CH2:33][C@@:16]2([CH3:15])[C@H:20]3[CH2:19][CH2:18][C:17]2=[O:36])[CH2:25]1
Reactant: C[C@]12CCC(=O)CC1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 99.2 %

Procedure:
K-Selectride® (98.39 mL, 98.01 mmol, 1M solution in THF) is added to a solution of Compound 1.13 (33.0 g, 109.27 mmol) in THF (330 mL) over 15 minutes under an inert atmosphere at −78° C. and is stirred for about 3-4 h at −78° C. The reaction mixture is quenched with aqueous NaOH solution (2M, 70 mL). The crude reaction mixture is diluted with ethyl acetate (500 mL) and the organic layer is washed with water (3×75 mL), saturated brine solution (100 mL) and dried over MgSO4 (75 g). The solvent is removed under vacuum to afford 33 g of crude material. The crude product is subjected to acetylation without purification.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=1>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:25]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)/C=C/c1ccc(N)cc1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCC#Cc1ccc(CNc2ccc(/C=C/C(=O)OCC)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynyl-benzaldehyde and ethyl (2E)-3-(4-aminophenyl)acrylate. (purification by flash chromatography on SiO2, EtOAc/c-Hex 1/7 to 1/6 in about 30 min.) as a yellow solid (61%). 1H NMR (CDCl3) δ: 7.59 (d, J=15.8 Hz, 1H), 7.36 (m, 4H), 7.26 (m, 2H), 6.57 (d, J=8.7 Hz, 2H), 6.21 (d, J=15.8 Hz, 1H), 4.35 (s, 2H), 4.23 (dd, J1=7.2 Hz, J2=14.3 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 1.66-1.52 (m, 2H), 1.50-1.39 (m, 2H), 1.38-1.24 (m, 11H), 0.87 (m, 3H). M+ (ESI): 418.1; M− (ESI): 416.2. HPLC, Rt: 6.1 min (purity: 98.7%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])=[O:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])=[O:28]
Reactant: COC(=O)CCCCC(=O)O
Reactant: COc1ccccc1C(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)NCC(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.2 %

Procedure:
Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.57 g, 18.62 mmol), 4-(dimethylamino)pryidine (463.8 mg, 3.79 mmol) and adipic acid monomethyl ester (2.97 g, 18.55 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(2-methoxy-phenyl)-ethanone hydrochloride (3.74 g, 18.55 mmol) and triethylamine (3.75 g, 37.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 22 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 NHCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter the drying agent and concentrate in vacuo to afford 4.57 g of the titled product (80%): mass spectrum: m/z 308.1 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:21](O)=O)=[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(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC.O.[CH3:62][N:63]([CH3:66])[CH:64]=[O:65]>O1CCCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:20][CH2:21][C:64]([N:63]([CH3:66])[CH3:62])=[O:65])[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CN(C)C=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (Compound SP444) (10.0 g, 23.5 mmol) was dissolved in dimethylformamide (70 ml), ((benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (12.5 g, 28.3 mmol) and dimethylamine (58 mmol) were added as a 2 mol/1 solution in tetrahydrofuran, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to afford tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(dimethylamino)-5-oxopentanoate (Compound SP447) (15.2 g) as a crude product.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:12])[C:9]=1[CH:10]=[O:11]>C(O)C>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:12])[C:9]=1[CH2:10][OH:11]
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
NaBH4 (0.838 g, 22.2 mmol) was added to a stirred solution of 3,5-dichloro-pyridine-4-carbaldehyde (3.0 g, 17 mmol) in ethanol (40 mL). After stirring for 35 min at room temperature, the reaction mixture was concentrated in vacuo, the residue was redissolved in ethyl acetate (200 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS (m/z): 178.1 [M+H+].