Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]([C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1CO)[CH3:26]>C1COCC1>[CH3:26][O:25][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH2:1][Br:5]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CBr)c1
Reaction time: 2 h

Procedure:
Carbon tetrabromide (0.47 g, 1.25 mmol) and triphenylphosphine (0.47 g, 1.25 mmol) were added to a solution of 2,5-dimethoxylbenzylalcohol (0.2 g, 1.19 mmol) in THF (10 ml) at room temperature. The mixture was stirred for two hours to form a precipitate which the preciptate was filtered off. The filtrate was evaporated and the crude product was chromatographed (ethyl acetate and hexane 7:3). The desired compound was isolated as a white solid (0.25 g, 93%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH2:21])[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH:33]([S:36](Cl)(=[O:38])=[O:37])([CH3:35])[CH3:34]>ClCCl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH:21][S:36]([CH:33]([CH3:35])[CH3:34])(=[O:38])=[O:37])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.7 %

Procedure:
0.08 g (0.239 mmol) of (3-((3-(trifluoromethyl)phenyl) ethynyl) imidazo[1,2-a]pyridin-2-yl) methanamine (prepared according to steps 1 to 4 of Example 11) were solubilised in 2 ml of dichloromethane with magnetic stirring, 0.208 ml (1.193 mmol) of diisopropylethylamine and 0.083 ml (0.716 mmol) of isopropylsulfonyl chloride were added. The mixture was stirred at r.t. for 16 h. A supplement of 0.083 ml (0.716 mmol) of isopropylsulfonyl chloride was added and the mixture was stirred at r.t. for 1 h before being concentrated in vacuo. The crude residue was directly purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol 95/5, v/v). 0.048 g (yield=22%) of N-((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl)propane-2-sulfonamide were obtained as a white solid. LC-MS: m/z=422 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.75 (d, J=6.8 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.85-7.61 (m, 4H), 7.53-7.38 (m, 1H), 7.15 (t, J=6.8 Hz, 1H), 4.44 (d, J=5.9 Hz, 2H), 3.25 (dd, J=13.6, 6.8 Hz, 1H), 1.21 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Br-].[C:2]([CH2:5][NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1)(O)=O.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=C.C(N(CC)CC)C>C1(C)C=CC=CC=1.O=[Mn]=O>[C:13]1([C:12]([O:16][CH3:17])=[O:15])[CH:2]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)C[NH+]1C=CC=CC1
Reactant: C=CC(=O)OC
Agent: O=[Mn]=O
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccn2ccccc12
Temperature: 90 °C

Procedure:
To a suspension of 6.55 g of the pyridinium salt obtained in Step A (30 mmol) in 240 mL of toluene there are added in succession 16.7 mL of methyl acrylate (150 mmol), 4.2 mL of triethylamine (30 mmol) and then, in portions, 20.9 g of MnO2 (240 mmol). The whole is subsequently heated at 90° C. for 3 hours. After cooling, the reaction mixture is filtered over a Celite cake and concentrated to dryness. The title product is then isolated by purification on silica gel (heptane/AcOEt gradient: 0-10%) in the form of an oil, which crystallises when cold.
Reaction SMILES: C(N([P:6](N(CC)CC)[C:7]1[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[CH:9][CH:8]=1)CC)C.[CH:25]1[CH:30]=[C:29]2[CH:31]=[CH:32][C:33]([OH:46])=[C:34]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][C:36]=3[OH:45])[C:28]2=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH:38]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=2[C:35]2[C:34]3[C:33]([O:46][P:6]([C:7]4[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:10]=[CH:9][CH:8]=4)[O:45][C:36]=2[CH:37]=1)=[CH:32][CH:31]=[C:29]1[C:28]=3[CH:27]=[CH:26][CH:25]=[CH:30]1
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: CCN(CC)P(c1cccc(NC(=O)C(C)(C)C)n1)N(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(-p2oc3ccc4ccccc4c3c3c(ccc4ccccc43)o2)n1

Procedure:
N-(6-(bis(diethylamino)phosphino)pyridin-2-yl)pivalamide (0.292 g, 0.60 mmol, 1 eq) was dissolved in toluene (12 ml). (S)-BINOL (0.172 g, 0.60 mmol, 1 eq) was subsequently added and the reaction mixture was refluxed for 3 hours. The solvent was removed under reduced pressure. The title compound could be obtained in the form of a white solid (0.276 g, 0.56 mmol, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccn2)cc1[N+](=O)[O-]

