Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40]C)=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].CCC1C(C)=C2NC=1C=C1N=C3C(C(C(C(OC)=O)C3=C3N=C(C=C4NC(=C2)C(C=C)=C4C)C(C)C3CCC(OC)=O)=O)=C1C>>[CH3:1][CH2:2][C:3]1[C:4]([CH3:45])=[C:5]2[NH:22][C:21]=1[CH:20]=[C:19]1[C:23]([CH3:32])=[C:24]3[C:25]([CH2:27][C:16]([C:17]3=[N:18]1)=[C:15]1[C@@H:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C@H:34]([CH3:35])[C:13]([NH:14]1)=[CH:12][C:10]1=[N:11][C:7]([C:8]([CH:43]=[CH2:44])=[C:9]1[CH3:42])=[CH:6]2)=[O:26]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Agent: C=Cc1c(C)c2cc3nc(c4c5nc(cc6[nH]c(cc1[nH]2)c(C)c6CC)C(C)=C5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Product: C=CC1=C(C)c2cc3[nH]c(c4c5nc(cc6[nH]c(cc1n2)c(C)c6CC)C(C)=C5C(=O)C4)[C@@H](CCC(=O)O)[C@@H]3C

Procedure:
Materials and General Methods. Melting points are uncorrected. UV-vis spectra were recorded on a Beckman DU-600 or a Perkin-Elmer Lambda spectrophotometer. Fluorescence emission was measured with a Perkin-Elmer LS-50B fluorometer. 1H NMR spectra were recorded on a Bruker ASPECT 360 MHz instrument. ESI-MS and HRMS spectrometry analysis were performed at the Mass Spectrometry Facility of the Department of Chemistry, University of Pennsylvania. Methyl pheophorbide a was obtained from Spirulina pacifica algae available from Cyanotech Corp., Hawaii. Purpurin-18 methyl ester (1) was synthesized from methyl pheophorbide according to a literature procedure. (Zheng, G.; Li, H.; Zhang, M.; Lund-Katz, S.; Chance, B.; Glickson, J. D., Low-density lipoprotein reconstituted by pyropheophorbide cholesteryl oleate as target-specific photosensitizer. Bioconjugate Chemistry 2002, 13, (3), 392-396.) Bacteriochlorophyll a (BChl) was extracted from R. Sphaeroides biomass purchased from Frontier Science, Utah. Bacteriopurpurin-18 methyl ester (6) and bacteriopheophorbide a methyl ester (11) were synthesized from BChl according to previously described procedures. (Kozyrev, A. N.; Zheng, G.; Zhu, C. F.; Dougherty, T. J.; Smith, K. M.; Pandey, R. K., Syntheses of stable bacteriochlorophyll-a derivatives as potential photosensitizers for photodynamic therapy. Tetrahedron Letters 1996, 37, (36), 6431-6434; Hartwich, G.; Fiedor, L.; Simonin, I.; Cmiel, E.; Schafer, W.; Noy, D.; Scherz, A.; Scheer, H., Metal-substituted bacteriochlorophylls. 1. Preparation and influence of metal and coordination on spectra. Journal of the American Chemical Society 1998, 120, (15), 3675-3683). Other chemicals were purchased from Aldrich. Where necessary, solvents were dried before use. For TLC, EM Science TLC plates (silica gel 60 F254) were used. Purity of the final conjugates was validated by reverse phase HPLC using a Waters Delta-600 analytical/semi-preparation system equipped with photodiode array and fluorescence detectors.
