Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:28])[C@@H:6]([NH2:27])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:12]1)=[O:10])[CH3:3].C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>ClCCl>[CH2:2]([O:4][C:5](=[O:28])[C@@H:6]([NH:27][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:12]1)=[O:10])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CNC(=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of N-[(R)-(1-benzyloxycarbonyl-3-piperidyl)carbonyl]-2(S)-amino-β-alanine ethyl ester hydrochloride (300 mg) in dichloromethane (3 ml) was added triethylamine (222 μl) and benzoyl chloride (93 μl) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted with dichloromethane. The extract was washed with water, saturated aqueous NaHCO3 solution, water and brine, and dried over MgSO4, and evaporated in vacuo. The residue was recrystallized from diethyl ether to give N-[(R)-(1-benzyloxycarbonyl-3-piperidyl)carbonyl]-2(S)-benzoylamino-β-alanine ethyl ester (349 mg).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH3:6][C:7]1[N+:12]2[C:13]3[C:18]([C:19]([CH3:21])([CH3:20])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3.N([CH:29]=[C:30]1[C:35](=[O:36])[N:34]([CH2:37][CH3:38])[C:33](=[S:39])[N:32]([CH2:40][CH3:41])[C:31]1=[O:42])C1C=CC=CC=1.CN(C)C(=N)N(C)C>C(#N)C>[CH2:37]([N:34]1[C:35](=[O:36])[C:30](=[CH:29][CH:6]=[C:7]2[N:12]3[C:13]4[C:18]([C:19]([CH3:21])([CH3:20])[C:11]3=[CH:10][CH:9]=[CH:8]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:31](=[O:42])[N:32]([CH2:40][CH3:41])[C:33]1=[S:39])[CH3:38]
Reactant: Cc1cccc2[n+]1-c1ccccc1C2(C)C
Reactant: CCN1C(=O)C(=CNc2ccccc2)C(=O)N(CC)C1=S
Agent: CN(C)C(=N)N(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CCN1C(=O)C(=CC=C2C=CC=C3N2c2ccccc2C3(C)C)C(=O)N(CC)C1=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6,10,10-Trimethylpyrido[1,2-a]indolium perchlorate (0.62 g.) and 5-anilinomethylene-1,3-diethyl-2-thiobarbituric acid (0.6 g.) are dissolved in acetonitrile. Tetramethylguanidine (0.23 g.) is added and the reaction mixture is stirred at room temperature overnight. The precipitated dye is filtered off and recrystallized from acetonitrile. The λmax of the product in a mixture of pyridine and methyl alcohol is 513 nm.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:46])[C@@H:20]([NH:36][C:37](=[O:45])[C@@H:38]([NH:42][CH:43]=[O:44])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2].[CH3:47][O:48][C@H:49]([CH2:55][CH2:56][CH:57]=[CH2:58])[C@@H:50](C)[C:51](O)=O.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>C(#N)C>[CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:46])[C@@H:20]([NH:36][C:37](=[O:45])[C@@H:38]([NH:42][C:43](=[O:44])[C@H:50]([CH3:51])[C@H:49]([O:48][CH3:47])[CH2:55][CH2:56][CH:57]=[CH2:58])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccnc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC=O)C(C)C)N2)c1
Reactant: C=CCC[C@@H](OC)[C@@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCc2cc(C=C)ccn2)N1)C(C)C
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of crude (S)-1-[(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-((S)-2-formylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 4-vinyl-pyridin-2-ylmethyl ester (0.52 mmol) and (2R,3R)-3-methoxy-2-methylhept-6-enoic acid 10d (90 mg, 0.52 mmol) in acetonitrile (10 mL) was stirred at room temperature. N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (140 mg, 0.73 mmol) and 1-hydroxybenzotriazole hydrate (containing 20% water, 85 mg, 0.52 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic extract was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:3 to neat ethyl acetate to afford the title compound (271 mg, 67%) as a gum. 1H NMR (300 MHz, CDCl3) δ0.17 (s, 6H), 0.86-0.98 (m, 15H), 1.17 (d, J=7.1 Hz, 3H), 1.5-2.2 (m, 11H), 2.45-3.00 (m, 5H), 3.33-3.44 (m, 1H), 3.40 (s, 3H), 3.60 (d, J=10.9 Hz, 1H), 4.27-4.33 (m, 2H), 4.97 (dd, J=10.2, 1.7 Hz, 1H), 5.05 (dd, J=17.2, 1.7 Hz, 1H), 5.28 (d, J=7.3 Hz, 1H), 5.56 (d, J=10.7 Hz, 1H), 5.73-5.87 (m, 2H), 6.03 (d, J=17.6 Hz, 1H), 6.50 (d, J=8.2 Hz, 2H), 6.66-6.82 (m, 4H), 7.04-7.10 (m, 1H), 7.31 (s, 1H), 8.56 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[OH:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[OH:27])=[O:15])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCc2ccccc2)c(Br)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ccccc2)c(Br)c1

Procedure:
In analogy to example 1f, 6-benzyloxy-5-bromo-nicotinic acid was coupled with (1R,2R)-2-amino-cyclohexanol hydrochloride (CAS [5456-63-3]) using TBTU and N,N-diisopropyl ethyl amine in N,N-dimethylacetamide to give 6-benzyloxy-5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-bromobenzyl bromide (5 g, 20 mmol) and N-Boc piperazine (4.47 g, 24 mmol) in DMF (25 mL), K2CO3 (5.52 g, 40 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. After completion of reaction (monitored by TLC), the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude product, V-1-I. This compound was used for next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[C:3]=1[CH3:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[C:3]=1[CH3:11]
Reactant: Cc1c(Br)ccc2[nH]cnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1ncn2C1CCCCO1
Temperature: 80 °C
Yield: 57.2 %

Procedure:
To a solution of 5-bromo-4-methyl-1H-benzo[d]imidazole (1.0 g, 4.74 mmol, CASRN 952511-48-7) and 3,4-dihydro-2H-pyran (2.0 g, 23.70 mmol) in THF (10 mL) was added p-TsOH.H2O (90 mg, 0.47 mmol). The mixture was heated at 80° C. overnight, cooled and the solvent was removed in vacuo. The residue was diluted with DCM (100 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to dryness in vacuo. The crude product was purified by SiO2 chromatography eluting with a petroleum ether/EtOAc gradient (10 to 50% EtOAc) to afford 800 mg (57%) of 5-bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (254) as light yellow solid: MS (ESI) m/z=295.1 [M+1]+.
Reaction SMILES: C([O:4][C:5]1[CH:34]=[CH:33][C:8]([C:9]([O:11][C:12]2[CH:32]=[CH:31][C:15]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C>O1CCCC1.CO.[OH-].[Li+].C(OCC)(=O)C>[OH:4][C:5]1[CH:34]=[CH:33][C:8]([C:9]([O:11][C:12]2[CH:32]=[CH:31][C:15]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(OC(=O)c2ccc(OC(C)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)c1ccc(OC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In pyridine was dissolved 5 g of dodecyl p-hydroxybenzoate, and a solution of 5 g of p-acetoxybenzoic acid chloride in chloroform was added dropwise to the solution and the mixture was stirred at room temperature for 4 hours. Water was added to the thus-obtained solution, the mixture was extracted with chloroform, and the extract was washed with a 0.5N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of sodium chloride in succession, dehydrated on anhydrous magnesium sulfate and concentrated. The concentrate was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 3.18 g dodecyl 4-(4-acetoxybenzoyloxy)benzoate. The obtained ester was dissolved in a mixed solvent of tetrahydrofuran and methanol at a volume ratio of 10/1, 7 ml of a 1N aqueous solution of lithium hydroxide was added to the solution, and the obtained mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. Then, the liquid was dried on anhydrous magnesium sulfate and concentrated, and the concentrate was recrystallized from a liquid mixture of n-hexane and ethyl acetate to obtain 2.22 g of dodecyl 4-(4-hydroxybenzoyloxy)benzoate.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CCO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:17]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:20]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:21][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC#N
Reactant: C1COCCN1
Reactant: O=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Solvent: CCO
Product: CCOC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 1.35 g of 1-benzyl-2-chloroindole-3-carbaldehyde in 30 ml abs. EtOH was added 1.5 ml of ethyl cyanoacetate and 3.5 ml of morpholine, and the mixture was stirred at room temperature for 2 days. The mixture was then heated to reflux for 5 hours, cooled to room temperature and filtered to give (2b). Yield 1.6 g of (2b), m.p. 151°-152° C.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([N:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]1=[O:17])[CH2:7][CH2:8][CH3:9]>CN(C=O)C>[Br:3][C:13]1[CH:14]=[CH:15][N:10]([CH2:6][CH2:7][CH2:8][CH3:9])[C:11](=[O:17])[CH:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCCCn1ccc(O)cc1=O
Solvent: CN(C)C=O
Product: CCCCn1ccc(Br)cc1=O
Temperature: 110 °C
Yield: 92 %

Procedure:
Phosphorus oxybromide (5.4 g, 18.9 mmol) was added to a solution of intermediate D5 (1.44 g, 8.6 mmol) in DMF (140 ml) and the mixture was heated at 110° C. for 1 hour. After cooling in an ice bath, the solution was partitioned between water and EtOAc. After three extractions with EtOAc, the combined organic fractions were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D6 (1.82 g, 93%).
