Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:6]=[CH:5][C:4]=1[NH:13][NH2:14].[F:15][C:16]([F:35])([F:34])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)=[C:23]([CH3:32])[CH:22]=1)=O>>[F:2][C:3]1[CH:8]=[C:7]([S:9]([NH2:10])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[N:13]1[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[CH:29][S:30][CH:31]=3)=[C:23]([CH3:32])[CH:22]=2)=[CH:18][C:17]([C:16]([F:35])([F:34])[F:15])=[N:14]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1F
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1cscn1
Agent: Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2F)ccc1-c1cscn1

Procedure:
The title compound was prepared according to the procedure of Example 60 using 2-fluoro-4-sulfamoylphenylhydrazine hydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and 4,4,4-trifluoro-1-[3-methyl-4-(4-thiazolyl)phenyl]butane-1,3-dione instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 95.2 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 1.18 ml (3.48 mmol) of stearoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.20 g of the desired compound (95.2%, colorless powder), mp: 88.0°-89.0° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:16][CH:4]1[CH2:5][O:6][C:7]1[C:8]([N+]([O-])=O)=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>COCCOC>[CH2:17]([O:24][C:8]1[C:7]([O:6][CH2:5][CH:4]2[O:3][CH2:16]2)=[CH:12][CH:11]=[CH:10][N:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ncccc1OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(COc2ncccc2OCC2CO2)cc1

Procedure:
3.6 g of a sodium hydride suspension (55%) are added in portions, at 0°-5°, to 15.7 g of 3-(2,3-epoxypropoxy)-2-nitro-pyridine and 9.0 g of benzyl alcohol dissolved in 150 ml of 1,2-dimethoxyethane, with stirring and cooling, and the mixture is stirred for a further 3 hours at 0°-5° and for 2 hours at 20°-25°. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, the solution is washed with water and the ethyl acetate solution is evaporated. The residue (20 g) is chromatographed on 400 g of silica gel and eluted with toluene (250 ml fractions). 2-Benzyloxy-3-(2,3-epoxypropoxy)-pyridine is obtained in the form of an oil from fractions 28-36.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:19][CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Yield: 92.9 %

Procedure:
The title compound (0.39 g, 93%) was prepared as a white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.23 g, 1.13 mmol), 1,1-dimethylethyl 4-{[(5-bromo-2-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.35 g, 0.94 mmol), 2M Na2CO3 (5 mL) and Pd(PPh3)4 (10 mg, 0.01 mmol) in DME (5 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CD3OD): δ 8.46 (d, 1H, J=2.7 Hz), 8.05-8.00 (m, 3H), 7.86 (d, 2H, J=8.5 Hz), 6.92 (d, 1H, J=8.6 Hz), 4.21 (d, 2H, J=6.3 Hz), 4.15-4.05 (m, 2H), 3.14 (s, 3H), 2.85-2.70 (m, 2H), 2.00-1.95 (m, 1H), 1.90-1.75 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19](=[O:29])[N:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@@H:32]([CH2:40][OH:41])[NH:31]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH2:25]([N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:19]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10]([N:31]2[C@H:32]([CH2:40][OH:41])[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30]2)=[O:11])[N:4]=1)=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C(=O)O)c(C)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 4.5 %