Procedure:
4-methoxy-3-nitrobenzoyl chloride (1.08 g, 0.005 mol), 2-aminopyridine (0.94 g, 0.01 mol) and DIPEA (1.8 mL, 0.01 mol) were allowed to stir in DCM (10 mL) for 48 h to form 4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide. Intermediate was purified via silica column chromatography using 0 to 100% EtOAc in hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:7][CH2:6]2.[C:18]([S:21][CH2:22][CH:23]([CH3:27])[C:24](Cl)=[O:25])(=[O:20])[CH3:19].O>CC(N(C)C)=O>[C:18]([S:21][CH2:22][CH:23]([CH3:27])[C:24]([N:13]([CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[CH2:14][C:15]([OH:17])=[O:16])=[O:25])(=[O:20])[CH3:19]
Reactant: COc1ccc2c(c1)CCCC2NCC(=O)O
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2c(c1)CCCC2N(CC(=O)O)C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
N-(6-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)glycine (3.0 g) is suspended in 30 ml of dimethylacetamide, then 3.3 g of 3-acetylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and thereafter stirring is continued at room temperature for 2 hours. The reaction mixture is poured into 200 ml of water, and extracted with 200 ml of ethyl acetate. The extract is washed with 20 ml of 10% hydrochloric acid and with water, and dried over anhydrous sodium sulfate. Ethyl acetate is distilled off under reduced pressure, 10 ml of ethyl ether is added to the residue, and the mixture is allowed to stand at room temperature. Collection of the resulting crystalline precipitate by filtration gives 1.9 g of N-(3-acetylthio-2-methylpropionyl)-N-(6-methoxy-1,2,3,4-tetrahydro-1-naphthyl)glycine as colorless needles. Melting point: 158°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[N:27][C:28]#[N:29])SC)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].O.[NH2:36][NH2:37]>C(O)C>[NH2:29][C:28]1[N:27]=[C:24]([NH:23][CH2:22][CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:37][N:36]=1
Reactant: CCOC(=O)C1=C(COCCNC(=NC#N)SC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(COCCNc2nc(N)n[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
N-{2-[(4{-2-Chlorophenyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl)methoxy]ethyl}-N'-cyano-S-methyl-isothiourea (0.4 g) and hydrazine hydrate (0.15 ml) were dissolved in ethanol (20 ml) and heated under reflux for 3 hours. The solvent was then evaporated and toluene (10 ml) was added to the residue, and again the solution was evaporated to dryness. The residue was chromatographed on Merck "Kieselgel 60H" (Trade Mark), eluting with 2% methanol in methylene chloride, to give a beige solid. The solid was recrystallized from ethyl acetate plus a trace of ether to give the title compound, yield 0.1 g, m.p. 137°-138°.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH2:25])[CH3:24])=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH:25][C:6](=[O:8])[CH:5]=[CH:4][C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[F:1])[CH3:24])=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1
Reactant: CC(N)c1ccc2c(c1)NCCO2
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)NCCO2
Reaction time: 72 h

Procedure:
A mixture of 2-fluorocinnamic acid (0.5 mmol), (±)-1-(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethylamine, Preparation 13 (28.5 mg, 0.16 mmol), EDC hydrochloride (192 mg, 1 mmol), DMAP (61 mg, 0.5 mmol), and triethylamine (202 mg, 2 mmol) in CH2Cl2 was stirred for 3 days. The reaction mixture was directly subjected to purification by flash column chromatography on silica using EtOAc/Hexane (8:1) to provide the desired product (149 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])=[CH:25][CH:24]=1
Reactant: NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCc3ccc(F)cc3)cc2c1=O
Yield: 12.5 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 4-fluoro-benzylamine according to the GPA affording 5 mg (12.5%) of a red powder. Rt=5.00 min.
Reaction SMILES: N.[CH2:2]([C@@H:8]1[C:11](=[O:12])[O:10][C@H:9]1[CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][C:29]([OH:31])=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[N:33](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:29]([CH2:28][CH2:27][O:26][C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][C@@H:9]1[O:10][C:11](=[O:12])[C@H:8]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:31])[NH2:33]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OCCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CC#N
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OCCC(N)=O
Yield: 81.4 %

