Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:5]([CH2:8][CH:9]([CH2:15][S:16]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:18])=[O:17])[C:10]([O:12]CC)=[O:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]>Cl>[CH2:1]([S:5]([CH2:8][CH:9]([CH2:15][S:16]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:18])=[O:17])[C:10]([OH:12])=[O:11])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)CC(CS(=O)(=O)CCCC)C(=O)OCC
Agent: Cl
Product: CCCCS(=O)(=O)CC(CS(=O)(=O)CCCC)C(=O)O

Procedure:
A mixture of 2-[(n-butylsulfonyl)methyl]-3-(n-butylsulfonyl)-propanoic acid, ethyl ester (1.0 g, 3.0 mmol) in 6N hydrochloric acid (20 mL) is refluxed overnight. The mixture is transferred to distilled water and extracted with ethyl acetate. The combined organic extracts are concentrated in vacuo to yield the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.[CH:25]([Sn](CCCC)(CCCC)CCCC)=[CH2:26]>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>[CH:25]([C:3]1[CH:2]=[C:1]2[CH:24]=[C:22]3[N:23]=[C:19]([CH:18]=[C:16]4[NH:17][C:13](=[CH:12][C:10]5[CH:9]=[CH:8][C:7](=[CH:6][C:4]=1[NH:5]2)[N:11]=5)[CH:14]=[CH:15]4)[CH:20]=[CH:21]3)=[CH2:26]
Reactant: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1cc2cc3nc(cc4ccc(cc5nc(cc1[nH]2)C=C5)[nH]4)C=C3
Yield: 77 %

Procedure:
One porphyrin that was not available via this route was the vinyl-porphyrin Zn10, owing to the lack of access to 5-vinyldipyrromethane (vide supra). The synthesis of Zn10 was achieved following the route outlined in Scheme 6. Diacyldipyrromethane 3248 was reduced with NaBH4 and the resulting 32-diol was condensed with dipyrromethane (36)41,49 in CH2Cl2 containing Yb(OTf)3 at room temperature. Subsequent oxidation with DDQ afforded free base porphyrin 37 in 33% yield. Porphyrin 37 was iodinated at the meso-position using I2 and (CF3CO2)2IC6H5 in CHCl3/pyridine50 to furnish free base porphyrin 8 in 82% yield. Zinc insertion afforded Zn8 in 75% yield. Porphyrin Zn8 was then subjected to a Stille cross-coupling reaction51 with (vinyl)tributyltin and Pd(PPh3)4 to afford vinylporphyrin Zn10 in 77% yield.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClC(Cl)C.O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH:19]([C:20]([CH:19]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Reaction time: 1 h
Yield: 82 %

