Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]#[N:12].[S:13]([OH:17])(=[O:16])(=[O:15])[CH3:14].[CH2:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH3:19]>ClC1C=CC=CC=1>[S:13]([OH:17])(=[O:16])(=[O:15])[CH3:14].[CH2:18]([C:20]1[CH:21]=[C:22]([NH:23][C:11]([NH:10][C:3]2[CH:4]=[C:5]([CH2:8][CH3:9])[CH:6]=[CH:7][C:2]=2[Cl:1])=[NH:12])[CH:24]=[CH:25][CH:26]=1)[CH3:19]
Reactant: CCc1cccc(N)c1
Reactant: CCc1ccc(Cl)c(NC#N)c1
Agent: CS(=O)(=O)O
Solvent: Clc1ccccc1
Product: CCc1cccc(NC(=N)Nc2cc(CC)ccc2Cl)c1

Procedure:
A mixture of 2-chloro-5-ethylphenylcyanamide (0.6 g, 3.08 mmol), 3-ethylaniline mesylate (0.64 g, 2.93 mmol), and chlorobenzene (12 mL) were combined in a dry round bottom flask equipped with a water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 3 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine mesylate, as a white solid (1.1 g, 91% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:17])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH3:19][NH2:20]>>[CH3:19][NH:20][C:3](=[O:2])[CH:4]([CH3:17])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: COC(=O)C(C)CNC(=O)OCc1ccccc1
Reactant: CN
Product: CNC(=O)C(C)CNC(=O)OCc1ccccc1

Procedure:
2.52 g of 3-benzyloxycarbonylamino-2(R,S)-methylpropionic acid methyl ester and 50 ml of 33% methylamine (in ethanol) are stirred at room temperature for 48 hours. The reaction mixture is concentrated by evaporation and the title compound is obtained from the residue by crystallisation from ethyl acetate: Rf (dichloromethane/methanol=95:5)=0.42; m.p. 128°-129° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)[CH3:4].F[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1>CN(C=O)C.O>[CH2:3]([C:5]1[N:6]=[CH:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)[CH:9]=1)[CH3:4]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cn(-c2ccc(C(C)=O)cc2)cn1
Temperature: 25 °C

Procedure:
NaH (0.068 g in 60% oil dispersion, 1.7 mmol) was added to a solution of compound 16 (0.180 g, 1.8 mmol) in DMF (6 mL) with stirring at room temperature. The mixture was stirred for 15 min and a solution of 4′-fluoroacetophenone (0.215 g, 1.56 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 80° C. for 1 h, and then cooled, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried, and evaporated to a yellow solid. Compound 17 crystallized to form white color needles upon standing at room temperature. The yield was 0.270 g, 67%. The structure was confirmed by 1H NMR in CDCl3. LC-MS: [M+1]=215. Purity was >98%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:28]([CH2:32][CH2:33][OH:34])[CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][OH:34])[C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:20]
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: OCCNCCO
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N(CCO)CCO

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to diethanolamine via General Procedure B. The product was purified via reverse phase HPLC to give 15.8 mg of 258. MS (Q1) 468.8 (M)+.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]2[C:28]3[CH:29]=[C:30]([CH:33]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[C:34]4[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=4)[CH:31]=[CH:32][C:27]=3[NH:26][C:25](=O)[CH2:24][S:23]2)[CH:19]=[CH:20][CH:21]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]2[C:28]3[CH:29]=[C:30]([CH:33]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[C:34]4[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=4)[CH:31]=[CH:32][C:27]=3[NH:26][C:25](=[S:2])[CH2:24][S:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=O)N2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=S)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Tetraphosphorus decasulfide (0.0097 mol) was added at room temperature to a solution of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (see Example B13) (0.0081 mol) in THF (50 ml). The mixture was stirred at room temperature for 2 hours and poured out into ice water. The precipitate was filtered off and taken up in K2CO3 10%. The mixture was extracted with DCM and a small amount of methanol. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 3.2 g (77.5%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepine-2(3H)-thione.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[C:3]=1[C:16]#[N:17].C(O[CH:26](OCC1C=CC=CC=1)[N:27]([CH3:29])[CH3:28])C1C=CC=CC=1>C1(C)C=CC=CC=1>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([C:4]2[C:3]([C:16]#[N:17])=[C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])[NH:6][N:5]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)n[nH]c1N
Reactant: CN(C)C(OCc1ccccc1)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(-c2ccc([N+](=O)[O-])cc2)c1C#N

