Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH3:23].C[S-](C)[C:26]([S-])=[N:27][C:28]#[N:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:26](=[N:27][C:28]#[N:29])[N:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=4[O:22][CH3:23])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(Nc2c(N)cnc3ccc(Br)cc23)c(OC)c1
Reactant: C[S-](C)C([S-])=NC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=NC#N)[nH]c3cnc4ccc(Br)cc4c32)c(OC)c1
Temperature: 80 °C

Procedure:
To the stirred solution of 6-bromo-N4-(2,4-dimethoxyphenyl)quinoline-3,4-diamine (10.69 mmol) in DMF (10 mL) was added dimethylcyanocarbonimidodithioate (16.03 mmol) followed by cesium carbonate (32.1 mmol) and the resulting reaction mixture was heated at 80° C. for 18 h. Completion of reaction was monitored by TLC, solvent evaporated under reduced pressure. Residue was diluted with water & extracted with ethyl acetate (250 mlx 5), organic layer were dried over anhydrous Na2SO4 and evaporated under vacuum. Crude product was further purified on silica gel column using MeOH/CHCl3 (8%) as elute to afford desired product as off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 13.72 (s, 1H), 8.93 (s, 1H), 8.03 (d, J=9 Hz, 1H), 7.77 (dd, J=3.9 Hz, 1H), 7.58 (d, J=9 Hz, 1H), 7.16 (d, J=3 Hz, 1H), 6.93 (d, J=3 Hz, 1H), 6.84 (dd, J=3, 9 Hz, 1H), 3.92 (s, 3H), 3.69 (s, 3H); MS (m/z): 424 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:40][CH2:39][CH2:38][C@H:35]1[CH:36]=O)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][CH2:36][CH:35]4[CH2:38][CH2:39][CH2:40][N:34]4[C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(N3CCN(CCc4cccc(NCC5CCCN5C(=O)OC(C)(C)C)c4)CC3)cccc2n1
Reaction time: 24 h
Yield: 39.8 %

Procedure:
3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 115 mg) and N-(tert-butoxycarbonyl)-L-prolinal (1.2 equiv., 79 mg) were stirred in methanol (2 mL) until the mixture became a clear solution. Then, sodium triacetoxyborohydride (1.2 eq., 85 mg) was added. After 24 h the reaction mixture was loaded onto an ion-exchange cartridge (SCX-2) and eluted with methanol followed by ammonia/methanol (1M). The combined basic fractions were concentrated in vacuo and purified by column chromatography (SPE cartridge, silica) using DCM-methanol (95:5) as eluent to afford the title compound (70 mg, 40% yield).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.[C:42]1(C)[C:43]([C:48]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=O)=[CH:44][CH:45]=[CH:46][CH:47]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:53]5[CH2:52][CH2:51][N:50]([C:48]6[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=6[CH3:42])[CH2:55][CH2:54]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1C(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride prepared in the manner of Example 23 (0.5 g) was added to a stirred mixture of N,N-diisopropylethyl amine (0.47 g), 4-(2-toluoyl)piperazine hydrochloride (0.51 g) and 4-(dimethylamino)pyridine (0.05 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonat, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol®. Refluxing the eluate with the gradual addition of hexane resulted in crystallization of the desired title compound (0.46 g) as colorless crystals, m.p. 141–143° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2c(c1C)OCO2
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1CBr)OCO2
Temperature: 0 °C
Yield: 21.5 %

Procedure:
A mixture of methyl 4-methyl-1,3-benzodioxole-5-carboxylate (9.9 g), N-bromosuccinimide (9.6 g) in carbon tetrachloride was irradiated with a 500 W medium pressure ultraviolet lamp for six hours at reflux. The mixture was cooled to 0° C., filtered and the filtrate evaporated to give an oil which was crystallised from toluene/hexane and recrystallised from cyclohexane to give methyl 4-bromomethyl-1,3-benzodioxole-5-carboxylate (3.0 g) as a beige solid, m.p. 95°.varies.98° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]([Si](C)(C)C)[O:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:28]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]([I:28])[O:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=c1ccn(Cc2ccccc2)c2oc(I)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 7-benzyl-3-phenyl-2-(trimethylsilyl)furo[2,3-b]pyridin-4(7H)-one 4d was taken up in N,N-dimethylformamide (50 mL), and N-Iodosuccinimide (15.704 g, 69.95 mmol) was added. The mixture stirred at room temperature for 1.5 h and was then concentrated. The residue was partitioned between dichloromethane and an aqueous solution of sodium thiosulfate. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange brown oil. Purification via column chromatography on silica gel (eluting with ethyl acetate) afforded 7-benzyl-2-iodo-3-phenylfuro[2,3-b]pyridin-4(7H)-one 4f as a brown solid. MS (MH+) 428.0; Calculated 427 for C20H14INO2.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]4[O:26][C:25]5[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=5[O:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[O:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22][C@@H:21]1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:12]2[CH2:13][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)[CH2:11]2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C2CN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)C2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2CN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)C2)cc1

Procedure:
A solution of 4-{1-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-azetidin-3-yl}-benzoic acid methyl ester (prepared from Intermediate A and 4-Azetidin-3-yl-benzoic acid methyl ester according to General Method G) (504 mg, 1.21 mmol) and lithium hydroxide monohydrate (210 mg, 5.0 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) is stirred at 50° C. for 16 h. The mixture is neutralized with 1M HCl and concentrated. The residue is triturated with water to give the title compound 254 as a solid. (LC/MS method 16: ES+ m/z 402.5 [M+H]+, Rt=2.70 min)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1C(=O)C.[N:12]1C=CC=[CH:14][CH:13]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][C:13]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:12]=1
Reactant: c1ccncc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nc2ccc(O)cc2o1
Temperature: 5 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
To a stirred solution of 1-(2,4-dihydroxyphenyl)ethanone (20 g, 131 mmol) in pyridine (80 mL) hydroxylamine hydrochloride (9.1 g, 131 mmol) was added over a period of 15 min in small portions at room temperature. The reaction mixture was stirred for 20 h and then diluted with water (600 mL) and extracted with ethyl acetate (2×250 mL). The combined organic extracts were washed with water (2×250 mL) and 5% aqueous HCl (250 mL). The solvent was removed in vacuo. Water (200 mL) was addded to the residue and then concentrated in vacuo, then toluene (200 mL) was added and concentrated in vacuo. The residue was dissolved in a mixture of acetonitrile (150 mL) and dimethylacetamide (25 mL). The solution was cooled to 5° C., phosphorus oxychloride (20.4 g, 12.2 mL, 133 mmol) was added dropwise allowing the temperature to exceed 10° C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h and then it was slowly poured into a mixture of sodium carbonate (55 g) and ice (ca 800 g). After the ice melted, the resulting slurry was filtered and the solid collected was washed with water (2×150 mL). The product was dried in vacuo to afford a yellow powder (14.4 g, 97 mmol, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]3[CH2:29][CH2:28][NH:27][CH2:26][C:19]3=[N:20][C:21]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]1.[CH:31](OC1C=CC=CC=1)=[O:32]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]3[CH2:29][CH2:28][N:27]([CH:31]=[O:32])[CH2:26][C:19]3=[N:20][C:21]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]1
Reactant: O=COc1ccccc1
Reactant: CC(C)Nc1nc2c(nc1N1CCC([C@@H](F)c3ccc(F)cc3F)CC1)CCNC2
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC([C@@H](F)c3ccc(F)cc3F)CC1)CCN(C=O)C2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of (R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (50.5 mg, 0.120 mmol) in THF (602 μL) at room temperature was treated with phenyl formate (232 μL, 1.806 mmol). The reaction mixture was stirred at 60° C. for 15 min. The reaction mixture was removed from heat and allowed to continue stirring at room temperature for 2 h. The reaction was purified by HPLC Method B using a 50% to 80% ACN gradient to give the title compound, as a TFA salt, as a pale yellow solid (6.0 mg, 8.9% yield). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.30 (m, 7H), 1.45 (d, J=13.2 Hz, 1H), 1.67 (m, 2H), 2.01 (m, 1H), 2.11 (m, 1H), 2.79 (m, 4H), 3.51 (m, 2H), 3.77 (t, J=5.9 Hz, 1.4H), 3.83 (t, J=6.1 Hz, 0.6H), 4.13 (m, 1H), 4.51 (s, 0.6H), 4.56 (s, 1.4H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H), 8.19 (s, 0.7H), 8.24 (s, 0.3H); ESI-MS m/z [M+H]+ 447.95.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][N:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:11]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:46]=[C:47]1[NH:56][CH:55]=[CH:54][C:53]2[N:52]=[C:51]([C:57]3[CH:64]=[CH:63][C:60](C=O)=[CH:59][CH:58]=3)[C:50](C3C=CC=CC=3)=[CH:49][C:48]1=2>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][N:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:60]3[CH:59]=[CH:58][C:57]([C:51]4[CH:50]=[CH:49][C:48]5[C:47](=[O:46])[NH:56][CH:55]=[CH:54][C:53]=5[N:52]=4)=[CH:64][CH:63]=3)[CH2:16][CH2:17]2)[CH:11]=1