Reaction SMILES: CC1[C:7]([S:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:5]=CC=1[N+]([O-])=O.N(OCCCC)=O.[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].Cl.[CH3:29][N:30](C)C=O>>[OH:25][C:23]1[CH:24]=[CH:5][CH:6]=[C:7]([S:8][CH2:9][CH2:10][CH3:11])[C:22]=1[C:29]#[N:30]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[O-]
Reactant: CCCSc1cccc([N+](=O)[O-])c1C
Agent: CCCCON=O
Agent: Cl
Agent: [K+]
Product: CCCSc1cccc(O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30 g (0.14 mol) of 2-methyl-1-nitro-3-propylsulfanylbenzene, 18.9 g (0.18 mol) of n-butyl nitrite were dissolved in 120 ml of dimethylformamide and cooled to (−20)° C. Then a solution of potassium t-butoxide in 120 ml of DMF is added dropwise over the course of 25 min. After the reaction mixture had been stirred at (−25)° C. for one hour, it was stirred into a mixture of ice and 150 ml of concentrated hydrochloric acid. The mixture was warmed to room temperature, and the resulting solid was filtered off with suction and washed several times with water and once with cyclohexane. The solid was purified by stirring with a little amount of methylene chloride. Yield: 12.4 g (46% of theory) of the desired product. 1H NMR (in CDCl3): δ=1.05 ppm (t, 3H, aliph. Me), 1.7 ppm (m, 2H, aliph. CH2), 3.0 ppm (t, 2H, S CH2), 6.8 ppm (d, 1H, arom. H), 6.9 ppm (d, 1H, arom. H), 7.35 ppm (m, 1H, arom. H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:15][O:1][C:2]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of Methyl 2-hydroxy-5-acetylbenzoate (12 g, 61.7 mmol) in DMF (200 ml) was added cesium carbonate (24.15 g, 74.1 mmol) and MeI (9.64 g, 68 mmol). The reaction mixture was stirred for 16 hours at 0° C. and then diluted with ethyl acetate, washed with aq Na2S2O5, brine, dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (ethyl acetate:hexane 1:2) to provide the title compound as an off white solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[Br:16][C:17]1[C:18](F)=[C:19]2[C:25]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1>CCCCO>[Br:16][C:17]1[C:18]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]2)=[C:19]2[C:25]([NH:26][C:27]([CH:29]3[CH2:30][CH2:31]3)=[O:28])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Yield: 9 %

Procedure:
(S)-tert-Butyl azepan-3-ylcarbamate (431 mg, 2.01 mmol; commercially available or Moon, Sung-Hwan, et al. “An Efficient Conversion of Chiral α-Amino Acids to Enantiomerically Pure 3-Amino Cyclic Amines.” Synthetic Communications. Vol. 28, No. 21 (1998): pp. 3919-3926) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (200 mg, 0.671 mmol) in n-BuOH (3 mL), and the reaction was heated for 18 hours to 160° C. in a sealed tube. After concentration, the residue was purified by chromatography (SP4, 25M, water/ACN 100/0->0/100, 40CV) to yield (5)-tert-butyl 1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)azepan-3-ylcarbamate (30 mg, 9% yield) as a solid.
