Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:35]=[CH:34][C:16]2[N:17]=[C:18]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[S:19][C:15]=2[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:18]2[S:19][C:15]3[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:35]=[CH:34][C:16]=3[N:17]=2)[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(NC(=S)Nc1ccc2nc(NC3CCN(Cc4ccccc4)CC3)sc2c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc2nc(NC3CCN(Cc4ccccc4)CC3)sc2c1

Procedure:
1-Benzoyl-3-[2-(1-benzyl-piperidin-4-ylamino)-benzothiazol-6-yl]-thiourea (Example 37, 29 mg, 0.058 mmol) was placed in an argon purged flask. THF (3 mL) was added followed by 2M NaOH (0.13 mL, 4.4 eq.). The mixture was heated to reflux for 44 hours. The solvent was evaporated. The mixture was diluted with water (2 mL) and ethyl acetate (10 mL). The layers were separated and the aqueous phase (saturated with NaCl) extracted with ethyl acetate (2×10 mL). The combined organic fractions were dried over MgSO4, filtered and evaporated to give a yellow oil which was dried under high vacuum overnight. (crude yield: 25.2 mg). The product was used directly in the subsequent step (Example 39).
Reaction SMILES: I[C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]([CH3:12])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(OC)(C)(C)C>CN(C=O)C.C(N(CC)C(C)C)(C)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:13][C:3]1[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[C:7]([C:8]([F:11])([F:10])[F:9])[N:6]=[C:5]([CH3:12])[N:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1nc(C)nc(C(F)(F)F)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Product: COc1nc(C)nc(C(F)(F)F)c1C#C[Si](C)(C)C
Temperature: 50 °C
Yield: 116.9 %

Procedure:
5-Iodo-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (5.0 g) was dissolved in DMF (50 ml) and N,N-diisopropylethylamine (6.5 g), copper(I) iodide (0.3 g), dichlorobis(triphenylphosphine)palladium(II) (1.12 g) and trimethylsilylacetylene (15.4 g) was added at room temperature with stirring. The mixture was heated (50° C.) in nitrogen atmosphere for 7 hr and cool to room tempeature. The reaction mixture was added methyl tert-butyl ether (MTBE) (200 ml). The insoluble matter was removed by filtration through Celite and the filtrate was washed with water and brine, respectively. The MTBE solution was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give crude 4-methoxy-2-methyl-6-trifluoromethyl-5-trimethylsilylethynylpyrimidine (5.3 g) as pale yellow oil. This crude 4-methoxy-2-methyl-6-trifluoromethyl-5-trimethylsilylethynylpyrimidine (5.2 g) was dissolved in THF (100 ml) and tetrabutylammonium fluoride (1M THF solution, 18 ml) was added under ice cooling with stirring. After stirring 30 min at this temperature, the reaction mixture was added water in one portion under ice cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate) to give 5-ethynyl-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (1.92 g) as colorless crystalline solid, mp 77° C.
Reaction SMILES: C[O:2][C@:3]1([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][O:14][C:15](=[O:20])[NH:16]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[NH:22]2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][O:14][C:15](=[O:20])[NH:16]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCCOC(=O)N3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CCCOC(=O)N3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: O=C1N[C@@H]2C[C@@H](CCCC=CCCCO1)O[C@@](O)([C@@H]1CSC(=O)N1)C2