Procedure:
120 kg (1.09 kmole) of resorcinol were suspended in 660 l of dichlorethane and 150 kg (1.12 kmole) of anhydrous aluminum chloride were added to the suspension while the temperature raised from 15° C. to 25° C. The complex obtained dissolved in the reaction medium. 171 kg (1.10 kmole) of phenyl-acetyl chloride were added over a period of one hour while the temperature raised to 35°-40° C. The mixture was stirred for one hour thereafter it was admixed with diluted hydrogen chloride (the mixture of 300 l of hydrogen chloride and 600 l of water), and it was treated as described in the preceding Examples. The solvent was removed by distillation, the residue was recrytallized from toluene, the product obtained was centrifuged and dried at 45°-50° C. 205-210 kg of 2,4-dihydroxy-phenyl-benzyl-ketone were obtained, yield 82-84.5%. Calculated amount: 248.5 kg. The physical data are identical with the data given in Example 1.
Reaction SMILES: [O:1]1[C:3]2([CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]2)[CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([CH2:2][C:3]2([OH:1])[CH2:4][NH:5][CH2:6]2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CC2(CO2)C1
Solvent: C1CCOC1
Product: OC1(CN2CCOCC2)CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
1,1-Dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (51 mg, 0.28 mmol) was taken into THF (1 mL) followed by addition of morpholine (123 μL, 1.4 mmol) and the mixture was stirred for one hour at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed once with water then brine and the organic layer dried over anhydrous sodium sulfate. Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents. The combined pure fractions were concentrated and the residue treated with neat TFA (1 mL) for 5 minutes then concentrated. The residue was taken into methanol (2 mL) and basified to pH>10 by addition of Biorad AG-1× hydroxide form resin. Filtration and concentration afforded 3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H), 3.49 (d, 2H), 2.66 (s, 2H), 2.57-2.55 (m, 4H).
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:20][C:19]([S:36][CH3:37])=[N:18][C:17]=2[CH2:16]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCCl>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:21]2[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]=3[N:18]=[C:19]([S:36][CH3:37])[N:20]=2)=[CH:27][CH:28]=1
Reactant: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
1-Chloroethyl chloroformate (572 mg, 4 mmol) was added dropwise to a mixture of 7-benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (860 mg, 2 mmol) and diisopropylethyl amine (516 mg, 4 mmol) in 1,2-dichloroethane (5 mL, anhydrous) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hr. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at room temperature overnight. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and was washed with saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. Solvent was removed in vacuo and residue was triturated with diethyl ether to yield the product as a beige solid (454 mg).
Reaction SMILES: O[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:22])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[Cl:22][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1ncnc(O)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COCc1ncnc(Cl)c1OC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
85.0 g (0.5 mol) of 4-hydroxy-5-methoxy-6-methoxymethylpyrimidine were suspended in 600 ml of dichloroethane, 50.5 g of triethylamine were added, and 260 g (1.7 mol) of phosphorus oxychloride were then added without cooling. The mixture was stirred for 3 hours at 80° C., poured into ice-water and neutralized by adding solid sodium carbonate, the organic phase was separated, and the water phase was extracted several times by stirring with methylene chloride. The combined organic phases were dried and concentrated. The residue was distilled under a water pump vacuum. 66.1 g (70% of theory) of a yellow oil were obtained. B.p. 93°-96° C./0.1mm.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C:13]([CH2:16][CH3:17])=[CH:14][O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[CH2:16]([CH:13]1[C:12]2[CH:18]=[CH:19][C:9]([OH:8])=[CH:10][C:11]=2[O:15][CH2:14]1)[CH3:17]
Reactant: CCc1coc2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
A mixture of 5.0 g of 2',4'-dihydroxypropiophenone, 5.4 g of benzyl bromide, 6.2 g of potassium carbonate and 50 ml of acetone was refluxed for 7 hours. After cooling, the solid was separated by filtration. The filtrate was concentrated, and the residue was separated by column chromatography to give 4.7 g of 4'-benzyloxy-2'-hydroxypropiophenone as a white solid (yield 61%, melting point 111.5°-112.5° C.). Then, a mixture of 4.5 g of this solid, 3.5 g of ethyl bromoacetate, 6.1 g of potassium carbonate and 45 ml of acetone was refluxed for 7.5 hours. After cooling, the solid was separated by filtration. The filtrate was concentrated, and the residue was purified by column chromatography to give 5.8 g of ethyl 3-benzyloxy-6-propionylphenoxyacetate as white crystals (yield 97%, melting point 81.5° to 82.0° C.). This ester (5.5 g) was dissolved in a solution composed of 1.3 g of potassium hydroxide and 55 ml of methanol, and the solution was stirred at room temperature for 2 hours to hydrolyze the ester. The hydrolysis product was worked up in a customary manner to give 3.9 g (yield 77%) of 3-benzyloxy-6-propionylphenoxyacetic acid as a pale yellowish orange solid. Then, 9.3 g of sodium acetate and 39 ml of acetic anhydride were added to this solid, and the mixture was heated at 155° C. for 30 minutes. The solvent was evaporated, and the residue was purified by column chromatography to give 2.8 g (yield 95%, melting point 69.5°-70.5° C.) of 6-benzyloxy-3-ethylbenzofuran as a white solid. Palladium (5%)-carbon (0.27 g) and 27 ml of acetic acid were added to 2.7 g of the resulting benzofuran, and the mixture was stirred at room temperature for 3 hours in an atmosphere of nitrogen. The catalyst was separated by filtration, and the filtrate was concentrated and then purified by column chromatography to give 1.7 g (yield 90%) of the desired product as a pale orange liquid.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[OH2:6]>>[O:6]=[CH:2][C@@H:1]([C@H:2]([C@@H:1]([C@@H:2]([CH2:1][OH:4])[OH:6])[OH:4])[OH:6])[OH:4]
Reactant: O
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h