Procedure:
Ammonia gas was blown into a solution of 40 mg of 3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]propionic acid (Example L) in 2.5 ml of acetonitrile until the solution is saturated and subsequently 50 mg of HBTU were added. Then, the mixture was filtered and evaporated and the residue was chromato-graphed on silica gel with 5 percent methanol in methylene chloride. There were obtained 32.5 mg of (3S,4S)-4-[(S)-2-(2-carbamoylethoxy)tridecyl]-3-hexyl-2-oxetanone, m.p. 35°.
Reaction SMILES: [CH3:1][SiH:2]([Cl:4])[Cl:3].[F:5][C:6]([F:13])([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH2:8]>>[F:5][C:6]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:7][CH2:8][Si:2]([CH3:1])([Cl:4])[Cl:3]
Reactant: C=CC(F)(F)C(F)(F)F
Reactant: C[SiH](Cl)Cl
Product: C[Si](Cl)(Cl)CCC(F)(F)C(F)(F)F
Yield: 91 %

Procedure:
Into a reaction vessel were put 200 g of methyldichlorosilane and the same amount of the same binary catalyst as in Example 1, followed by the addition of 242 g of 3,3,4,4,4-pentafluorobutene. After the completion of the reaction at 70° C under 6 atmospheres, the reaction product was subjected to distillation to produce 3,3,4,4,4-pentafluorobutylmethyldichlorosilane (Boiling point: 130° C) at the yield 91% of the theoretical.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10]2.[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35]([C:38](=[O:43])N(OC)C)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35]([C:38]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([Si:16]([CH:17]([CH3:18])[CH3:19])([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:24])[CH3:25])[CH:11]=[CH:10]3)=[O:43])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)C3CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
tert-Butyllithium (1.7 M in pentane, 13 mL, 22.13 mmol) was added to a solution of 5-bromo-1-triisopropylsilanyl-1H-indole (3.54 g, 10.06 mmol) in THF (35 mL) at −78° C. under nitrogen atmosphere. The pale yellow reaction mixture was stirred at −78° C. for 15 minutes, then a solution of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.60 g, 10.06 mmol) in THF (5 mL) was slowly added. The resulting mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature over a period of 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl and was partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (10% to 25% of EtOAc in hexane) to give 2.66 g (56% yield) of 3-(1-triisopropylsilanyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[NH:9][C:8](=O)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:8]1[NH:7][C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=[C:2]([I:1])[C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(I)c2[nH]1
Product: FC(F)(F)c1cc(I)c2nc(Cl)[nH]c2c1

Procedure:
4-Iodo-6-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (328 mg, 1 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a off-white solid. MS (ESI, pos. ion) m/z: 347(M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([OH:18])=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].[N:19]1([CH2:25][CH2:26]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C(O)C>CC(C)=O>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:26][CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: ClCCN1CCCCC1
Reactant: COc1c(NC(C)=O)c(O)c(OC)c2occc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1c(NC(C)=O)c(OCCN2CCCCC2)c(OC)c2occc12

Procedure:
A mixture of 25.1 g (0.1 mole) of 5-acetamido 4,7-dimethoxy 6-hydroxy benzofuran, 22.2 g (0.15 mole) of 2-piperidino chlorethane and 41.6 g (0.3 mole) of potassium carbonate in 250 ml of acetone was brought to reflux for 2 hours. Then it was filtered, the solvent evaporated, the residue obtained was taken up again in acetone and 20 ml of 7 N hydrochloric ethanol were added. It was filtered and recrystallized in 400 ml of propanol.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28](O)=[O:29])=[C:22]([C:31]([F:34])([F:33])[F:32])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN1C(=O)CCC1>C1COCC1>[C:16]([C:20]1[N:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:29])=[C:22]([C:31]([F:34])([F:32])[F:33])[CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cc(C(F)(F)F)c(C=CC(=O)O)cn1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(F)(F)F)c(C=CC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cn1
Yield: 62.7 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (41.2 mg, 0.162 mmol) was reacted with 3-(6-tert-butyl-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (1.0 eq, 44.2 mg) DMTMM (1.0 eq, 44.8 mg) and NMP (1.2 eq, 22 μl) in THF to give the title compound (48 mg, 62.6%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:4]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COC(=O)c1sccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1sccc1NC(=O)c1cccc(OC)c1