Reactant: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccn3)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2nc(-c3ccc(CN4CCC(n5cnc(-c6ccccn6)c5)CC4)cc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidine-1-carboxylate (300 mg, 0.9 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was dried under vacuum for a further 2 h. The residue was dissolved in a solution of triethylamine (1 mL) in CH2Cl2 (3 mL). The reaction mixture was stirred for 1 h at room temperature and sodium triacetoxyborohydride (381 mg, 1.8 mmol), 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (295 mg, 0.9 mmol) and molecular sieves were added. Stirring was continued at room temperature for 16 h and the reaction quenched by addition of methanol. The residue was purified by HPLC (phenomenex column, 35%-100% acetonitrile/water+0.1% TFA) to afford 3-phenyl-2-(4-{[4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidin-1-yl]methyl}phenyl-1,6-naphthyridin-5(6H)-one trifluoroacetic acid salt as a yellow oil. 1H NMR (500 MHz, CD3OD) δ 8.56 (m, 3H), 8.28 (s, 1H), 8.10 (m, 1H), 7.99 (m, 1H), 7.45 (m, 1H), 7.42 (m, 5H), 7.21 (m, 3H), 7.15 (m, 2H), 6.77 (m, 1H), 4.62 (m, 1H), 4.34 (s, 2H), 3.55 (m, 2H), 3.21 (m, 2H), 2.39 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH3:9])[CH:3]([OH:6])[C:4]#[CH:5].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:18]([Si:15]([CH3:17])([CH3:16])[O:6][CH:3]([CH:2]([CH3:1])[CH2:7][CH2:8][CH3:9])[C:4]#[CH:5])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC(O)C(C)CCC
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CC(O[Si](C)(C)C(C)(C)C)C(C)CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of 4-methyl-hept-1-yn-3-ol (2.53 g, 0.02 mol) in dry DMF (25 mL) were added imidazole (1.63 g, 0.024 mol) and tert-butyldimethylsilyl chloride (3.62 g, 0.024 mol). The resulting solution was stirred at RT for 18 h and then treated with saturated NH4Cl (15 mL) and EtOAc (120 mL). The organic layer was washed with saturated NH4Cl (20 mL), water (4×20 mL), brine (2×20 mL), dried over sodium sulfate, and concentrated in vacuo to afford a crude product (4.65 g, 97%), as a yellow oil, which was used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.08 (s, 3H), 0.12 (s, 3H), 0.96-0.85 (m, 15H), 1.57-1.10 (m, 4H), 1.69-1.61 (m, 1H), 2.33 (t, J=2.20 Hz, 1H), 4.22-4.18 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25](=[O:27])[N:31]([CH2:32][CH2:33][OH:34])[CH3:30])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: CNCCO
Product: CN(CCO)C(=O)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 55 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 2-methylamino-ethanol in 55% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-])=O)=[C:17]([C:19](=[O:22])[CH:20]=[CH2:21])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:23])=[C:17]([C:19](=[O:22])[CH2:20][CH3:21])[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(=O)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1N
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
1-[5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-nitrophenyl)-2-propen-1-one (325 mg) is dissolved in ethanol (15 ml) and thereto is added 10% palladium-carbon (40 mg), and the mixture is stirred under hydrogen atmosphere for 1.5 hour. After removing the catalyst by filtration, the filtrate is concentrated and purified with a silica gel column chromatography to give 1-[5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-aminophenyl]propan-1-one (248 mg) as yellow powders.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)=[CH2:2].[C:12]1([CH3:27])[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.NC(N)=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][C:23]2[CH:24]=[CH:25][C:20]([C:19]#[C:18][C:15]3[CH:16]=[CH:17][C:12]([CH3:27])=[CH:13][CH:14]=3)=[CH:21][CH:22]=2)=[O:10])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: Cc1ccc(C#Cc2ccc(O)cc2)cc1
Reactant: C=CC1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: NC(N)=O