Procedure:
The substrate used for the assay is a maltodextrin (Maltrin-100 available from the Grain Processing Company, Muscatine, Iowa). 0.1 ml of the enzyme solution was mixed with 0.6 ml of a 5% maltodextrin solution, 0.1 ml of 500 mM sodium acetate solution (pH 5) and water is added to make a total volume of 1 ml. After the mixture is incubated at 60° C. for 30 minutes, the reaction is terminated by immersing the mixture in a boiling water bath for 10 to 20 minutes. Glucose is then determined by the glucose-oxidase method using a glucose analyzer (Yellow Springs Instrument Company, Yellow Springs, Ohio). One glucoamylase unit is defined as the amount of enzyme required to produce 1 gram of glucose in 1 hour under the assay conditions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]2[NH:9][CH:12]=[CH:13][C:3]=12
Reactant: C=C[Mg]Br
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1ncc(Br)c2cc[nH]c12
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
5-Bromo-2-methyl-3-nitropyridine (217 mg, 1 mmol) was dissolved in THF (10 mL) and the solution was cooled to −50° C. under argon. Vinylmagnesium bromide (3 mL, 1M in THF) was added immediately in one portion, resulting in a bright orange solution. The orange solution was stirred at −40° C. for 30 min and the reaction was quenched by the addition of NH4Cl (10 mL of saturated. aqueous solution). The mixture was diluted with water and extracted with EtOAc (2×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude material was purified by chromatography on silica (Si—PPC) using EtOAc in cyclohexane (20-80%) as eluent to give the product as a pale yellow crystalline solid (63 mg, 30%). 1H NMR (CDCl3) 8.23 (s, 1H), 7.41-7,45 (m, 1H), 6.62-6.65 (m, 1H), 2.73 (s, 3H)
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[CH:4]=[CH:5][C:6]2[C:15]=1[S:14](=[O:17])(=[O:16])[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[N:7]=2.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[OH:18][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14](=[O:17])(=[O:16])[C:15]=2[C:2]=1[OH:1])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1C=CC2=Nc3ccccc3S(=O)(=O)C2=C1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=S1(=O)c2ccccc2Nc2ccc(O)c(O)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 4-hydroxy-3H-phenothiazine-3-one-5,5-dioxide (0.8 g) in a mixture of water (20 ml) and ethyl acetate (20 ml) there was added sodium dithionite (2 g) and the resulting mixture was stirred at room temperature for 20 minutes. The insoluble solid was then filtered, washed with water and dried to afford the title compound, m.p. (dec.) 261° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10].[CH:18]([C@@H:20]1[C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C@H:31]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[C:32]([O:34]CC2C=CC(OC)=CC=2)=[O:33])[CH2:21]1)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C@@H:20]2[C@@H:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][N:22]([C@H:31]([CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:32]([OH:34])=[O:33])[CH2:21]2)[CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1ccccc1OC(=O)NC1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Product: Cc1ccccc1OC(=O)NC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
The title compound was prepared from 4-((2-methylphenyl)oxycarbonylamino)-piperidine and 2-(R)-(3-(R)-formyl-4-(S)phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-methoxybenzyl ester (Aldehyde 5) according to the method described in Example 1, Step C. ESI-MS: 534 (M+H); HPLC A: 2.29 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>[OH-].[Na+]>[S:22]([NH:1][CH2:2][C:3]1([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)NCC2(N3CCN(C)CC3)CCCCC2)cc1
Yield: 46.3 %

