Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:17]=O)[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.[C-]#N.[Li+].O1CCCC1.[C:27](P(=O)(OCC)OCC)#[N:28].C(O)(C)(C)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH2:17][C:27]#[N:28])[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1
Reactant: O=Cc1cc(OC2CCCCO2)cc2ccoc12
Reactant: CCOP(=O)(C#N)OCC
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: N#CCc1cc(OC2CCCCO2)cc2ccoc12
Reaction time: 0.33 h

Procedure:
Combine 5-(tetrahydropyran-2-yloxy)benzofuran-7-carboxaldehyde (3.75 g, 0.015 mol) with lithium cyanide-tetrahydrofuran (1:1.5 complex, 0.215 g, 0.1 equivalent) in tetrahydrofuran (80 mL) under nitrogen. Add diethyl cyanophosphonate (3.0 mL, 1.3 equivalents) and stir at 20° C. for 2 days. Add tert-butanol (1.6 mL, 1.1 equivalents) then SmI2 in tetrahydrofuran (0.1 M solution, approximately 400 mL). Concentrate the solution in vacuo then redissolve in a solution of ethyl acetate:diethyl ether (approximately 3:1, 100 mL). Add saturated aqueous ammonium chloride and stir for 20 min, until the release of hydrogen cyanide is complete. Filter to remove insoluble material, then extract against 1 N hydrochloric acid. Dry over sodium sulfate, then filter and concentrate. Purification by a plug column (4:1 hexanes:ethyl acetate) to provide the tide compound as a light yellow oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][CH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:16]=2[O:15][C:14]1=[O:30]>C(Cl)(Cl)Cl>[CH3:12][CH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([S:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[O:9])[C:16]=2[O:15][C:14]1=[O:30]
Reactant: CC1C(=O)Oc2c(Sc3ccccc3Cl)cccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1C(=O)Oc2c1cccc2S(=O)c1ccccc1Cl
Yield: 63.2 %

Procedure:
A solution of m-chloroperbenzoic acid (1.3 g) in chloroform (20 ml) was added dropwise to a solution of 3-methyl-7-(2-chlorophenylthio)-2,3-dihydrobenzofuran-2-one (1.8 g) in chloroform (20 ml) in 10 minutes at a temperature below 6° C. with stirring, and the mixture was stirred at the same temperature for 30 minutes and then filtered. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and water in turn, dried and evaporated under reduced pressure. The oily residue was crystallized with ethanol to give 3-methyl-7-(2-chlorobenzenesulfinyl)-2,3-dihydrobenzofuran-2-one (1.2 g), mp. 120°-122° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[N:10]1([CH2:15][CH:16]([N:18]2[C:31]3[CH:30]=[C:29]([C:32](=[S:34])N)[CH:28]=[CH:27][C:26]=3[S:25][C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.S>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:32]([C:29]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:16]([CH3:17])[CH2:15][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:31]=2[CH:30]=1)=[S:34]
Reactant: Cc1ccccc1CN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: Cc1ccccc1CNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 20 h

Procedure:
2-Methylbenzylamine (6.0 cc) is added to a solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (3.70 g) in absolute ethanol (50 cc). The mixture is saturated with hydrogen sulphide and brought to 110° C. for 20 hours. After cooling to 20° C., the mixture is concentrated to dryness under reduced pressure (30 mm Hg, 4 kPa) at 40° C. and the residue is purified by chromatography on a column (height: 22 cm; diameter: 4.2 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with pure ethyl acetate (400 cc) and then with a 90:10 (by volume) mixture (400 cc) of ethyl acetate and methanol and collecting 80-cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give N-(2-methylbenzyl)-10- [(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2.6 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:2]2[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNc2nccnc2Cl)CC1