Procedure:
In 1 ml of toluene, 57.3 mg (0.25 mmol) of 5-amino-3-(4-nitro-phenyl)-1H-pyrazole-4-carbonitrile and 79.3 μl of N,N-dimethylformamide dibenzylacetal are boiled overnight. Filtering of the suspension and washing with hexane yield N'-[3-(4-nitro-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine; TLC: Rf =0.15 (ethyl acetate:hexane=2:1); TRet (Grad20-100)=8.8.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]#[N:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][C:17]([NH2:18])=[S:26])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(CC#N)cc(C(C)(C)C)c1O
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(CC(N)=S)cc(C(C)(C)C)c1O

Procedure:
3,5-Di-tert-butyl-4-hydroxyphenylacetonitrile (20.0 g) and 11.4 ml of triethylamine were dissolved in 40 ml of pyridine, and hydrogen sulfide was blown into the solution at room temperature over 13 hours. The reaction mixture was concentrated, and the crude product thus obtained was purified by silica gel column chromatography (diethyl ether-hexane =3:7) to give 4.9 g of the desired compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14]O)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][N:42]=[N+:43]=[N-:44])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(CN=[N+]=[N-])o1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
99.4 mg of (5-hydroxymethyl-furan-2-ylmethyl)-carbamic acid tert-butyl ester was added to 4.5 mL of toluene, added successively with 83.7 mg of 1,8-diazabicyclo[5,4,0]undec-7-ene and 151.6 mg of diphenylphosphoryl azide, and stirred at room temperature under nitrogen atmosphere for 1 hour and 45 minutes. Then the solvent was evaporated, followed by purification and separation by silica gel column chromatography, to afford 88.6 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[CH3:18][N:19]1[C:23]([NH2:24])=[C:22]([CH3:25])[CH:21]=[N:20]1>>[CH3:18][N:19]1[C:23]([NH:24][C:15]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=23)=[O:17])=[C:22]([CH3:25])[CH:21]=[N:20]1
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Reactant: Cc1cnn(C)c1N
Product: COCc1cc2c(C(=O)Nc3c(C)cnn3C)ccc(OC)c2o1
Yield: 28 %

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.1 g) and 2,4-dimethyl-2-H-pyrazol-3-ylamine (56 mg). Purification by column chromatography on silica eluting with 20% heptane in ethyl acetate and gradient preparative HPLC on a Phenomenex LUNA(2)™ C18 column eluting with 0.05% trifluoroacetic acid in 20%-65% acetonitrile in water gave the title compound as a pale yellow solid (39 mg).
Reaction SMILES: C(C1C=CC(C[S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.Cl[CH2:26][C:27]1[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:26][C:27]2[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=2)[CH:10]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2ccc(C(F)(F)F)nc2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 3-(chloromethyl)-6-trifluoromethylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1COCC1>[CH2:1]([O:8][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To 2.5 mL benzyl alcohol in 80 mL THF is added 1.87 g NaH. After one hour stirring at room temperature, 5.0 g of 2,4-Difluorobenzonitrile is added. After stirring one hour, the reaction is quenched with excess water and concentrated in vacuo. The residue is redissolved in ethyl acetate and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product is recrystallizde in carbon tetrachloride to give 3.24 g (39.7%) of the title compound.
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].[CH3:10][C:11]([CH3:18])([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH3:12]>O1CCCC1>[C:11]([C:13]([OH:17])([CH2:14][CH2:15][CH3:16])[C:8]#[C:7][CH:6]([OH:9])[CH3:5])([CH3:18])([CH3:12])[CH3:10]
Reactant: CCCC(=O)C(C)(C)C
Reactant: C#CC(C)O
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCCC(O)(C#CC(C)O)C(C)(C)C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Over a period of 30 min, a solution of 40.7 g (374 mmol) of ethyl bromide in 100 mL of dry tetrahydrofuran was added dropwise to a stirred suspension of 9.08 g (374 mmol) of magnesium turnings in 5 mL of dry tetrahydrofuran, with the reaction being initiated by occasional heating with a heat gun. The reaction mixture was then stirred for additional 3 h at reflux. The reaction was allowed to cool down to room temp., and a solution of 12.6 g (180 mmol) of but-3-yn-2-ol in 80 mL of dry tetrahydrofuran was added dropwise with stirring. The reaction mixture was then again heated to reflux for 4 h, prior to removal of the heating bath. At room temp., a solution of 25.0 g (195 mmol) of 2,2-dimethylhexan-3-one in 90 mL of dry tetrahydrofuran was added with stirring within 35 min, and the reaction mixture was refluxed for another 2 d with stirring. The reaction mixture was then allowed to cool to room temp., and quenched with 500 mL of an aqueous satd. NH4Cl solution. The aqueous layer was extracted three times with 500 mL of ether each, the combined organic extracts were dried with sodium sulfate, and the solvent was evaporated on a rotary evaporator to provide 32.3 g (90%) of crude 5-tert-butyloct-3-yne-2,5-diol as a slightly yellowish oil, which was employed without further purification. A solution of 20.8 g (105 mmol) of this product in 300 mL of ethanol was hydrogenated by stirring at ambient pressure and temp. in an atmosphere of hydrogen in the presence of 3.11 g (2.92 mmol) of 10% palladium on barium sulfate and 300 mg (2.32 mmol) of quinoline. After 10 h of stirring, the catalyst was filtered off over a pad of Celite, and the solvent was removed on a rotary evaporator to provide 20.7 g (99%) of crude (3Z)-5-tert-butyloct-3-ene-2,5-diol, of which 19.6 g (98 mmol) was heated for 45 min in a Kugelrohr apparatus to 155° C./280 mbar in the presence of 2.00 g (14.7 mmol) of KHSO4. The evaporating reaction product was trapped in a bulb at −80° C., and further purified by flash chromatography (400 g of silica-gel, pentane/ether, 98:2) to afford 7.26 g of product. This was then distilled in a Kugelrohr apparatus to furnish at 70-80° C./20 mbar 6.24 g (34%) of the title compound as a colorless odoriferous liquid.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([C@:13]12[CH2:21][CH2:20][C@@H:19]3[C@@H:22]4[C:27]([CH2:28][CH2:29][C@H:18]3[C@@H:17]1[CH2:16][CH2:15][C@@H:14]2[OH:31])=[CH:26][C:25](=[O:30])[CH2:24][CH2:23]4)[CH3:12]>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:11]([C@:13]12[CH2:21][CH2:20][C@@H:19]3[C@@H:22]4[C:27]([CH2:28][CH2:29][C@H:18]3[C@@H:17]1[CH2:16][CH2:15][C@@H:14]2[O:31][C:8](=[O:9])[CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:26][C:25](=[O:30])[CH2:24][CH2:23]4)[CH3:12]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)CCC1CCCC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCC1CCCC1