Solvent: Cc1ccccc1
Product: C=CC1CCC(C(=O)Oc2ccc(C#Cc3ccc(C)cc3)cc2)CC1
Temperature: 25 °C

Procedure:
5.0 g of 4-vinylcyclohexanecarboxylic acid, 6.7 g of 4-p-tolylethynylphenol, 4.0 g of 4-(dimethylamino)pyridine and 250 ml of toluene were mixed at RT, 7.3 g of DCC in 50 ml of toluene were added, and the mixture was stirred vigorously overnight at RT, during which the urea formed precipitated. 1 g of oxalic acid was then added, and the mixture was stirred at RT for a further hour in order to destroy the excess DCC. The conventional work-up gave 4-p-tolylethynylphenyl 4-vinylcyclohexanecarboxylate in the form of colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:9]=2[N:10]=1.[CH3:11][N:12]=[C:13]=[S:14]>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:13](=[S:14])[NH:12][CH3:11])[CH2:7][CH2:8][C:9]=2[N:10]=1
Reactant: Nc1nc2c(s1)CNCC2
Reactant: CN=C=S
Solvent: CN(C)C=O
Product: CNC(=S)N1CCc2nc(N)sc2C1
Yield: 54.7 %

Procedure:
1.55 G (10 mmol) of 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine was dissolved in 25 ml of dimethylformamide and the solution was cooled in an ice-water bath. 0.88 g (12 mmol) of methyl isothiocyanate was then added. After 71/2 hours the solvent was removed by evaporation and the residue (about 2.2 g) was crystallized from acetonitrile. 1.25 g (55% yield) of the pure title compound (m.p. 188°-190° C. with decomposition) were obtained.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH3:26][C@H:27]1[CH2:32][C:31](=O)[CH2:30][CH2:29][C@H:28]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>C1COCC1>[CH3:2][O:3][CH:4]=[C:31]1[CH2:30][CH2:29][C@@H:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C@@H:27]([CH3:26])[CH2:32]1
Reactant: CCOC(=O)[C@@H]1CCC(=O)C[C@@H]1C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H]1CCC(=COC)C[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (1.7 g, 5.0 mmol) in THF (10 mL) was added sodium hydride (108 mg, 4.5 mmol, 60 wt %) in several portions at 0° C. The resulting mixture was stirred at 0° C. for 1 hour. Then ethyl rel-(1R,2S)-2-methyl-4-oxocyclohexanecarboxylate (500 mg, 2.7 mmol) in THF (5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. Water was then added dropwise at 0° C. and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give ethyl rel-(1R,2S)-4-(methoxymethylidene)-2-methylcyclohexanecarboxylate, which was dissolved in THF and aqueous hydrochloric acid (6 M) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then diluted with water. The mixture was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl rel-(1R,2S)-4-formyl-2-methylcyclohexanecarboxylate. MS ESI calc'd for C11H19O3 [M+H]+ 199. found 199. 1H NMR: (400 MHz, CDCl3) δ 9.67-9.57 (m, 1H), 4.22-4.05 (m, 2H), 2.65-1.52 (m, 9H), 1.25 (t, J=7.2 Hz, 3H), 1.03-0.88 (m, 3H).
Reaction SMILES: N1CCCCC1.C1C2C(COC([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:41][C:42]3[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=3)[CH2:34][C:35]3[N:36]([CH3:40])[CH:37]=[CH:38][N:39]=3)[C:26]([OH:28])=[O:27])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[NH2:24][C@@H:25]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:41][C:42]1[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=1)[CH2:34][C:35]1[N:36]([CH3:40])[CH:37]=[CH:38][N:39]=1)[C:26]([OH:28])=[O:27]
Reactant: Cn1ccnc1CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Piperidine (0.80 mL) was added to a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)hexanoic acid (556 mg, 1.00 mmol) in DMF (4.0 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by Amberchrom to afford (S)-2-amino-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino) hexanoic acid (330 mg, 99%). 1H NMR (400 MHz, DMSO-d6) 7.94 (s, 1H), 7.04 (d, J=3=1.2 Hz, 2H), 6.74 (d, J=1.2 Hz, 2H), 3.54 (s, 4H), 3.98 (brs, 1H), 2.88 (s, 3H), 2.72 (s, 3H), 2.35 (t, J=6.8 Hz, 2H), 1.60-1.54 (m, 1H), 1.43-1.29 (m, 3H), 1.16-1.11 (m, 2H); MS (ESI), 335 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:6]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:6]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
To a solution of 253 (71.4 mg, 0.21 mmol) in acetic acid (2.1 mL) at 100° C., was added iron powder (59 mg, 1.05 mmol). The reaction mixture was stirred for 5 minutes, filtered through a Celite® pad and concentrated under reduced pressure. The residue was purified by column chromatography, eluent EtOAc/hexane (2:1), to afford title compound 254 (27.9 mg, 40% yield). MS (m/z): 321.1 (M+1).