Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH3:13][C:14]1[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]2[CH2:25][CH2:26][O:27][CH2:28][C:16]=2[CH:15]=1.[N:29]1([S:34]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.C([SiH](CC)CC)C>C(Cl)Cl>[OH:27][CH2:26][CH2:25][C:17]1[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]([CH3:13])=[C:15]([CH2:41][C:40]2[CH:43]=[CH:44][C:37]([S:34]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:36])=[O:35])=[CH:38][CH:39]=2)[C:16]=1[CH3:28]
Reactant: O=Cc1ccc(S(=O)(=O)N2CCCC2)cc1
Reactant: CCOC(=O)Cn1c(C)cc2c1CCOC2
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)N3CCCC3)cc2)c(C)c1CCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a flame-dried vial was charged with DCM (2 ml) and trimethylsilyl trifluoromethanesulfonate (0.081 ml, 0.448 mmol) was added at 0° C., followed by a solution of ethyl 2-(2-methyl-6,7-dihydropyrano[4,3-b]pyrrol-1(4H)-yl)acetate (50 mg, 0.224 mmol) and 4-(pyrrolidin-1-ylsulfonyl)benzaldehyde (53.6 mg, 0.224 mmol) in CH2Cl2 (5 ml) (cannulated), the mix was stirred at 0° C. for 15 min, neat triethylsilane (0.143 ml, 0.896 mmol) was added slowly, stirred for 30 min at 0° C., then slowly warmed to r.t. TLC confirmed that reaction was done. Therefore, it was quenched with sat. NaHCO3, extracted with DCM. Combined DCM was dried with Na2SO4, filtered and concentrated under vacuum. The residue was chromatographed on silica using a Biotage automated system (5-30-50% ethyl acetate/hexanes) to give ethyl 2-(2-(2-hydroxyethyl)-3,5-dimethyl-4-(4-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (34 mg, 0.076 mmol, 33.8% yield).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(Cl)(Cl)[Cl:13].S(Cl)(Cl)(=O)=O.[OH-].[Na+]>O>[Cl:13][C:6]1[S:2][C:3]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[C:4]=2[CH:5]=1
Reactant: NC1CCCc2sccc21
Reactant: ClC(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: NC1CCCc2sc(Cl)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A sample of 11.4 grams 4,5,6,7-tetrahydrobenzo[b]-thiophen-4-amine hydrochloride is stirred in 150 ml. of chloroform at about 10° C., and 6.1 ml. of sulfuryl chloride is added dropwise. The mixture is stirred for 3.5 hours at room temperature, and then about 20 ml. of 50% sodium hydroxide solution is added gradually to dissolve the suspended solid. The mixture is then poured into water and extracted with chloroform twice. The extracts are dried, evaporated to dryness, and the residue is distilled to give 7.4 grams of 2-chloro-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine, boiling point 94° C. to 98° C./0.5 Torr.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:20])[CH:3]1[O:8][CH:7]([C:9](Cl)([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.CC(C)([O-])C.[K+]>CS(C)=O>[Cl:20][C:2]([Cl:1])=[C:3]1[O:8][C:7](=[C:9]([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1
Reactant: NC(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc2c(c1)C(=C(Cl)Cl)OC(=C(Cl)Cl)O2

Procedure:
A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxamide (3.14 g.) and potassium t-butoxide (2.5 g.) in 50% aqueous dimethylsulphoxide (50 ml.) was heated at 80°-90° C. for 2 hours. The solid product was filtered off, dried and crystallised from ethanol to give 2,4-bis(dichloromethylene)benzo[1,3]dioxin-6-carboxamide, m.p. 217°-218° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]1[CH:14]([OH:15])[CH:13]=[CH:12][C:11]1=O)([OH:3])=[O:2].[OH-:17].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:14](=[O:15])[CH2:13][CH:12]([OH:17])[CH:11]=1)([OH:3])=[O:2]
Reactant: [OH-]
Reactant: O=C(O)CCCC/C=C\C1C(=O)C=CC1O
Agent: [Na+]
Product: O=C(O)CCCC/C=C\C1=CC(O)CC1=O

Procedure:
A solution of 1.0mmole of all-cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone (Example 1106) and 3.0 mmoles of sodium carbonate in 15 ml. of water is allowed to stand at room temperature for 3 hours. The solution is acidified with HCl, saturated with sodium chloride, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a mixture of the title compound and the isomeric compound, 2-(6-carboxy-2-cis-hexenyl)-3-hydroxycyclopent-4-en-1-one. Further treatment of this mixture with N/10 sodium hydroxide at room temperature for 30 minutes causes the rearrangement of the latter isomer to the title compound, which is isolated from basic solution as above.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)=[O:2].[SH:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O.O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][S:12][C:13]2[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CN1CCN(CCO)CC1
Reactant: Sc1nc2ccccc2[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Yield: 75.4 %