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:8]=[C:9]([OH:20])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-])=O.Cl>[Fe].O>[NH2:4][C:7]1[CH:8]=[C:9]([OH:20])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Oc1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(O)ccc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
120 ml of ethanol and 120 ml of water were added to 23.1 g of 3-nitro-4-phenoxyphenol, and the mixture was made into a solution by heating at 60° C. 2.3 ml of 4N hydrochloric acid was added thereto. While maintaining the reaction temperature at 65°-70° C., 16.8 g of an iron powder was added thereto in portions in 20 minutes. Stirring was conducted for 30 minutes at the same temperature. The reaction mixture was hot-filtered. 50 ml of water was added to the filtrate and the mixture was allowed to stand. The resulting crystal was collected by filtration to obtain 16.5 g (yield: 82.1%) of 3-amino-4-phenoxyphenol having a melting point of 156°-157° C.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:28][N:35]=[C:31]([CH2:32][CH2:33][CH3:34])[N:30]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CCCC(N)=NO
Product: CCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
150 mg (0.373 mmol) of the compound from Example 44A and 70 mg (0.746 mmol) of N′-hydroxybutanimidamide were reacted according to the General Method 2. Yield: 174 mg (93% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)#[N:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(C#N)cc3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 88, the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(4-cyano-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-cyanobenzoyl chloride instead of 4-fluorobenzoyl chloride and was obtained as a light brown oil. MS m/e: 542.1 [M+H]+.
Reaction SMILES: [Br:1][CH:2]([CH2:8][Br:9])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:11]1([NH:10][C:6]([NH:5][C:3](=[O:4])[CH:2]([Br:1])[CH2:8][Br:9])=[O:7])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc2ccccc12
Reactant: O=C=NC(=O)C(Br)CBr
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(NC(=O)C(Br)CBr)Nc1cccc2ccccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
26.0 g of 2,3-dibromopropionyl isocyanate in 100 ml of toluene are added dropwise at 5 to 10° C to a solution of 14.5 g of 1-aminonaphthalene in 200 ml of dry benzene. After stirring for 2 hours at 20° C., the reaction product is diluted with petroleum ether, filtered and dried. Yield: 35.0 g, m.p: 194° - 195° C. (decomp.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.[Na].C(=O)([O-])O>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: C1=COCCC1
Reactant: OCCCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na]
Solvent: ClCCl
Solvent: c1ccncc1
Product: ClCCCCCOC1CCCCO1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
5-chloro-1-pentanol (12.26 g, 0.1 mol) was dissolved in dry dichloromethane (400 mL). 3,4-Dihydro-2H-pyrane (12.62 g, 0.15 mol) and pyridine toluene-4-sulphonate (1.26 g, 5 mmol) was then added and the reaction mixture was stirred magnetically in a nitrogen atmosphere at room temperature over night. Sodium-hydrogen-carbonate, saturated solution (150 mL) was added and the phases were separated. The aqueous phase was then extracted with dichloromethane (4×25 mL). The combined dichloromethane phases were washed with water (2×20 mL) and then dried (MgSO4). Dichloromethane was then distilled out on a rotary evaporator and yielded 19.6 g (95%) of a pale yellow oil. NMR indicated a pure product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=N[CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.BrC1C=CC=[C:27]([F:31])C=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:27]([F:31])[CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: Fc1cccc(Br)c1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=343.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=S)[CH2:6][CH2:5][C:4]([N+:15]([O-:17])=[O:16])([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:3]1.[BH4-].[Na+].O>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([N+:15]([O-:17])=[O:16])([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:3]1
Reactant: CN1CC(c2ccncc2)([N+](=O)[O-])CCC1=S
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCCC(c2ccncc2)([N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
To a solution of 105 mg (0.418 mmol) rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4′]bipyridinyl-6-thione in 2.1 ml methanol was added 144 mg (3.8 mmol) NaBH4. The mixture was stirred at room temperature for 20 minutes. Water (1.0 ml) was added. The mixture was stirred for 1 hour. The methanol was removed in vacuo. The residue was diluted with water and extracted 3 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 53 mg (57%) of the title compound as a yellow oil. MS (m/e): 222.3 (M+H).