Procedure:
2,3-Dichloropyrazine (1.0 g, 0.0067 mol), tert-butyl-4-(aminomethyl)piperidine-1-carboxylate (1.6 g, 0.0075 mol) (Astatech) and cesium carbonate (2.4 g, 0.0075 mol) in acetonitrile (10 mL) were heated to 90° C. under nitrogen for 18 h. The reaction was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic extract was dried over sodium sulfate, filtered and chromatographed on silica using a gradient of 10 to 30% ethyl acetate/hexane to give the title compound as a foam. M.S.(M+1): 327.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:38]([O:42][C:43](=[O:61])[C@@H:44]([NH2:60])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=2)=[CH:48][CH:47]=1)([CH3:41])([CH3:40])[CH3:39]>C1COCC1>[C:38]([O:42][C:43](=[O:61])[CH:44]([NH:60][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=2)=[CH:48][CH:47]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccn2)cc1
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccn2)cc1)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
The product from Example Z (1.15 g, 4.50 mmol) was dissolved in 50 mL of THF at room temperature with stirring. To the solution were added O-(7-azabenzotriazol-1-y-)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 3.11 g, 8.18 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 1.11 g, 8.18 mmol), N,N-diisopropylethylamine (DIEA, 2.84 mL, 16.36 mmol) followed by the product from Example M (1.34 g, 4.09 mmol) in 50 mL of THF. After 3 hours, the solution was concentrated under reduced pressure, partitioned between ethyl ether and water (100 mL each), and separated. The organic layer was washed with 5% sodium bicarbonate (2×50 mL), brine (2×50 mL), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a solid. The solid was purified by silica gel chromatography with ethyl acetate. Appropriate fractions were combined and concentrated under reduced pressure to a solid (2.17 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C@@H:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([O:14]C(C)(C)C)=[O:13])[C:7]1=[O:23].FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C@@H:11]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:12]([OH:14])=[O:13])[C:7]1=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2cccc(O)c2)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2cccc(O)c2)C1=O
Yield: 99.7 %

Procedure:
A solution of Example 143B (0.026 g, 0.072 mmol) in dichloromethane (1.5 mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with a gradient of 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.022 g, 100%).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[F:18][C:19]1([F:32])[O:31][C:22]2=[CH:23][C:24]3[NH:28][C:27]([SH:29])=[N:26][C:25]=3[CH:30]=[C:21]2[O:20]1>C(O)(C)C>[ClH:2].[ClH:1].[F:32][C:19]1([F:18])[O:31][C:22]2=[CH:23][C:24]3[NH:28][C:27]([S:29][CH2:3][C:4]4[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]5[O:14][CH:15]=[CH:16][CH:17]=5)[CH:7]=[CH:6][N:5]=4)=[N:26][C:25]=3[CH:30]=[C:21]2[O:20]1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2cc3c(cc2[nH]1)OC(F)(F)O3

Procedure:
Following the procedure described in Example 12, the reaction of 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride with 2,2-difluoro-6-mercapto-5H-[1,3]dioxolo-[4,5-f]benzimidazole in isopropanol gives the title compound as a colorless solid; m.p. 180-183° C. (decomp.).
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][OH:14].Cl[C:16]1[N:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][CH:17]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[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:16]1[N:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: N#Cc1cccc(Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1cccc(C#N)n1
Temperature: 50 °C
Yield: 24 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0 mmol) and 6-chloropyridine-2-carbonitrile (150 mg, 1.0 mmol) in toluene (10 mL) was added sodium hydride (55% dispersion in mineral oil, 100 mg, 2.0 mmol) and the mixture heated at 50° C. for 6 h. Then 18-crown-6 (18 mg) was added and the mixture heated at 100° C. overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded the title compound (70 mg, 24%) as a white solid after trituration with diisopropylether. MS: m/e=292.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=2I)[N:5]=[C:4]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:19][CH2:18]2)[N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>CCOC(C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=2[C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[N:5]=[C:4]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:19][CH2:18]2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2c(I)c1OC
Solvent: CCOC(C)=O
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2c(-c2ccc(F)cc2)c1OC

