Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[CH:5]([C:17]([NH:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:18])[NH:6][C:7]([O:9]CC1C=CC=CC=1)=O)(C)C.[NH3:34]>>[NH2:34][CH:5]([C:17]([NH:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[C:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:23])=[O:18])[NH:6][C:7]([CH2:22][C:21]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:20]=1)=[O:9]
Reactant: N
Reactant: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1C(=O)c1ccccc1
Product: NC(NC(=O)Cc1ccccc1)C(=O)Nc1ccccc1C(=O)c1ccccc1

Procedure:
The crude product 24 (9.3 g, 20.17 mmol) was dissolved in 133 mL of dry tetrahydrafuran. This solution was saturated with ammonia at 0° C. for 30 minutes and then mercuric chloride (6 g, 22.09 mmol) was added in one portion to the stirred solution while ammonia gas was bubbled through the solution. After bubbling ammonia gas for 2 hours at 0° C. it was bubbled for an additional hour at room temperature. The suspended solids were filtered and the solvent evaporated to yield 25 (9.7 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([F:11])[CH:3]=1.Cl[C:13]1[C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=[CH:15][N:14]=1.[H-].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[C:19]=2[C:20]#[N:21])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1cccnc1Cl
Reactant: Fc1cc(Br)ccc1N=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1c(Nc2ccc(Br)cc2F)sc2ncccc12
Temperature: 80 °C
Yield: 8 %

Procedure:
4-Bromo-2-fluoro-1-isothiocyanatobenzene (250 mg, 1.08 mmol) and (2-chloropyridin-3-yl)acetonitrile (D. H. Bremner et al., Synthesis, 1997, 949) (165 mg, 1.08 mmol) were stirred in DMSO (20 mL) and sodium hydride (52 mg, 1.3 mmol) added portionwise. After evolution of gases had finished the reaction mixture was heated for 4 h at 80° C. After this time the reaction mixture was added to ice (50 mL) and a precipitate formed. This was filtered and purified by preparative HPLC (pH 10, 2-3 min) to give the title compound as a white powder (30 mg, 9%). δH (DMSO-d6) 10.45 (1H, s), 8.31 (1H, d, J 3.9 Hz), 7.75 (2H, m), 7.51-7.38 (3H, m). LCMS (ES+) RT 3.49 minutes, 350 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].IC>CO>[CH3:20][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C@@H:17]([OH:19])[CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-benzyloxycarbonyl-4-hydroxy-L-trans-proline 9 (47.5 g; 179 mmol) in anhydrous methanol (900 ml) is adjusted to pH=9.0-9.5 using caesium carbonate. The mixture is subsequently stirred at room temperature for 30 min., and then concentrated. After having been dried for 30 minutes under high vacuum, the residue is taken up in anhydrous N,N-dimethylformamide (900 ml). Iodomethane (28.0 g; 197 mmol) is added, and the mixture is stirred at room temperature for 21 h. The solution is concentrated, and the residue is subsequently distilled repeatedly with toluene, taken up in chloroform (1.8 l), and then extracted by shaking once with each of water and a 10% solution of sodium hydrogen carbonate, and once again with water (600 ml on each occasion). The organic phase is dried (magnesium sulphate) and concentrated. Yield: 50.0 g (quantitative).
Reaction SMILES: [N:1]1([C:6]2[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][NH:13]C(=O)CC)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:20]>>[ClH:20].[ClH:20].[N:1]1([C:6]2[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCC(=O)NCCOc1ccc(-n2ccnc2)cc1
Agent: Cl
Product: NCCOc1ccc(-n2ccnc2)cc1

Procedure:
To 40 mL of 2M aqueous hydrochloric acid add 10.3 g (39 mmol) of N-[2-[4-(1H-imidazol-1-yl)phenoxy]ethyl]propionamide. Reflux the reaction mixture. Monitor the progress of the reaction by thin-layer chromatographyon silica gel (9:1, CH2Cl2 :MeOH). Upon completion of the reaction, remove the solvent in vacuo and triturate with isopropanol. Recrystallization of the resulting solid from ethanol affords the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[C:11]1=[O:17])([CH3:4])([CH3:3])[CH3:2].Cl.I[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:26]2[CH:21]=[CH:22][C:23]([C:31]([F:32])([F:34])[F:33])=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=2)[C@@H:12]([CH3:16])[C:11]1=[O:17])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1NCCN(CCCC(=O)OC(C)(C)C)C1=O
Reactant: FC(F)(F)c1ccc(I)cc1C(F)(F)F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: C[C@H]1C(=O)N(CCCC(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Temperature: 120 °C
Yield: 35 %