Procedure:
Add 3-cyclopentylpropionyl chloride (2 g.) in benzene (6 cc.) to 13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (6 cc.) at -15°. Keep the mixture at -10° for 17 hours, work up and recrystallize the product from methanol to give the title compound, m.p. 88-89°; ultraviolet absorption peak at 241 mμ (ε17,000); infrared absorption peaks at 5.80; 6.00, 6.18 μ.
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8](=[O:13])([O:11][CH3:12])OC.[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([C:25](=[O:27])[CH3:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>>[O:27]=[C:25]([C:23]1[S:24][C:20]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)=[CH:21][CH:22]=1)[CH2:26][C:8]([O:11][CH3:12])=[O:13]
Reactant: CC(=O)c1ccc(-c2ccncc2)s1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(-c2ccncc2)s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 38.3 %

Procedure:
To a 100 mL round bottom flask was added a suspension of sodium hydride (0.1574 g, 3.936 mmol) in tetrahydrofuran (16.000 mL, 197.26 mmol). Dimethyl carbonate (0.663 mL, 7.872 mmol) was added followed by 1-(5-pyridin-4-yl-2-thienyl)ethanone (0.400 g, 1.968 mmol) which was added in portions. The red reaction mixture was heated to 60° C. and allowed to stir for 18 hours. The reaction was cooled to ambient temperature and quenched by the dropwise addition of water (5.00 mL). The mixture was neutralized to pH 7 by the addition of a saturated aqueous solution of ammonium chloride (10.00 mL) and extracted with EtOAc (70.00 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using ISCO (12 g cartridge, gradient hexanes to 100% EtOH over 30 min) to afford the title compound (0.197 g, 36%) as a yellow oil. LC/MS (AA) ES+ 262. 1H NMR (dmso-d6, 400 MHz): δ 8.67-8.65 (m, 2H), 8.08 (d, 1H), 7.94 (d, 1H), 7.78-7.77 (m, 2H), 4.20 (s, 2H), 3.67 (s, 3H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:38]([OH:40])=[O:39])[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(=O)C.[ClH:45]>O1CCOCC1>[ClH:45].[NH2:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:38]([OH:40])=[O:39])[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
The title compound is prepared using the previously described procedures and the following reagants: 1.85 grams (3.4 mmoles) t-butyloxycarbonyl-phenylalanyl-valyl-tryptophan, 10 ml of glacial acetic acid and 7.25 ml of 6.07 N hydrochloric acid in dioxane. Yield is 1.6 g (100 percent). Analysis calculated for C25H30N4O4.HCl.2H2O: C, 56.99; H, 6.93; N, 9.17. Found: C, 56.70; H, 6.43; N, 8.82.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][C:23]([NH2:26])([CH3:25])[CH3:24]>CS(C)=O.C(Cl)Cl>[C:23]([NH:26][C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)(C)N
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)Nc1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Yield: 25 %