Procedure:
This was prepared by the method of Example 1(a) from the product of step (c) (1.2/1 mixture, w/w) and 4-fluorophenylboronic acid. The crude product was purified on silica gel, eluting initially with hexane/EtOAc (4/1, v/v) followed by EtOAc. The title compound (63% based on the compound of step (c)) was obtained as a white foam. Rf 0.18 (EtOAc). MS m/z 511 (MH+). 1H NMR (CDCl3) δ: 2.00 (2H, m), 3.14 (4H, m), 3.35 (2H, m), 3.48 (3H, s), 3.55 (2H, m), 3.66 (4H, m), 3.84 (2H, m), 3.94 (2H, m), 3.97 (3H, s), 4.52 (2H, bs), 6.90 (1H, bs), 7.16 (2H, m), 7.32 (2H, m). Found: C,60.91; H,6.32; N,15.73; C26H31N6O4F 0.2.EtOAc requires C,60.90; H,6.17; N,15.91%.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:4]=1.C[O:16][C:17](=[O:30])[CH2:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][CH2:24]2>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[C:3]([CH2:2][S:29][C:26]3[CH:27]=[CH:28][C:20]([O:19][CH2:18][C:17]([OH:30])=[O:16])=[C:21]4[C:25]=3[CH2:24][CH2:23][CH2:22]4)[O:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: ClCc1cc(-c2ccc(Cl)cc2)no1
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(Cl)cc3)no2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 5-chloromethyl-3-(4-chloro-phenyl)-isoxazole and 12C. mp 92-94° C.; MS m/z 430 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:27]=1)#[N:2].[SH2:28]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:27]=1)(=[S:28])[NH2:2]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)ccc3o2)cc1
Reaction time: 16 h

Procedure:
Ethyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate (1.49 g, 4.09 mmol) was dissolved in a mixed solvent of pyridine (50 ml) and triethylamine (5 ml). A hydrogen sulfide gas was blown in for 10 minutes at room temperature and the mixture was stirred for 16 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give ethyl 4-[(5-thiocarbamoyl-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. Acetone (100 ml) and iodomethane (10 ml) were added to this solid, and the mixture was refluxed under heating for 2 hours. The reaction mixture was heated to room temperature. The resulting precipitate was collected by filtration to give ethyl 4-[[5-[(1-methylthio)iminomethyl]-2-benzofuranyl]carbonylamino]phenoxyacetate as a yellow solid. To this solid was added ethanol (50 ml) and benzylamine (0.5 ml, 4.6 mmol), and the mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated to about 10 ml under reduced pressure, and diethyl ether (40 ml) was added. The resulting precipitate was collected by filtration to give 1.970 g of hydriodide of compound (1) as a yellow solid (69% in three steps).
Reaction SMILES: C([O:3][C:4](=[O:30])[C@@H:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]=[CH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:28]([O:27][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:15]=[CH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:12]=1)[C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC=Cc2ccc3ccccc3n2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OCC=Cc2ccc3ccccc3n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-2-Ethoxy-3-[4-(3-quinolin-2-yl-allyloxy)-phenyl]-propionic acid ethyl ester (example 41) (150 mg, 0.37 mmol) was dissolved in ethanol (2 mL) and sodium hydroxide (1N, 2.0 mL, 2.0 mmol) added. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, added 2-propanol (2 mL) and diethyl ether (2 mL). The title compound was isolated by filtration.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=3)[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:42][N:41]=[N:40][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:25]=[C:26]([C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=3)[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1>[CH3:21][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:6]=2[C:19]([CH3:20])=[CH:18]1
Reactant: Cc1cn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CN1CCN(C)CC1)c1ccccc1NC2=O
Yield: 70.9 %

Procedure:
A solution of 1.75 g of 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one and 1.15 g of N-methylpiperazine in 50 ml of dry dioxane is warmed at 50° C. for 5 hours with stirring. After the mixture has cooled, the precipitate formed is filtered off. The filtrate is concentrated, 50 ml of saturated sodium bicarbonate solution are added, and the thus-prepared mixture is extracted several times with ethyl acetate. The combined extracts are dried over sodium sulfate and concentrated. 1.5 g of the title compound of m.p. 205° to 207° C. (from ethyl acetate) are obtained. M.p. of the dihydrochloride: 212° C. (D., from water). M.p. of the hemifumarate: 173° C. (from ethanol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>CN(C)C(=O)C>[C:10]([C:9]1[CH:8]=[CH:15][C:14]([F:16])=[CH:13][C:12]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)#[N:11]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(F)cc1F
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(F)cc1N1CCNCC1
Temperature: 122 °C
Reaction time: 1.5 h