Procedure:
A mixture of 0.20 g (0.78 mmol) of 4-((S)-3-Methyl-2-oxo-piperazin-1-yl)-butyric acid tert-butyl ester, 0.1 eq. of HCl, 0.53 g (1.56 mmol) of 4-iodo-1,2-bis-trifluoromethyl-benzene (WO2007034282), 0.04 g (0.078 mmol) bis(tri-tert-butylphosphine)palladium(0) and 0.33 g (1.56 mmol) tripotassium phosphate in 2 ml of 1,2-dimethoxyethane was degased and heated at 120° C. for 2 h under microwave irradiation, diluted with dichloromethane, filtered and evaporated. Purification on a SiO2-column (1-propanol in n-heptane 2 to 5%), gave the titled compound in 35% yield as light brown oil. MS: 413.13 (M[-C4H8]H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=1[CH3:21])[CH:8]=2)([O-])=O>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=1[CH3:21])[CH:8]=2
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc([N+](=O)[O-])cnc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(N)cnc2c1
Reaction time: 8 h
Yield: 40.2 %

Procedure:
In a mixture of ethanol (20 mL) and ethyl acetate (10 mL) was suspended 3-nitro-7-(5-methyl-2-phenyl-4-oxazolylmethoxy)quinoline (740 mg, 2.1 mmol.), and to the suspension was added 10% palladium/carbon (50 mg). Then, catalytic reduction was performed overnight. After the completion of reaction was confirmed, the reaction mixture was filtered over Celite®, and the filtrate was placed under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/7 to ethyl acetate), to give 280 mg of the desired compound as brown oil (yield 42%).
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([OH:26])=[O:25])=O.[OH-].[Na+].[Cl-].[Ca+2].[Cl-]>O>[CH2:23]1[S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])[C:11](=[O:12])[N:8]2[C:7]([C:24]([OH:26])=[O:25])=[C:6]1[CH2:5][OH:4]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCCC(=O)O)[C@H]2SC1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reaction time: 2.5 h
Yield: 83 %

Procedure:
Glutaryl 7ACA (4.0 g) is slurried in 60 ml water and the pH is adjusted to 3.5 to 4.0 with 20% sodium hydroxide to dissolve the glutaryl 7ACA. To the solution is added 2.2 g calcium chloride and the pH is adjusted to 5.5 to 6.0 with 20% sodium hydroxide. Yeast esterase (0.4 g) is added and the solution is stirred at 22°-25° C. for 2.5 hours while maintaining the pH at 5.9-6.1 with 20% sodium hydroxide. The yield by HPLC to desacetyl glutaryl 7ACA is 97% with the ratio of desacetyl glutaryl 7ACA to glutaryl 7ACA >99%. The resulting solution is filtered with filter aid to remove the yeast and is diluted with water to 90 ml. Desacetyl glutaryl 7ACA calcium salt is precipitated by the addition of 450 ml ethanol. The crystals are filtered, washed with ethanol, and dried. Subsequent crystals which come out in the filtrate are similarly filtered and dried. (Crystal purity as desacetyl glutaryl 7ACA is 63%). The crystallization yield is 83%. The desacetyl glutaryl 7ACA calcium salt was characterized by NMR and IR:
Reaction SMILES: [N:1]1([CH:6]([C:10]2[S:14][C:13]([CH2:15]O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.Cl.[C-:22]#[N:23].[Na+].N>CS(C)=O>[N:1]1([CH:6]([C:10]2[S:14][C:13]([CH2:15][C:22]#[N:23])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(CO)s1)n1ccnc1
Reactant: [C-]#N
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CS(C)=O
Product: CCCC(c1ccc(CC#N)s1)n1ccnc1
Reaction time: 20 h