Procedure:
Application of the method shown in Example 46, with the modification that (1R,13R,15R,Z)-15-methoxy-15-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-4,14-dioxa-2-aza-bicyclo[11.3.1]heptadec-8-en-3-one is substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][C:7]=1[CH2:8][CH:9]([C:17](=O)C)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C=O>C1COCC1>[Br:1][C:2]1[N:3]=[N:4][C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][C:7]=1[CH2:8][C:9](=[CH2:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(=O)C(Cc1cc(-c2ccccc2)nnc1Br)C(=O)OC(C)(C)C
Agent: C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1cc(-c2ccccc2)nnc1Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a stirred solution of compound 5D, (0.160 g, 0.39 mmol) in 3 mL of THF at room temperature under argon was added 0.43 mL (in THF, 0.43 mmol) of 1M lithium bis(trimethylsilyl)amide over 2 min and, after 20 min, powdered, dry paraformaldehyde (0.059 mg, 1.97 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then quenched with saturated NaCl and extracted twice with dichloromethane. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. Purification by silica gel chromatography (7:93 Ether/CH2Cl2) provided the title compound, tert-butyl 2-((3-bromo-6-phenylpyridazin-4-yl)methyl)acrylate (0.142 g, 97%) as a light yellow oil. MS [M+H]+: found 375.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=1.[CH2:17]([O:19][C:20](=[O:22])C)[CH3:18]>C(Cl)(Cl)Cl.CCCCCC>[CH2:17]([O:19][C:20](=[O:22])[NH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH3:18]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)NCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
Chloro ethyl formate (1.92 mL) and 2N Na2CO3 solution (20 mL) were added to a stirred solution of 2-(4-chloro-phenyl)-ethylamine (I-1b: 2.6 g, 0.01667 mmol) in chloroform (20 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (20% ethylacetate in hexane). The reaction mixture was partitioned between water and chloroform. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (10% ethylacetate in hexane) afforded 2 g of the product (52.6% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([Cl:27])[CH:3]=1.[CH:28]1([CH2:34]I)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:3][C:4]=1[Cl:27])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ICC1CCCCC1
Reactant: CC(C)(C)[Si](OCc1ccc(Br)cc1Cl)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](OCc1ccc(CC2CCCCC2)cc1Cl)(c1ccccc1)c1ccccc1

Procedure:
In the same manner as in Preparation Example 70-2, the objective compound (797 mg, 56%) was obtained as a colorless oil from 4-bromo-1-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene and cyclohexylmethyl iodide.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.[C:47](O)(=[O:67])[CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56]/[CH:57]=[CH:58]\[CH2:59]/[CH:60]=[CH:61]\[CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH3:66]>>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:47](=[O:67])[CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56]/[CH:57]=[CH:58]\[CH2:59]/[CH:60]=[CH:61]\[CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH3:66])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCCCO
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OCCCCCOC(=O)CCCC/C=C\C/C=C\C/C=C\CCCCC

Procedure:
As for Example 2, Part 2 but replacing 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane with 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-5-hydroxypentane and z-octadeca-9-enoic acid with z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoic acid. Chromatography yielded 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-5-(z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyloxy)pentane as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.Cl.[C:40]1([CH3:53])[CH:45]=[CH:44][C:43]([C:46]2[N:51]=[C:50]([NH2:52])[CH:49]=[CH:48][CH:47]=2)=[CH:42][CH:41]=1>ClCCCl.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:52][C:50]3[CH:49]=[CH:48][CH:47]=[C:46]([C:43]4[CH:42]=[CH:41][C:40]([CH3:53])=[CH:45][CH:44]=4)[N:51]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1ccc(-c2cccc(N)n2)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)cc5)n4)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 56 mg, 0.1486 mmol) in 1,2-dichloroethane (0.15 ml) and DMF (1 drop) was added oxalyl chloride (15.56 μl, 0.1783 mmol), and the reaction was stirred for 2 hours. To this, pyridine (0.6 ml) and 6-p-tolylpyridin-2-amine hydrochloride (36.08 mg, 0.1635 mmol) were added, and the reaction was heated to 80° C. for 16 hours. The reaction was diluted with EtOAc and washed with 10% citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography, eluting with a gradient of 5-70% EtOAc/hexanes to yield the desired compound (49 mg, 0.09024 mmol, 60.72% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:41](=[CH:42][C:43]=1[OH:44])[C:8]1[N:9]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[C:7]=1[CH2:6]2.[H-].[Na+].C1(N[S:54]([C:57]([F:60])([F:59])[F:58])(=[O:56])=[O:55])C=CC=CC=1>C1COCC1>[F:58][C:57]([F:60])([F:59])[S:54]([O:44][C:43]1[CH:42]=[C:41]2[C:5]([CH2:6][C:7]3[C:11]([C:12]4[CH:17]=[CH:16][C:15]([C:18]5[CH:19]=[CH:20][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:23]=5)=[CH:14][CH:13]=4)=[N:10][N:9]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]=32)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:56])=[O:55]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: COc1cc2c(cc1O)-c1c(c(-c3ccc(-c4ccc(OCOCC[Si](C)(C)C)cc4)cc3)nn1COCC[Si](C)(C)C)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)-c1c(c(-c3ccc(-c4ccc(OCOCC[Si](C)(C)C)cc4)cc3)nn1COCC[Si](C)(C)C)C2
Yield: 115.6 %