Procedure:
A mixture of piperazine (Aldrich; 3.99 g), 2,4-difluorobenzonitrile, and N,N-dimethylacetamide (20 mL) is stirred for 1.5 h at 122° C. After cooling, the mixture is partitioned between dichloromethane and satd. aq. sodium bicarbonate. The organic layers are dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel and the appropriate fractions are combined and concentrated to give 1.44 g of 1(2-cyano-5-fluorophenyl)piperazine; 1H NMR (CDCl3) δ 3.01, 3.30, 6.56, 6.63, 7.40.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:30](Br)[CH:31]=[CH2:32]>>[CH2:32]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: C=CCOc1ccc(-c2nc(CCC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 363 and allyl bromide, white powdery 3-[2-(4-allyloxy-3-difluoromethoxy phenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])[CH3:36]>>[C:35]([C:38]1[CH:43]=[C:42]([C:23]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:22]=2[O:21][C:16]2[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=2)[O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=2)[CH:41]=[CH:40][CH:39]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: CC(=O)c1cccc(-c2cc(C(F)(F)F)ccc2Oc2cc(C)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c1
Yield: 72 %

Procedure:
The compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester is reacted with 3-acetyl phenyl boronic acid as in Example 38 to afford 0.186 g (72%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C32H28O5F3 549.1888, found 549.1880.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][O:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][NH:26][C:27](=[O:33])[CH:28]([CH3:32])[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27](=[O:33])[CH:28]([CH3:32])[C:29]([NH:1][CH:2]2[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]2=3)=[O:30])=[CH:34][CH:35]=1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: COc1ccc(CNC(=O)C(C)C(=O)O)cc1
Product: COc1ccc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)cc1

Procedure:
The title compound, MS: m/e=458.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(4-methoxy-benzyl)-2-methyl-malonamic acid.
Reaction SMILES: [O:1]=[C:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O[CH:27](N(C)C)[N:28]([CH3:30])[CH3:29])(C)(C)C>>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2](=[O:1])[C:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:27][N:28]([CH3:30])[CH3:29])[CH3:8]
Reactant: CCOC(=O)C(C(=O)Cc1ccccc1)c1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOC(=O)C(C(=O)C(=CN(C)C)c1ccccc1)c1ccccc1

Procedure:
Ethyl 3-oxo-2,4-diphenyl-butyrate (76 mg, 0.3 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (102 mg) as a red oil which was used directly in the next step.
Reaction SMILES: [CH2:1]1[CH2:13][N:12]2[C:4]3[C:5]([CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.CN(C)[CH:30]=[O:31]>>[CH2:10]1[CH2:11][N:12]2[CH2:13][CH2:1][CH2:2][C:3]3=[C:4]2[C:5](=[CH:6][C:7]([CH:30]=[O:31])=[CH:8]3)[CH2:9]1
Reactant: c1cc2c3c(c1)CCCN3CCC2
Reactant: CN(C)C=O
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c3c(c1)CCCN3CCC2
Reaction time: 0.17 h

Procedure:
9-JA is synthesized by the formulation julolidine with phosphorus oxychloride in N,N-dimethyl formamide by a procedure similar to that described for the formulation of N,N-dimethylaniline (Organic Synthesis, Coll. Vol. 4, Wiley, New York, 1963, pp 331-333). N,N-Dimethyl formamide (45 mL) is added to a round bottom flask fitted with a magnetic stirrer, pressure equalizing dropping funnel, and a Claisen head whose sidearm was fitted with a drying tube. The flask is flushed with dry nitrogen and then cooled in a dry ice/isopropyl alcohol bath. Phosphorus oxychloride (16 mL, about 26.3 g) is added. After 10 min, 19 g of julolidine is added dropwise with stirring. The reaction mixture is stirred for 15 min after addition of the julolidine is complete, heated on a steam bath for 2 hr, and poured into a slurry of about 400 mL of crushed ice and water. The resulting solution is carefully neutralized by the addition of 150 g of sodium acetate in 250 mL of water. The precipitated aldehyde is collected by filtration, and the filtrate is kept at 0° C. overnight. The additional precipitate thus formed is collected and combined with the first crop. The combined precipitates are treated with activated charcoal (Darco® G-60) and recrystallized from ethanol/water to give 21.2 g (96%) of 9-JA as light yellow needles, mp 81° C.-82° C. [lit. 83° C., J. Org. Chem., 17, 1281 (1952)].