Procedure:
0.2 g of the alcohol of example 8 is converted, with thionyl chloride (2 hours at room temperature, concentration by evaporation, redistillation three times with toluene) into the hydrochloride of the chloromethyl compound, which is dissolved in 2 ml of dimethyl sulfoxide and is mixed with 0.2 g of sodium cyanide. After stirring for 20 hours, it is added to dilute ammonia solution, extracted with ethyl acetate and the ethyl acetate extract is dried and concentrated by evaporation. After distillation on a bulb tube, the title compound is obtained as oil. Boiling point: 210°-230° C./0.03 mbar.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]2[CH:16]=1.C(=O)(O)[O-].[Na+]>Cl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]2[CH:16]=1
Reactant: CCOC(=O)c1cccn2cc(CCl)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)c1cccn2cc(CCl)nc12
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Ethyl 2-chloromethylimidazo[1,2-a]pyridine-8-carboxylate (8.4 g, 35.2 m moles) was added to conc. hydrochloric acid 1100 ml), and the mixture was refluxed under heating for 5 hours. The reaction mixture was cooled to room temperature and adjusted to pH 4 with saturated aqueous solution of sodium bicarbonate. The precipitating crystals were collected by filtration to give the object compound (5.67 g, yield 98.4%) as crystal. m.p. 250° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[C:8](F)=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1[NH2:4].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[NH2:4][C:3]1[C:2]([F:1])=[C:8]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:7]([F:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(F)c(Oc2ccc(C=O)cc2)c1F

Procedure:
2,3,4-Trifluoro-6-nitroaniline (5 g, 26 mmol), 4-hydroxybenzaldehyde (3.5 g, 28.6 mmol) and Cs2CO3 (10.5 g, 32.6 mmol) were stirred in 150 mL of dimethylformamide at 65 degrees Centigrade for approximately 18 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed five times with brine, dried over Mg2SO4 and concentrated onto basic alumina. The residue was purified by silica gel column chromatography (hexane to ethyl acetate gradient) to give 4-[(3-amino-2,6-difluoro-4-nitrophenyl)oxy]benzaldehyde. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.29 (d, J=8.8 Hz, 2 H) 7.46 (s., 2 H) 7.93 (d, J=8.8 Hz, 2 H) 7.98 (dd, J=11.0, 1.7 Hz, 1 H) 9.93 (s., 1 H)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH2:12][CH2:11]2.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C@@H:25]([NH2:30])[CH2:24][CH2:23]2>>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C@@H:25]([N:30]1[CH2:12][CH2:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)[CH:9]=3)[C:14]1=[O:18])[CH2:24][CH2:23]2
Reactant: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Reactant: N[C@H]1CCc2cc(Br)ccc2C1
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1[C@H]1CCc2cc(Br)ccc2C1

Procedure:
According to method O, 6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]isochroman-1-one was reacted with (S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-ylamine (J. Org. Chem. 1995, 60, 4324). The product was thus obtained with the molecular weight of 456.38 (C24H26BrNO3); MS (ESI): 456 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Br[C:29]([CH3:35])([CH3:34])[C:30]([O:32][CH3:33])=[O:31]>>[CH3:34][C:29]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:3]=3[O:2][CH3:1])=[CH:15][CH:14]=2)=[CH:17][CH:18]=1)([CH3:35])[C:30]([O:32][CH3:33])=[O:31]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)C(C)(C)Br
Product: COC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3cc(Cl)ccc3OC)cc2)cc1
Yield: 19 %