Reaction SMILES: I.[NH2:2][C:3]1[N:4]([CH3:8])[CH2:5][CH2:6][N:7]=1.[OH-].[Na+].[C:11]1([N:17]=[C:18]=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:8][N:4]1[CH2:5][CH2:6][NH:7][C:3]1=[N:2][C:18]([NH:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:19]
Reactant: CN1CCN=C1N
Reactant: S=C=Nc1ccccc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Product: CN1CCNC1=NC(=S)Nc1ccccc1
Yield: 86.1 %

Procedure:
2-Amino-1-methylimidazoline hydroiodide (26.75 g, 0.117 mole) is converted to its free base form by treatment with 50% sodium hydroxide. The base is extracted with methylene chloride and the extract dried over potassium carbonate and filtered. To this solution is added phenylisothiocyanate (15.81 g, 0.117 mole) and the reaction mixture is refluxed for three hours. The hot solution is filtered, concentrated to a small volume in vacuo, ether added, chilled, and the solid filtered off to give 23.6 g (86.1%) of N-(1-methyl-2-imidazolidinylidene)-N'-phenylthiourea; m.p. 205°-208° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]([C:8]1[C:9]([C:29]([F:32])([F:31])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)(=O)[CH3:6].C([BH3-])#N.[Na+]>CO.CC(O)=O>[OH:4][CH2:3][CH2:2][NH:1][CH:5]([C:8]1[C:9]([C:29]([F:31])([F:32])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)[CH3:6]
Reactant: NCCO
Reactant: CC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NCCO)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 100 °C
Yield: 14.9 %

Procedure:
To a solution of 2-aminoethanol (103 mg, 1.689 mmol) in MeOH (1.5 mL), AcOH was added until the pH reached 5. 2-(2-(4-acetyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.121 mmol) was added before the addition of (7.6 mg, 0.121 mmol) of sodium cyanoborohydride. The reaction was heated by microwave irradiation to 100° C. for 20 min. The reaction mixture was filtered before purification by preparative reverse phase HPLC. The product fractions were acidified to pH 4 before applying to a strong cation exchange cartridge (500 mg). The cartridge was washed with DCM/MeOH (1:1) before eluting the product with 2M NH3 in MeOH. The solvent was removed in vacuo to give the title compound (8.3 mg, 0.018 mmol, 15%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][O:19][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[O:30])[CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Product: CCOC(Cc1cccc(CCOC(=O)Nc2ccc(OC)cc2)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(O)(=O)C>ClCCCl>[C:24]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(C)=O)cc3Cl)c2n1
Yield: 82.2 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg) was dissolved in 1,2-dichloroethane (1.5 ml), and acetic anhydride (148 mg) and acetic acid (87 mg) were added at room temperature. The mixture was refluxed under heating for 1 hr. The reaction mixture was concentrated under reduced pressure, and ice water, a saturated aqueous sodium hydrogencarbonate solution were successively added to the residue. The precipitated white crystals were collected by filtration, washed with water, and dried under reduced pressure to give the objective compound (139 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A158) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[O:7])=[CH:18][CH:17]=1
Reactant: Brc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 90 °C

Procedure:
4-Fluorobenzoyl chloride (238 g, 1.5 mol) is added under an atmosphere of nitrogen over a period of 1 hour to a suspension of anhydrous aluminium chloride (224 g, 1.68 mol) and 700 ml bromobenzene while maintaining the temperature below 30° C. After the addition is complete, the solution is heated at 90° C. for 3 hour. The reaction solution is added to 500 g crushed ice. The mixture is allowed to warm to room temperature and the water phase is extracted with dichloromethane (3 times with 200 ml). The organic extracts are combined, washed with water (200 ml), saturated sodium hydrogene carbonate solution (200 ml), water (200 ml), dried over sodium sulphate, filtered, and evaporated to dryness. The residue is crystallized twice from petroleum ether (b.p.: 36-80° C.) to obtain a pale yellow powder. The yield is 240-278 g (57-67%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:20][NH:21][C@H:22]1[CH2:27][NH:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:13]([O:20][N:21]1[C:2](=[O:4])[N:26]2[CH2:27][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 8 h