Procedure:
To a solution of methyl-3-amino-2-thiophenecarboxylate, 20, (8.0 g) in acetonitrile (100 mL) was added potassium carbonate (7.73 g) followed by m-anisoyl chloride, 23, (7.51 mL). The reaction mixture was heated to reflux, then cooled and diluted with water. 3-(3-Methoxy-benzoylamino)-thiophene-2-carboxylic acid methyl ester, 24, (12.78 g) was subsequently collected as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=[C:13]([CH:14]([OH:16])[CH3:15])[C:8]=3[N:7]=[CH:6]2)[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[Cl:32][C:33]([Cl:37])([Cl:36])[C:34]#[N:35]>C(OCC)C>[Cl:32][C:33]([Cl:37])([Cl:36])[C:34](=[NH:35])[O:16][CH:14]([C:13]1[C:8]2[N:7]=[CH:6][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:9]=2[CH:10]=[C:11]([C:17]([F:19])([F:20])[F:18])[CH:12]=1)[CH3:15]
Reactant: CC(O)c1cc(C(F)(F)F)cc2c1ncn2CC1CC1
Reactant: N#CC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2c1ncn2CC1CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(1-(Cyclopropylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethanol (0.283 g, 0.996 mmol) was dissolved in diethyl ether (13 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (341 μL, 2.27 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (300 μL, 2.93 mmol) dropwise over 10 min. The reaction was allowed to warm up to room temperature overnight and concentrated. Flash chromatography on silica gel (50% ethyl acetate/hexanes) gave 195 mg (45.6%) as an light yellow oil. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 8.33 (s, 1 H), 8.15 (s, 1 H), 7.69 (s, 1 H), 7.64 (s, 1 H), 6.81 (q, J=6.4 Hz, 1 H), 4.05 (d, J=7.0 Hz, 2 H), 1.82 (d, J=6.4 Hz, 3 H), 1.29-1.39 (m, 1 H), 0.70-0.80 (m, 2 H), 0.40-0.50 (m, 2 H); 19F-NMR (470 MHz, CHLOROFORM-D) δ ppm −61.19.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:97][CH2:96][CH2:95][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:91]([O:93][CH3:94])=[O:92])[CH2:79][CH2:80][CH2:81][CH2:82][NH:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[H][H]>CO>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:97][CH2:96][CH2:95][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:91]([O:93][CH3:94])=[O:92])[CH2:79][CH2:80][CH2:81][CH2:82][NH:83][C:84]([O:86][C:87]([CH3:88])([CH3:89])[CH3:90])=[O:85])=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:52])[CH3:53])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Reactant: [H][H]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC

Procedure:
145 mg of Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys(Boc)-OMe (Example 4) are dissolved in 2.5 ml of 95% strength MeOH and, after the addition of 15 mg of Pd-on-carbon, hydrogenated by passing hydrogen through and stirring with a small magnetic rod until the starting material has disappeared completely (according to thin layer chromatography monitoring). The whole is filtered, the filtrate is concentrated to dryness, dissolved in 3 ml of H2O and lyophilised, yielding H-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys(Boc)-OMe; Rf (D)=0.32; Rf (M)=0.25; Rf (N)=0.3.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][CH2:11][NH:12][C:13]([C:15]2[S:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)=[O:14])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Br[CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C>[C:38]1([CH2:37][CH2:36][CH2:35][N:7]2[CH2:8][CH2:9][N:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]3[S:25][C:24]4[N:26]5[C:17](=[CH:18][N:19]=[C:20]5[CH:21]=[CH:22][CH:23]=4)[CH:16]=3)=[O:14])[CH2:5][CH2:6]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(NCCN1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: BrCCCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 1.63 g (3.71 mM) of N-[2-(1-piperazinyl)ethan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride and 3.0 ml (21.5 mM) of triethylamine in ethanol (16 ml) was added 0.68 ml (4.47 mM) of 1-bromo-3-phenylpropane at room temperature, and the mixture was refluxed under nitrogen for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 20-50%) to provide the title compound.
Reaction SMILES: [CH:1]([N+:4]1[CH2:8][CH2:7][CH2:6][C:5]=1OC)([CH3:3])[CH3:2].[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14].[CH3:17][NH:18][CH3:19]>C1C=CC=CC=1>[CH:1]([N+:4]1[CH2:8][CH2:7][CH2:6][C:5]=1[N:18]([CH3:19])[CH3:17])([CH3:3])[CH3:2].[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14]
Reactant: CNC
Reactant: COC1=[N+](C(C)C)CCC1
Agent: COS(=O)(=O)[O-]
Solvent: c1ccccc1
Product: CC(C)[N+]1=C(N(C)C)CCC1

Procedure:
Add dropwise, with stirring, 161 g of 1-isopropyl-2-methoxy-1-pyrrolinium-methylsulfate to a solution of 43.8 g of dimethylamine in 283 ml of benzene. Subsequently, boil the resulting reaction mixture under reflux for 1.5 hours; separate off the heavy phase and wash it 4 times with, in each case, 50 ml of diethyl ether. Dry the washed product under a high vacuum to obtain 154 g (91% of theory) of the title compound as reddish oil.