Procedure:
To a solution containing 1-formyl-4-(2-hydroxyethyl)piperazine (1.58 g, 10 mmol), 2-mercaptobenzimidazole (5.56 g, 37 mmol), and triphenylphosphine (9.26 g, 35.3 mmol) in dimethylformamide (100 mL), diethyl azodicarboxylate (5.19 g, 29.8 mmol) was added dropwise over 5 minutes with ice-cooling and stirring under argon. The mixture was stirred for 80 minutes at room temperature, and then water (2 mL) was added to the mixture so as to deactivate the reagent. The reaction mixture was concentrated under reduced pressure, and chloroform (200 mL) was added to the residue. Insoluble material was removed through filtration, and the filtrate was concentrated under reduced pressure. 2N Hydrochloric acid (20 mL) and ethyl acetate (100 mL) were added to the residue, and the liquid was partitioned. The organic layer was extracted with 2N hydrochloric acid (20 mL×2). The aqueous extract and the aqueous layer were combined, and the mixture was washed with chloroform (50 mL×2) . The pH of the mixture was adjusted to about 9 through addition of potassium carbonate, followed by extraction with chloroform (50 mL×3), washing the organic layer with saturated brine, drying over sodium sulfate anhydrate, and removing the solvent. The thus-formed crude product was crystallized from acetone-diethyl ether, thereby yielding 2.19 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 76%) as a colorless crystalline powder. The crystallization mother liquor was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (eluent: chloroform:methanol=50:1 to 20:1), thereby yielding 0.42 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 14%) as a colorless crystalline powder. The overall yield was 90%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]C([O-])(C)C.[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:18])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of 3-oxo-piperazine-1-carboxylic acid benzyl ester (2.00 g, 8.54 mmol) in DMF (30 mL) was added KOtBu (1.54 g, 13.7 mmol) under Ar. The resulting solution was stirred at room temperature for 15 min and cooled to 0° C. MeI (0.85 mL, 14 mmol) was then added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. DMF was removed in vacuo and the residue was chromatographed on silica (5-50% EtOAc:hexane) to obtain the title compound (1.40 g, 66%). 1H-NMR (CDCl3; 400 MHz): δ 7.32 (m, 5H), 5.13 (s, 2H), 4.13 (s, 2H), 3.70 (m, 2H), 3.34 (m, 2H), 2.97 (s, 3H)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:32])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[CH3:31][O:30][C:23]1[C:24]([O:28][CH3:29])=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH3:33])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:32])[CH:20]=1
Reactant: CN
Reactant: COc1cccc(-c2cc(C)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1OC
Product: CNCC1Cc2cc(C)cc(-c3cccc(OC)c3OC)c2O1

Procedure:
The title compound was prepared (0.094 g, 44%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethoxyphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.18 g, 0.40 mmol) and methylamine (0.123 g, 4.0 mmol). mp 85-89° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].[CH3:24][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:24])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:6])=[O:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N(CCO)CCBr
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N(CCO)CCBr)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-{[(2-bromoethyl)(2-hydroxyethyl)amino]sulfonyl}-5-hydroxy-1H-indole-2-carboxamide, described in Step B of Example 51, in 2:1 dichloromethane/MeOH was added excess trimethylsilyldiazomethane (solution in hexane). After stirring at room temperature for 16 hours, the mixture was concentrated in vacuo. Purification by preparative reversed phase HPLC afforded the titled product. HRMS (ES) exact mass calculated for C14H18BrN3O5S (M+H+): 420.0224. Found 420.0221.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.CN(C1C=CC=CN=1)C>C1COCC1>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[O:19])[O:7][N:6]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: Nc1cccc(O)c1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CC(C)(F)c1cc(NC(=O)Nc2cccc(O)c2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To THF (10 mL) was added phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from the previous step (500 mg, 1.9 mmol), 3-aminophenol (207 mg, 1.9 mmol) and dimethylaminopyridine (60 mg, 0.5 mmol) and the mixture stirred overnight at room temperature. The mixture was concentrated in vacuo and purified by chromatography on silica gel (10-50% EtOAc/hexanes) to afford 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-hydroxyphenyl)urea (390 mg, 1.4 mmol, 74%). LC-MS (ESI) m/z 280 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:26][C@@H:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(-c2ccc(F)cc2)cc1
Product: Fc1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
4′-Fluoro[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].I[CH3:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: CI
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Product: CC(C(=O)O)c1ccc(Cl)cc1Cl