Procedure:
A solution of 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (210i, 75 mg, 0.266 mmol) and 2-methylpropan-2-amine (56.1 μl, 0.531 mmol; Aldrich) in DMSO (2.6 ml) was stirred at 100° C. for 1 h. The mixture was diluted with DCM (150 ml), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. The impure material was dissolved in DMSO (˜20 mg/ml) and injected (4×1.0 ml) onto a Shimadzu preparatory LC (rpHPLC: Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% MeCN/water with 0.1% TFA) before the pure fractions were combined, basicified with NaHCO3 (saturated, aq.), extracted with DCM, separated, dried over Na2SO4, and concentrated via rotary evaporation to give 2-(3-(tert-butylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (210, 25% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 9H) 2.87 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.85, 2.35 Hz, 2H) 6.95 (br. s., 1H) 7.07 (d, J=2.15 Hz, 1H) 7.34 (t, J=7.82 Hz, 1H) 7.58 (s, 1H) 7.61 (dd, J=7.92, 1.27 Hz, 1H) 7.90 (dd, J=7.53, 1.27 Hz, 1H) 8.38 (s, 1H) 12.13 (br. s., 1H). MS (ESI, pos. ion) m/z: 336.2 (M+1).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5](O)[C:6]#[C:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CCOCC.N1C=CC=CC=1>[Br:2][CH2:5][C:6]#[C:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrP(Br)Br
Reactant: CCCCC/C=C\C/C=C\CC#CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CC#CCBr
Temperature: 23 °C
Yield: 236.2 %

Procedure:
A solution of phosphorous tribromide (0.47 g, 1.73 mmol) in absolute ether (0.5 ml) was added dropwise during five minutes to a mixture of (Z,Z)-5,8-tetradecadien-2-yn-1-ol (1.03 g, 5 mmol), and dry pyridine (14 mg, 0.18 mmol) in 8 ml of absolute ether. The reaction mixture was heated under reflux for 2.5 h, cooled to 23° C., then poured onto ice-water. It was extracted three times with ether. The combined ether extracts were washed with dilute aqueous sodium bicarbonate solution, water, dried over Na2SO4 and concentrated in vacuo. Evaporative distillation of the crude product at 145°-148° C./0.15 mm afforded 1.1 g (80.5%) of (Z,Z)-1-bromo-5,8-tetradecadien-2-yne as a pale yellow oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1>CS(C)=O>[S:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:6]([CH2:5][C:1]#[N:2])=[CH:7]1
Reactant: ClCc1csc2ccccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
To a stirred solution of NaCN (1.4 g, 28.5 mmol) in DMSO (8 mL) was added 3-(chloromethyl)-1-benzothiophene (4 gm, 21.9 mmol) in DMSO (6 mL) over 15 min. The reaction mixture was stirred at room temperature for 18 h and then quenched with water and extracted with ether (2×50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography using ethyl acetate-hexane (1:1) to furnish 1-benzothien-3-ylacetonitrile (2.5 g, 65%). 1H NMR (200 MHz, CDCl3): δ 3.69 (s, 2H), 7.25-7.91 (m, 5H).
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[N:3]1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[N:2]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: c1c[nH]nn1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cn1ccnn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
129.2 g (5.6 mmol) of sodium are added slowly to 4.0 litres of ethanol. 400.0 g (5.6 mol) of 1,2,3-1H-triazole are then added, and 623 ml (938.2 g, 5.6 mol) of ethyl bromoacetate are added dropwise at an internal temperature of 20-25° C. The mixture is stirred at RT for 48 h. The precipitated solid is filtered off, the ethanol is removed under reduced pressure and the mixture is filtered again. The residue is taken up in ethyl acetate, filtered, again concentrated under reduced pressure and purified by distillation on a 30 cm column. The product is obtained at a bath temperature of 140° C., a head temperature of 60-115° C. and a pressure of 1 mbar. Yield: 440.0 g (50% of theory)
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:23]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:4]1[CH:3]=[C:2]([F:1])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1c(Nc2ccc(F)cc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(F)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4-fluoroanilino)benzo[b]thiophene-3-carboxylate is obtained.