Reaction SMILES: [OH:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5](=[O:13])[C:4]2[S:14][CH2:15][CH2:16][S:17][C:3]1=2.[H-].[Na+].Cl[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22]>O1CCCC1>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([C:21]([O:13][CH:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:2](=[O:1])[C:3]3[S:17][CH2:16][CH2:15][S:14][C:4]2=3)=[O:22])[CH2:24][CH2:25]1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccccn1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccccn2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
A solution of 5-hydroxy-7-oxo-6-(pyrid-2-yl)-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (6.0 g.) in anhydrous tetrahydrofuran (60 cc.) is treated for 17 minutes at about 5°-10°C, with sodium hydride (0.64 g.), and a solution of 1-chlorocarbonyl-4-methylpiperazine (11.0 g.) in anhydrous tetrahydrofuran (80 cc.) is then added, at 5°C. The reaction mixture is stirred for 4 hours at 5°C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is dissolved in diethyl ether (300 cc.). The diethyl ether solution is washed three times with N sodium hydroxide solution (total 450 cc.) and then three times with distilled water (total 300 cc.), treated with vegetable charcoal (0.1 g.), dried over anhydrous potassium carbonate, filtered and evaporated. The residue (7.6 g.; m.p. 145°C.) is dissolved in boiling ethanol (20 cc.). After being cooled for two hours at 2°C, the crystals which have appeared are filtered off, washed twice with ice-cold ethanol (total 12 cc.) and dried under reduced pressure (20 mm.Hg). 5-(4-Methylpiperazin-1-yl)carbonyloxy-7-oxo-6-(pyrid-2-yl)-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (3.9 g.), melting at 150°C, is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6](=[O:13])[CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-:16].[Na+].[I-].[CH3:19][S+](C)(C)=O.CCCCCCCCCCCCCC[N+](C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:13])([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH2:19][OH:16])=[CH:14][CH:15]=1
Reactant: [OH-]
Reactant: C[S+](C)(C)=O
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1
Agent: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCC(O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of p-chlorophenacyl-1H-1,2,4-triazole (10.3 g, 40 mmol) in 65 mL of toluene and 65 mL of 20% w/w NaOH at 60° C., add trimethylsulfoxonium iodide (8.84 g, 40 mmol) and cetrimide (0.39 g). Continue to stir the so-formed mixture at 60° C. for 1.5 h. Separate the toluene layer, add 20 mL of H2O to the aqueous layer and extract with two 100 mL portions of ethyl acetate (EtOAc). Combine both the toluene and EtOAc layers, dry oyer MgSO4, filter, and evaporate off the solvents. Add 100 mL of acetone, 6 mL of concentrated H2SO4, 20 mL of H2O, and reflux for 3 hr. Eyaporate the acetone at 45° C. under reduced pressure. Add 20 mL of sat. sodium bicarbonate and extract with two 100 mL portions of EtOAc. Wash the combined EtOAc layers with sat. brine, dry oyer MgSO 4, and evaporate the EtOAc to obtain a syrup. Chromatograph the syrup on 300 g of silica gel using 5% MeOH/CH2Cl2 as the eluent under flash chromatography conditions to obtain 3.63 g of the title product.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(N(CC)CC)C.C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:27](=[O:28])[O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)Oc5ccccc5)c4c(c23)C1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3), in 5 mL of dichloromethane, 75 μL of phenyl chloroformate and 85 μL (2 molar equivalents) of triethylamine were added. The mixture was magnetically stirred at 20° C. during 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 94 mg (yield: 69%) of the desired product (formula below) as a red powder.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[CH:6][N:7]=1.[Cl:13]C1N=CC(OC)=C(Cl)N=1.C([Mg]Br)=C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[C:6]([Cl:13])[N:7]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C=CC1(Cl)NC(Cl)=NC=C1OC
Agent: C=C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. To a solution of 2,6-dicholoro-5-methoxy pyrimidine (100 g, 0.55 mol) in dry tetrahydrofuran (THF) solvent was added, dropwise, 1M vinyl magnesium bromide in THF solvent (124 g, 0.94 mol) for one hour at room temperature. The mixture was then stirred for 4 h at room temperature. Excess Grignard reagent was quenched by addition of acetone (200 mL) while the temperature of the mixture was maintained at a temperature below 20° C. Thereafter, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (151 g, 0.67 mol) was added at once and stirred overnight. A yellow solid precipitated out. The solid was filtered and washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure and the resulting crude compound was diluted with ethyl acetate (2 L). The resulting undissolved, dark, semi-solid was separated by filtration using ethyl acetate. It was further concentrated under reduced pressure to provide a crude compound, which was purified by column chromatography. The compound was eluted with 5% to 10% ethyl acetate in hexane mixture to provide the title compound (70 g, 60% yield): mp 60-61° C.; 1H NMR (CDCl3) δ 3.99 (s, 3H), 5.85 (d, 1H). 6.75 (d, 1H), 6.95 (dd, 1H).