Procedure:
Methyl 2-Methyl-2-{4-[2-(2-methoxy-5-chloro-benzamido)-ethyl]biphenyl-4'-oxy}-propionate was prepared from 4-[2-(2-methoxy-5-chloro-benzamido)-ethyl]-4'-hydroxy-biphenyl and methyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield: 19% of theory; m.p. <20° C.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]=[C:12]([CH2:14][C:15]([O:17]C(C)C)=[O:16])[O:11][N:10]=2)=[O:8])=[CH:3][CH:2]=1.S(=O)(=O)(O)O>>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][N:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2noc(CC(=O)OC(C)C)n2)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=O)c2noc(CC(=O)O)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a flask containing 7.0 g of isopropyl [3-(4-toluoyl)-1,2,4-oxadiazol-5-yl]acetate was added 50 ml of cold concentrated sulfuric acid. This mixture was swirled and stirred for 10 minutes. The resulting solution was poured gradually into one liter of ice water with mechanical stirring to precipitate the product. The solid was collected by filtration, washed with water and dried in vacuo at room temperature. Recrystallization from acetone/hexane gave 3.3 g (56%) of a solid, m.p. 140°-141°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])=[O:12])=[CH:3][CH:2]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:31][CH2:30][NH:29][C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:20])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Reactant: NCCN1CCCC1
Product: O=C(NCCN1CCCC1)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 403) and N-(2-aminoethyl)pyrrolidine (Aldrich).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[C:15](=[NH:16])[O:14][NH:13][C:12]3=[NH:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[NH:17]=[C:12]1[CH:11]([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[C:15](=[NH:16])[O:14][NH:13]1
Reactant: N=C1NOC(=N)C1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: N=C1NOC(=N)C1C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 4-(1,4-dioxa-spiro[4.5]dec-8-yl)-isoxazolidine-3,5-diylidenediamine (as prepared in the previous step, 0.078 g, 0.326 mmol) in acetonitrile (10 mL) was treated with 1N aqueous HCl (3.2 mL, 3.2 mmol), and stirred at ambient temperature for 6 h. After removing the MeCN in vacuo, the reaction was treated with saturated aqueous NaHCO3 (ca. 7 mL), stirred at ambient temperature overnight, and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as an orange gum.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Br:11]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:11][C:5]1[S:1][C:2]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:3]=2[CH:4]=1
Reactant: BrBr
Reactant: O=C1CCCc2sccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2sc(Br)cc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
6,7-Dihydro-4-Benzo[B]thiophenone (1.5 g, 9.86 mmol) was dissolved in acetic acid (10 mL) and water (10 mL). The mixture was cooled to 0° C. and bromine (0.51 mL, 9.86 mmol) was added drop-wise. After 20 min at 0° C. the reaction was warmed to room temperature and stirred for 18 hr. The reaction mixture was cooled in ice and then treated with 1 M aqueous sodium hydroxide solution until the mixture was basic. A precipitate formed which was collected by filtration, washed with water and dried in a vacuum oven at 50° C. to afford the title compound as a grey solid (2.1 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8](C(=O)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl-].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]#N>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[C:24]3[C:23](=[N:22][CH:27]=[CH:26][CH:25]=3)[NH:28][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:17][CH:18]=1
Reactant: N#[N+]c1ccccn1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ncccc2c1-c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-(4-methoxybenzyl)-3-oxobutyrate in EtOAc stirred at ice bath temperature under an argon atmosphere is added an aquious solution of NaOH. This is immediately followed by the addition of an aqueous solution of pyrid-2-yldiazonium chloride [prepared from 2-aminopyridine in 6 N HCl and NaNO2 ]. The mixture is partitioned between EtOAc and H2O. The aqueous layer is washed with EtOAc. The combined organic extracts are washed with saturated aqueous NaCl solution, dried (Na2SO4) and the solvent is removed in vacuo. The residue is dissolved in EtOH and the solution is saturated with HCl gas. This is refluxed then cooled to room temperature and partitioned EtOAc and saturated aqueous NaHCO3 solution. The aqueous layer is washed with EtOAc. The combined organic extract is washed with H2O then saturated aqueous NaCl solution, dried (Na2SO4) and the solvent is removed in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1.C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](/[CH:8]=[CH:7]/[C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:18]=1
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Reactant: Brc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(/C=C/c2cncc(Br)c2)c1
Reaction time: 4 h