Procedure:
prepared from 2,4-dichlorophenylacetic acid and iodomethane;
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)ccc1C(C)C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc(C(C)C)c(C)c1

Procedure:
A solution of 4-isopropyl-3-methylphenol (10.0 g, 67 mmol), methyl bromoacetate (6.6 mL, 70 mmol) and anhydrous potassium carbonate (10.1 g, 73 mmol) in 2-butanone (100 mL) was heated to reflux for 20 h. The mixture was cooled and partitioned between water (350 mL) and ethyl acetate (100 mL). The organic phase was washed with brine, and the aqueous phases were back-extracted in sequence with more ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford sufficiently pure product, methyl 2-(4-isopropyl-3-methylphenoxy)acetate, as an oil (15.0 g, 67 mmol, 100%). 1H NMR (CDCl3, 300 MHz): δ 7.05 (1H, d, J=9.3 Hz), 6.64-6.58 (2H, m), 4.51 (2H, s), 3.71 (3H, s), 2.98 (1H, J=7.0 Hz), 2.22 (3H, s), 1.11 (6H, d, J=7.0 Hz).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([C:18]#[C:19][CH2:20][O:21]C2CCCCO2)[NH:12]4)[CH2:5][C@H:4]([NH:28][C:29](=[O:35])[N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH2:3]1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:21][C:20]#[C:19][CH2:18][C:13]1[NH:12][C:11]2[C:17]3[C:14]=1[CH2:15][C@@H:16]1[C@@H:6]([C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]([NH:28][C:29](=[O:35])[N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])[CH2:3][N:2]1[CH3:1]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#CCOC5CCCCO5)c(c34)C[C@H]2N(C)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(CC#CO)c(c34)C[C@H]2N(C)C1
Yield: 50.7 %

Procedure:
213 mg (0.45 mmol) of 3-[6-methyl-2-[3-(tetrahydropyran-2-yloxy)propynyl]-8α-ergolinyl]-1,1-diethylurea is heated under reflux in 10 ml of ethanol with 2 ml of water and 176 mg (0.7 mmol) of pyridinium p-toluenesulfonate under argon for one hour. After evaporation and distribution in ethyl acetate and saturated bicarbonate solution, the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed over silica gel first with ethyl acetate/acetone=1:1 and later with methylene chloride/acetone=12:1. Recrystallization from ethyl acetate/hexane yields 90 mg (51%) of 3-[2-(1-hydroxypropyn-3-yl)-6-methyl-8α-ergolinyl]-1,1-diethylurea,
Reaction SMILES: [CH3:1]OC([C@@H]1C[C@@H](O)CCN1C(OC(C)(C)C)=O)=O.[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@H:26]([NH2:28])[CH2:25][N:24]1[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:22]>>[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@H:26]([NH2:28])[CH2:25][CH2:1][N:24]1[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:22]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@H](N)CCN1CC1CCCCC1

Procedure:
(2S,4R)-4-amino-1-cyclohexylmethyl-piperidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C14H27N2O2 [(M+H)+] 255, obsd. 255.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)=[CH:3][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccc(O)cc1
Product: Oc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 29.3 %