Yield: 125 %

Procedure:
Triphosgene (21.3 g, 72 mmol) was added in portions to a solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate (50 g, 0.18 mol) and DIPEA (128 mL, 0.72 mol) in DCM (2000 mL) at 0° C. After stiffing at 20° C. overnight, the reaction mixture was washed with H3PO4 (10%), sat. NaHCO3 and saturated NaCl. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (27.4 g, 50%) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C(OCC)C>[C:11]([N:1]1[CH2:3][CH2:2]1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, distilled aziridine solution (500 mL, 0.1 mol) in a round-bottom flask cooling with an ice bath, three equivalents of potassium carbonate was added. After all of the solid dissolved, benzyl chloroformate (1.5 equivalents) in ethyl ether (150 mL) was added over 2 h. The solution was stirred overnight and warmed to room temperature, and the aqueous phase was extracted with methylene chloride (5×30 mL). The organic phases were combined and passed through a flash silica gel pad and concentrated to afford the Cbz-aziridine as colorless thick oil, yield: 7.2 g, 81%.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:22]1([CH2:28][CH2:29]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1CCOCC1.Cl>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:29][CH2:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:3]=1
Reactant: BrCCC1CCCCC1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)n(CCC2CCCCC2)c2nc(Cl)[nH]c12
Temperature: 38.5 °C
Reaction time: 65 h

Procedure:
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.442 mmol) was stirred with sodium carbonate (52 mg, 0.486 mmol) in dry DMF (3 ml) for 30 min. Cyclohexylethyl bromide (93 mg, 0.486 mmol) was added, and the mixture was stirred at 37-40° C. under nitrogen for 65 h, followed by heating at 90° C. for 18 h. After cooling, the solution was degassed by evacuating and introducing nitrogen several times, and tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.066 mmol) and morpholine (0.385 ml, 4.42 mmol) were added and the mixture stirred for 18 h. A further quantity of tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) and morpholine (0.2 ml) were added and stirring continued for a further 1 h. Ethyl acetate and 2M aqueous HCl were added (ca. 10 ml each) and the organic layer separated, washed with brine and evaporated. The residue was dissolved in THF and loaded onto a 5 g aminopropyl SPE cartridge. The cartridge was washed with THF followed by MeOH, and the acidic product eluted with AcOH in MeOH (5% rising to 10%). The product thus obtained was further purified by autoprep HPLC to provide the title compound, 5.5 mg, 3%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:21]3[CH2:23][CH2:22]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.[CH:24]([O:27][C:28](Cl)=[O:29])([CH3:26])[CH3:25]>N1C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH:24]([O:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:21]3[CH2:23][CH2:22]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: COc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CC3)c2c1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C)cc3)n(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of the compound obtained in step E (61 mg, 0.2 mmol) in dry pyridine (2.0 mL) is added isopropylchloroformate (0.3 mL, 1.0 M, 0.3 mmol) in toluene. The mixture is stirred at room temperature overnight and diluted with water (10 mL). The organic layer is extracted with DCM (10 mL) and washed with HCl (2N, 2×3 mL), water (2×4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, [4-(3-cyano-1-cyclopropyl-6-methoxyindol-2-yl)phenyl]carbamic acid isopropyl ester (66 mg, 85%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([CH3:13])[CH:5]=1>C(O)C.[Pd]>[CH3:14][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH3:13])[CH:5]=1)[CH3:1]
Reactant: Cc1cc(CN(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(CN(C)C)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
N,N-Dimethyl-1-(3-methyl-4-nitrophenyl)methanamine (0.80 g, 4.1 mmol) was dissolved in ethanol (5.0 mL) and 10% palladium on carbon (0.18 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 4-[(dimethylamino)methyl]-2-methylaniline (0.65 g, y. 96%).