Procedure:
A mixture of 3-nitrostyrene (5.36 ml), 3,5-dibromopyridine (10.0 g), palladium(II) acetate (259 mg), tetra-n-butylammonium chloride (10.7 g) and sodium bicarbonate (8.07 g) in N,N-dimethylformamide (50 ml) was stirred at 120pbC. for 4 hours. The mixture was poured into sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated. The resultant solid was washed with diisopropyl ether to give 3-bromo-5-[(E)-2-(3-nitrophenyl)vinyl]pyridine (5.74 g).
Reaction SMILES: CC(O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([SiH2][O:28][C:29](C1C=CC=CC=1)(C1C=CC=CC=1)[C:30]1[N:34]([CH:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]([C:45](=[O:53])[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:37][C:36]2([CH3:55])[CH3:54])[CH:33]=[N:32][CH:31]=1)(C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[OH:28][CH2:29][C:30]1[N:34]([CH:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]([C:45](=[O:53])[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:37][C:36]2([CH3:55])[CH3:54])[CH:33]=[N:32][CH:31]=1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cncn1C1c2ccccc2N(C(=O)Cc2ccccc2)CC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)CN(C(=O)Cc2ccccc2)c2ccccc2C1n1cncc1CO
Temperature: 25 °C

Procedure:
HOAc (0.05 mL, 0.88 mmol) and TBAF (0.3 mL, 0.37 mmol) are added to a solution of 1-{4-[5-(tert-butyl-diphenyl-silanyloxymethyl)-imidazol-1-yl]-3,3-dimethyl-3,4-dihydro-2H-quinolin-1-yl}-2-phenyl-ethanone (115 mg) in THF (6 mL) at room temperature. The mixture is stirred at room temperature. In the next 4 h, TBAF (0.3 mL×2) are added and the mixture is stirred at room temperature for overnight. The reaction is adjusted by sat. NaHCO3 to basic and extracted into ethyl acetate and washed with brine; dried with anhydrous sodium sulfate and concentrated to give the crude compound, which is purified by reverse phase HPLC (CH3CN:H2O=10 to 80% over 20 mins) to the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.73 (s, 3 H), 0.97 (s, 3 H), 3.53 (br. s., 1H), 3.65 (d, J=13.1 Hz, 1 H), 3.83 (d, J=13.1 Hz, 1 H), 4.00 (s, 2 H), 4.70 (dd, 2 H), 5.30 (s, 1 H), 6.89-6.95 (m, 2 H), 7.03 (t, J=7.5 Hz, 1 H), 7.10 (s, 1 H), 7.24-7.37 (m, 6 H), 7.61 (br. s., 1 H).
Reaction SMILES: Cl.Cl.[O:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])[NH:19][C:18]=4[CH:27]=3)=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][CH2:4]1.CN(C=O)C.CCN(C(C)C)C(C)C.[F:42][CH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50](Cl)=[O:51])[CH2:46][CH2:45]1>ClCCl>[F:42][CH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([N:6]2[CH2:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]5[N:21]=[C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])[NH:19][C:18]=5[CH:27]=4)[CH:11]=[CH:10][C:9]=3[O:3][CH2:4][CH2:5]2)=[O:51])[CH2:46][CH2:45]1
Reactant: O=C(Cl)N1CCC(CF)CC1
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCC(CF)CC3)CCO4)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate dihydrochloride salt (51.7 mg, 0.13 mmol) was taken into DMF (1 mL) and dichloromethane (1 mL) followed by addition of DIPEA (88 uL, 0.52 mmol) and the mixture was cooled to 0° C. 4-(Fluoromethyl)piperidine-1-carbonyl chloride (reagent preparation 37) (33 mg, 0.13 mmol) was added to the mixture in a minimum of dichloromethane then stirred for 30 minutes. The mixture was partitioned with ethyl acetate and water and the organic phase washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (4:1 ethyl acetate:hexanes) to give methyl [6-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate (40.3 mg, 66% yield) as a white solid. 1H NMR (400 MHz, d6-DMSO): 7.58 (s, 1H), 7.47 (s, 1H), 7.45-7.42 (m, 2H), 7.31 (dd, 1H), 7.02 (d, 1H), 4.42 (s, 2H), 4.37 (d, 1H), 4.26 (d, 1H), 4.17 (br s, 1H), 3.77 (s, 3H), 3.60 (br m, 4H), 2.75 (tr, 2H), 1.85 (br, 1H), 1.63 (d, 2H), 1.25 (q, 2H). MS (EI) for C25H18FN5O4: 483 (MH+).