Procedure:
Using the procedure of example 1, 4-aminophenol (177 mg) was reacted with compound 1f (200 mg) to provide compound 39 (48 mg, 29%). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=8.0 Hz, 1H), 8.24 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.12 (d, J=4.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.05 (dd, J=8.0 Hz, 5.6 Hz, 1H), 7.00 (d, J=5.2 Hz, 1H), 6.98 (m, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H). MS (ESI) m/z: 304 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[ClH:15].[Cl:16][CH2:17][C:18]1[NH:19][CH2:20][CH2:21][N:22]=1>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:16].[ClH:15].[NH:22]1[CH2:21][CH2:20][N:19]=[C:18]1[CH2:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Reactant: ClCC1=NCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc2cc3[nH]c(SCC4=NCCN4)nc3cc2c1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
10.0 g of 1H-Naphth[2,3-d]imidazole-2-thiol and 8.0 g of 2-chloromethylimidazoline-hydrochloride were heated for 3 hours at 90° in 50 ml of dimethylformamide. The reaction mixture was cooled to room temperature and then diluted with 200 ml of toluene. The residue was suctioned filtered, washed well with toluene, and crystallised from 700 ml of methanol, with the addition of 300 ml of ether. 10.3 g of 2-[(2-Imidazoline-2-ylmethyl)thio]-1H-naphth[2,3-d]imidazol-dihydrochloride having an m.p. of 227°-228° were obtained.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:14]=1[C:28]1[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1>>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:14]2[CH:15]=[CH:16][C:17]([C:2]3[C:3]([O:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:18][C:13]=2[F:12])=[CH:29][N:30]=1
Reactant: OCCOc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3cccnc3OCCO)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-((3-bromopyridin-2-yl)oxy)ethanol and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C17H15FN4O2, 326.12; m/z found, 326.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=1.3, 2H), 8.15 (dd, J=4.9, 1.8, 1H), 7.84 (dd, J=7.4, 1.8, 1H), 7.65-7.52 (m, 3H), 7.08 (dd, J=7.4, 5.0, 1H), 6.87 (s, 2H), 4.80 (s, 1H), 4.40-4.32 (m, 2H), 3.70 (t, J=5.0, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C@@H:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][C:6]=2[CH:22]=1.[N:23]1[C:32]2[NH:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[CH2:33][CH2:34]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:23]1[C:32]2[NH:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[CH2:33][CH2:34][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C@@H:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][C:6]=2[CH:22]=1
Reactant: OCCc1ccc2c(n1)NCCC2
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(O)cc2Cc2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1Cc2ccc(OCCc3ccc4c(n3)NCCC4)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
To a solution of ethyl (S)-10,11 -dihydro-3-hydroxy-5H-dibenzo[a,d]cycloheptene-10-acetate (200 mg, 0.67 mmole), 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1 -ethanol (241 mg, 1.35 mmole), and PPh3 (354 mg, 1.35 mmole) in dry THF (5 mL) was added diisopropyl azodicarboxylate (0.27 mL, 1.35 mmole) at 0° C. The mixture was allowed to warm to RT as the bath warmed. After 18 hr, the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (1:4.5 hexanes/Et2O) to give the title compound (94 mg, 31%) as a clear oil: MS (ES) m/e 457 (M+H)+.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C:20]3[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=3[CH:18]([CH2:29][CH3:30])[C:17]([CH3:31])=[N:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>O1CCOCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C:20]3[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=3[CH:18]([CH2:29][CH3:30])[C:17]([CH:31]=[O:2])=[N:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCC1C(C=O)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Yield: 97.4 %

Procedure:
6.05 g of selenium dioxide are added within 1.5 hours to a stirred suspension of 19.1 g (0.05 mole) of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine in 150 ml of 80% aqueous dioxane at an inner temperature of 84° to 87° C. The metallic selenium is removed from the mixture by clarification, and the yellow solution is evaporated in vacuo. The thick, honey-like residue is stirred with 100 ml of water, whereupon the title compound separates as a yellow powder. The product is filtered off, washed five times with 10 ml of water each and dried in vacuo. 19.3 g (96%) of crude 1-(3,4-dimethoxyphenyl)-4-formyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine are obtained; m.p.: 103°-105° C. When recrystallized from acetone and cyclohexane the product melts at 108°-110° C. C22H24N2O5 =396.45.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31](=[O:33])[NH:37][CH2:36][C:35]([F:39])([F:38])[F:34])[CH2:25]2)=[O:22])=[CH:19][N:20]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NCC(F)(F)F)C2)cn1
Yield: 62 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) was converted, using 2,2,2-trifluoroethylamine instead of methylamine, to the title compound (51 mg, 62%) which was obtained as an off white solid. MS: m/e=532.0 [M+H]+.
Reaction SMILES: O1CCCC1.[CH2:6]([NH:13][C:14](=O)[C:15]1[C:16](=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>CO>[CH2:20]([NH:19][CH2:17][C:16]1[C:15]([CH2:14][NH:13][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCNC(=O)c1ccccc1C(=O)NCCCCCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNCc1ccccc1CNCCCCCCC
Yield: 12.9 %

Procedure:
To a 1M solution of borane-tetrahydrofuran complex (24 ml) was added dropwise under ice cooling a 5 ml tetrahydrofuran solution containing 3.6 g of N,N'-diheptylphthalamide obtained in Example 2 under an argon gas stream, and the mixture was warmed up slowly and then heated under reflux for one hour. After cooling, 2 ml methanol was added dropwise under ice cooling, and the mixture was heated under reflux for 30 minutes. After cooling in ice, 4.24 ml concentrated hydrochloric acid was added, and the mixture was again heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was basified by addition of an aqueous solution of caustic soda and extracted with chloroform. After distilling off the chloroform from the extract, the residue was purified by silica gel column chromatography, giving 0.43 g of N,N'-diheptyl-o-xylylenediamine.