Procedure:
1-(1-Aminomethylcyclohexyl)-4-methylpiperazine (0.5 g) was added to 10% sodium hydroxide solution (10 ml) and p-toluene sulphonyl chloride (0.5 g), and the mixture shaken vigorously. The solid was filtered, washed with water and recrystallised from 95% ethanol to give colourless needles (0.4 g, 46.2%) of 1-(1-tosylaminomethylcyclohexyl)-4-methyl piperazine, m.p. 128°-130°.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[F:15][C:16]([F:32])([O:23][C:24]1[CH:30]=[CH:29][C:27]([CH3:31])([NH2:28])[CH2:26][CH:25]=1)[CH:17]([F:22])[C:18]([F:21])([F:20])[F:19]>C(O)(=O)C>[F:15][C:16]([F:32])([O:23][C:24]1[CH:25]=[CH:26][C:27]([N:28]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:9])([CH3:31])[CH2:29][CH:30]=1)[CH:17]([F:22])[C:18]([F:19])([F:20])[F:21]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC1(N)C=CC(OC(F)(F)C(F)C(F)(F)F)=CC1
Solvent: CC(=O)O
Product: CC1(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C=CC(OC(F)(F)C(F)C(F)(F)F)=CC1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
In 30 ml of acetic acid were dissolved 1.93 g of 3-nitrophthalic anhydride and 2.73 g of 4-(1,1,2,3,3,3-hexafluoropropoxy)-1-methylaniline. A reaction was carried out for 3 hours with heating under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was washed with a mixture of ether and hexane, whereby 4.4 g of the objective compound was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]1[CH2:24][CH2:23][CH:22]([CH:30]=O)[CH2:21][C:20]2=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]1[CH2:24][CH2:23][CH:22]([CH2:30][NH:1][CH:2]3[CH2:14][O:13][C:12]4[CH:11]=[CH:10][C:9]5[CH2:8][NH:7][C:6](=[O:15])[C:5]=5[C:4]=4[CH2:3]3)[CH2:21][C:20]2=1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Reactant: O=CC1CCc2[nH]c3ccc(F)cc3c2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCc2ccc3c(c21)CC(NCC1CCc2[nH]c4ccc(F)cc4c2C1)CO3
Reaction time: 0.67 h

Procedure:
To a mixture of (1) (60 mg, 0.294 mmol), 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carbaldehyde ((28), 64 mg, 0.294 mmol) in acetic acid (38 mg, 0.588 mmol) and methanol (3 ml) was added NaBH3CN (37 mg, 0.588 mmol) in portions. The resulting mixture was stirred for 40 min. The solvent was removed in vacuo and the residue was dissolved in methylene chloride. The organic solution was washed with 1N NaOH and saturated NaCl before being dried over with Na2SO4. The concentration of organic solution in vacuo gave crude (27), which was purified on silica gel eluting with 80% EtOAc/Hexane to give a white solid (71 mg, 60%). MS (ES) m/z 406.2
Reaction SMILES: [Na].[NH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH2:14].CO[C:17](=[O:35])[C@H:18]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[NH:19][CH2:20][C:21]([O:23]C)=O>CO>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH:18]2[NH:19][CH2:20][C:21](=[O:23])[NH:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:17]2=[O:35])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: NCCNCCNCCNCCN
Reactant: COC(=O)CN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Agent: [Na]
Solvent: CO
Product: O=C1CNC(Cc2ccc([N+](=O)[O-])cc2)C(=O)NCCNCCNCCNCCN1
Yield: 50 %