Procedure:
To the solution of Example 267H (1.29 g, 2.04 mmol) in THF (10 mL) at room temperature was added 95% NaH (51.6 mg, 2.04 mmol). The mixture was stirred for half an hour, and N-phenyltrifluoromethane sulphonamide (0.88 g, 2.45 mmol) was added. The reaction mixture was stirred at 40° C. overnight. The reaction mixture was purified by flash chromatography to give the desired product (1.80 g, 100%). MS (APCI) m/z 763 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([O:15][C@H:16]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:19]([CH3:38])[O:18][CH:17]1[OH:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOC(C)=O>CS(C)=O>[CH2:8]([O:15][C@H:16]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:19]([CH3:38])[O:18][C:17]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 24 h
Yield: 62.7 %

Procedure:
Acetic anhydride (7.40 mL, 78 mmol, commercially available from Sigma Aldrich) was added to a solution of (3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-ol (1.70 g, 3.91 mmol) in DMSO (12 mL), and the resulting mixture was stirred for 24 h at P. EtOAc was added, and the mixture was washed with water (3×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography (0 to 40% EtOAc/hexanes gradient) to give (3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one as a colorless oil (1.06 g, 62.6% yield). ESI (M+H) 433.1; calc for C27H28O5 432.2.
Reaction SMILES: [CH2:1]([O:8][CH:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C(OCC)C>[CH2:14]([O:13][CH:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:10]([NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[C:24]([O:23][C:22]([F:21])([F:31])[F:32])[CH:25]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C(OCc1ccccc1)OCc1ccccc1
Reactant: Nc1cccc(OC(F)(F)F)c1
Solvent: CCOCC
Product: O=C(Nc1cccc(OC(F)(F)F)c1)C(OCc1ccccc1)OCc1ccccc1
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A solution of dibenzyloxyacetic acid (23.1 g) in diethyl ether (200 ml) was added to a solution of 3-trifluoromethoxyaniline (15 g) in diethyl ether (100 ml). A solution of dicyclohexyldicarbodiimide (16.5 g) in diethyl ether (100 ml) was then added in two portions. The mixture was left overnight and the precipitated solid then filtered off and the filtrate diluted with a mixture of diethyl ether and hexane (5:95) and refrigerated for an hour. The solid which separated was collected and washed with hexane, giving the title compound (10 g) with a melting point of 75°-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[C:12]3[CH:13]4[N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][CH2:18][N:14]4[C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl>CO>[NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[C:12]3[CH:13]4[NH:21][CH2:20][CH2:19][CH2:18][N:14]4[C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCN2C(=O)Nc3nccc(Oc4ccc(N)cc4)c3C21
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2ccnc3c2C2NCCCN2C(=O)N3)cc1

Procedure:
The title compound was synthesized by de-protection of 78 by HCl in MeOH. LC-MS (M+H=312, obsd.=312).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15]1([C:24]([O-])=[O:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[Cl:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:24]([C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]1)=[O:25]
Reactant: CCOC(=O)C1(C(=O)[O-])CCC1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)CCC1