Procedure:
Sodium (20 mmol) was dissolved in dry methanol (100 ml) at room temperature under nitrogen atmosphere and to this solution was added tetraethylenepentamine (18 mmol) and N-((Methoxycarbonyl)methyl)-4-Nitrophenylaianine methyl ester (3) (18 mmol). This solution was refluxed for 72 hours after which the solvent was removed and the residue was purified on silica gel chromatography with chloroformelmethanol/NH3 (aq) (75:20:5), affording a yellow powder. The yield was 50%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:35][CH3:36]>CN(C=O)C.C(OCC)C>[CH2:25]([O:24][C:18]1[CH:19]=[CH:20][C:21]([Br:23])=[CH:22][C:17]=1[CH2:16][CH2:15][N:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:13][N:12]=1)[CH2:35][CH3:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)c1ccc(NCCc2cc(Br)ccc2OCc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(CCc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cn1
Reaction time: 0.25 h

Procedure:
A mixture of tert-butyl2-[N-(2-benzyloxy-5-bromophenethyl)-amino]-5-pyridinecarboxylate (850 mg), and sodium hydride (101 mg, 50% dispersion in oil) in DMF (20 ml) was stirred for 15 minutes then iodoethane (150 ml) was added and the mixture stirred for 2 hours. The mixture was diluted with diethyl ether (50 ml) washed with water, dried (MgSO4), filtered through silica gel, evaporated and the residue re-dissolved in dichloromethane and evaporated to give tert-butyl 2-[N-(2-benzyloxy-5-bromophenethyl)-N-ethylamino]-5-pyridine carboxylate (800 mg).
Reaction SMILES: Br[CH:2]([C:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH:2]([C:4]3[N:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH3:3])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Reactant: CC(Br)c1ncc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(c1ncc2ccccc2n1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 2-(1-Bromo-ethyl)-quinazoline (43 mg, 0.18 mmol) and 1-(4-Bromo-benzenesulfonyl)-piperazine (67 mg, 0.22 mmol), potassium iodide (30 g, 0.18 mmol) and potassium carbonate (37 mg, 0.27 mmol) in acetonitrile (1 mL) was heated at 65° C. for 1 day. The reaction mixture was then concentrated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium thiosulphate solution, saturated sodium bicarbonate solution and then with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was dissolved in DMSO and purified by HPLC. 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.06 (m, 3H), 7.80 (t, J=7.9 Hz, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 4.86 (q, J=7.0 Hz, 1H), 3.65 (m, 2H), 3.43 (m, 6H), 1.88 (d, J=7.0 Hz, 3H) HPLC ret. time 2.45 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 461.1 (M+1)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]2[CH2:28][CH2:27]2)[N:5]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[Cl:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([F:37])=[C:34]([CH:36]=1)[NH2:35].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:35][C:34]1[C:33]([F:37])=[C:32]([C:2]2[N:3]=[C:4]([CH:26]3[CH2:28][CH2:27]3)[N:5]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=2)[CH:31]=[C:30]([Cl:29])[CH:36]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(NCCC#N)n1
Reactant: CC1(C)OB(c2cc(Cl)cc(N)c2F)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(-c2cc(Cl)cc(N)c2F)c1-c1ccnc(NCCC#N)n1
Temperature: 25 °C

Procedure:
Two separate reaction vials were each charged with 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (I-1c, ˜200 mg, 0.43 mmol), a solution of 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.2 M in dioxane, 8 mL, 1.6 mmol), DME (8 mL) and aqueous 2.0 M Na2CO3 solution (2.3 mL, 4.6 mmol). The resulting mixture was sparged with Argon and Pd(PPh3)4 was added. The reaction vials were sealed and irradiated at 120° C. for 20 minutes in a microwave reactor. LCMS indicated near complete conversion. Additional 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.2 M in dioxane, 8 mL, 1.6 mmol) was added and the reaction was irradiated at 120° C. for 7 minutes. The reactions were allowed to cool to room temperature which partitioned upon standing. The layers were separated and the organic portions of the two reactions were combined and concentrated. The resulting residue was partitioned between EtOAc (200 mL) and water (20 mL). The layers were separated and the organic portion was washed with aqueous 0.1 N HCl solution (40 mL), brine, dried (Na2SO4), and concentrated to give 3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile as a crude residue which was carried forward without further purification: LCMS (m/z) 528.2 (MH+), tR=0.90 minute.