Procedure:
23.1 g of 5-chlorotryptamine hydrochloride, 17.3 g of monoethyl cyclobutanedicarboxylate, 36 ml of diisopropylethylamine and 33.7 g of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate are stirred for 20 hours at ambient temperature in 200 ml of dichloromethane. After washing with water, drying over sodium sulphate and filtering off the organic phase over Celite, evaporation under reduced pressure enables the expected product to be isolated.
Reaction SMILES: NC1C(N[C@@H]2CC[C@H](C(NC(C)C)=O)CC2)=CC(OCCN2CCCCC2)=NC=1.[CH:30]([NH:33][C:34]([C@H:36]1[CH2:41][CH2:40][C@@H:39]([NH:42][C:43]2[C:48]([N+:49]([O-])=O)=[CH:47][N:46]=[C:45]([O:52][CH2:53][CH2:54][O:55]C3CCCCO3)[CH:44]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])[CH3:31]>>[NH2:49][C:48]1[C:43]([NH:42][C@@H:39]2[CH2:40][CH2:41][C@H:36]([C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:35])[CH2:37][CH2:38]2)=[CH:44][C:45]([O:52][CH2:53][CH2:54][OH:55])=[N:46][CH:47]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCOC3CCCCO3)ncc2[N+](=O)[O-])CC1
Agent: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCO)ncc2N)CC1

Procedure:
The title compound was synthesized using a method analogous to the preparation of cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide starting from cis-N-isopropyl-4-(5-nitro-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide, resulting in the deprotection of the -THP alcohol. MS m/z=337.2 [M+H], calc 336.43 for C17H28N4O3.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-])=O)=[O:6])([CH3:3])[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:17][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)NC(C)C)c(N)c1
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To a solution of methyl 4-[(isopropylamino)carbonyl]-3-nitrobenzoate (0.48 g, 1.78 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) was added 10% palladium on carbon (0.19 g, 0.18 mmol). The mixture was purged with H2 gas (3×) and stirred under an atmosphere of H2 for 1 d. The reaction mixture was then filtered through Celite, washed with MeOH and concentrated to afford methyl 3-amino-4-[(isopropylamino)carbonyl]benzoate (0.42 g, quant.). LC-MS: (FA) ES+ 237.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12]1>[Pd].CO>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]2([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C1(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(c2ccc(N)cc2F)CC1
Reaction time: 2 h

Procedure:
A suspension of t-butyl 1-(2-fluoro-4-nitrophenyl)cyclopropane-1-carboxylate (110 mg) and palladium catalyst (10% on charcoal, 11 mg) in methanol (5 mL) was hydrogenated at 1 atm for 2 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give t-butyl 1-(4-amino-2-fluorophenyl)cyclopropane-1-carboxylate. To a solution of crude t-butyl 1-(4-amino-2-fluorophenyl)cyclopropane-1-carboxylate thus obtained in tetrahydrofuran (5 mL) was added sodium hydrogencarbonate (39 mg), water (1 mL) and benzyl chloroformate (61 L) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After quenching the reaction by the addition of saturated sodium hydrogencarbonate solution, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=6:1) of the residue gave t-butyl 1-(4-benzyloxycarbonylamino-2-fluorophenyl)cyclopropane-1-carboxylate. MS (EI+) m/z: 385 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(NCC)C>CN(C)C=O>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([NH:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(CCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCOC(=O)CNc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminophenethyl alcohol (25 g) in N,N-dimethylformamide (500 ml) were added potassium carbonate (30 g) and ethyl bromoacetate (24 ml), and the mixture was stirred for 16 hours at room temperature. Diethylamine (38 ml) was added to the reaction mixture, and the resulting mixture was stirred for 1 hour. The insoluble material was filtered off and the filtrate was concentrated in vacuo. To the residue was added diethyl ether, and the resulting insoluble material was filtered off. The filtrate was washed with 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and brine subsequently, and dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave ethyl N-[4-(2-hydroxyethyl)phenyl]aminoacetate (35.5 g).