Procedure:
To a stirred solution of 2-(4-chloro-3-dibutylcarbamoyl-5-methyl-pyrazol-1-yl)-5-methoxy-benzoic acid (0.35 g, 0.82 mmol) and (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (0.13 g, 0.82 mmol) in dichloromethane (8 mL) under nitrogen atmosphere was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.16 g, 0.82 mmol) and hydroxybenzotriazole (0.13 g, 0.82 mmol). The mixture was stirred at ambient temperature for 5 minutes. Triethylamine (0.34 mL, 2.5 mmol) was added to the mixture. The reaction was stirred for 60 hours at ambient temperature. The mixture was washed with water and purified by eluting through a silica gel column with a 10 to 100% ethyl acetate/heptane gradient to afford the title compound (21 mg, 4.5% yield). MS (ESI) [m/e, (M+H)+]=567.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.75-7.36 (m, 7H), 4.13-5.41 (m, 4H), 3.80-3.96 (m, 3H), 2.51-3.71 (m, 8H), 2.17-2.32 (m, 3H), 1.48-1.68 (m, 4H), 1.19-1.44 (m, 4H), 0.70-0.97 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27](OCC)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1 H), 8.57 (s, 1 H), 7.67 (s, 1 H), 7.21 (dd, J=8.6, 5.5 Hz, 2 H), 7.01 (t, J=8.7 Hz, 2 H), 4.39 (t, J=7.8 Hz, 2 H), 4.12 (s, 2 H), 3.65 (m, 2 H), 3.59 (m, 2 H), 3.41 (s, 3 H), 3.14 (t, J=7.0 Hz, 2 H), 2.95 (s, 3 H), 2.21 (m, 2 H); HRMS C23H26FN3O6S (M+H)+ calcd 492.1526, found 492.1603.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH2:8][O:9][C:10]([CH:12](P(OCC)(OCC)=O)[CH3:13])=[O:11].[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1)=O>C1(C)C=CC=CC=1>[Br:31][C:27]1[CH:26]=[C:25]([C:23]([CH3:22])=[C:12]([CH3:13])[C:10]([O:9][CH2:8][CH3:7])=[O:11])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(=O)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)=C(C)c1cccc(Br)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a suspension of potassium tert-butoxide (183.1 g, 1.63 mol) in toluene (1400 ml) under an atmosphere of nitrogen was slowly added triethyl 2-phosponopropionate (361.1 g, 1.52 mol) with ice cooling at such a rate that the internal temperature was maintained at approximately 20° C. The resultant yellow solution was stirred at room temperature for 3 h after which time it was cooled in an ice bath. To this cooled solution was added a solution of 3-bromoacetophenone (274.2 g, 1.38 mol) in toluene (400 ml) at such a rate that the internal temperature did not rise above 20 ° C. The resultant red-brown solution was then stirred at room temperature for 18 h. After this time, more potassium tert-butoxide (38.7 g, 0.34 mol) was added, and the resultant mixture was stirred at room temperature for an additional 20 h. The reaction was quenched by the cautious addition of water (2000 ml), and the layers were separated. The organic layer was washed with water (4×2000 ml), and was then concentrated in vacuo to give the crude product as a brown oil (344 g) which was distilled under reduced pressure to give the impure title compound (2:3 mixture of geometric isomers) as a colourless liquid (212 g) which was contaminated with small amounts of triethyl 2-phosphonopropionate and 3-bromoacetophenone. In the present synthetic route the impure title compound was taken forward into the next step without any further purification. However, purification, for example using flash chromatography eluting with 5% ethyl acetate in hexane, affords the analytically pure title compound as a clear colourless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[CH2:4][CH:3]1[NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25].[C:27](=O)([O-])[O-].[K+].[K+].IC.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:27][N:8]1[C:2](=[O:1])[CH:3]([NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH2:4][C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]1=2
Reactant: O=C(CCc1ccc(Cl)cc1Cl)NC1CC(=O)c2ccccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(NC(=O)CCc2ccc(Cl)cc2Cl)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
A 100 mL round bottom flask was charged with N-(2,5-dioxo-3,4-dihydro-1H-benzo[b]azepin-3-yl)-3-(2,4-dichlorophenyl)-propionamide (2.5 g, 6.38 mmole), potassium carbonate (1.76 g, 12.7 mmole), DMF (20 mL), and iodomethane (3.55 g, 25 mmole). The reaction mixture was stirred at room temperature for 5 hr. and then poured into saturated sodium bicarbonate (500 mL). The aqueous mixture was extracted with ethyl acetate (3×200 mL). The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting solid was swished with a minimum of warm ether and filtered to give 2.1 g (81%) of the product. mp 182°-184° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.C(N)(=[S:15])C.Cl.O>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH2:10])=[S:15])=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=S)c1ccc(C(F)(F)F)cc1
Temperature: 95 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
A solution of α,α,α-trifluoro-p-tolunitrile (603.5 g, 3.53 mol) in dry DMF (2 L) under N2 was heated at 70° C. and the Thioacetamide (505 g, 1.9 eq.) was added. The reaction mixture was treated with HCl gas before 15 minutes and was stirred at 95° C. for 6 hours. This treatment was operated 3 times and the mixture was stirred at rt for 24 hours. After cooling at 0° C., water was added and the residue was extracted with diethyl ether (4*1 L). The organic layer was washed with water (3*1 L), dried over Na2SO4 and then evaporated off. The brownish powder was washed with pentane (3 L) to give the title compound (530.3 g, 2.59 mol) as brown solid in a 73% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:11](OC)=[O:12])([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[H-].C1(C)C=CC=CC=1>ClCCl>[CH:11]([C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:12]
Reactant: COC(=O)C1(C(=O)OC)CCOCC1
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C1(C=O)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of dimethyl tetrahydro-4H-pyran-4,4-dicarboxylate (3.9 g, 19.3 mmol) in dichloromethane (38 mL) was added dropwise a 1.01 M solution of diisobutylalminium hydride in toluene (38.2 mL, 38.6 mmol) at −78° C. over 30 min period. After being stirred at this temperature for 3 h, the mixture was quenched with followed by addition of aq. ammonium chloride and 2N hydrochloric acid. The mixture was allowed to warm to room temperature and filtered through a pad of celite. The filtrate was washed with water and dried over sodium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethylacetate 5:1) to affored 2.14 g (64%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]([CH2:32][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=c1[nH]n2c(=O)[nH]nc2c(-c2ccncc2)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2c(=O)c(-c3ccc(Cl)cc3)c(-c3ccncc3)c3n[nH]c(=O)n32)cc1
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
To the solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione (8 mg, 0.023 mmol), prepared as described in Example 9 in DMF (0.3 ml) was added K2CO3 (5 mg, 0.036 mmol) followed by 4-(bromomethyl)benzonitrile (5 mg, 0.025 mmol). After 15 min, the reaction mixture was diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 4-((7-(4-chlorophenyl)-3,6-dioxo-8-(pyridin-4-yl)-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-5(6H)-yl)methyl)benzonitrile, (4.2 mg, 32%) as a mono trifluoroacetate salt as a yellow foam. MS M+H=454; 1H (CD3OD) δ 8.68(2H), 7.71-7.65(6H), 7.28(2H), 7.20(2H), 5.94(2H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH2:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH:23]=[CH2:24]>>[CH2:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:27][CH2:26]1)[CH:23]=[CH2:24]
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: C=CCN1CCNCC1
Product: C=CCN1CCN(CCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 39 %

Procedure:
Using the procedure of Example 7, 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one was reacted with 1-allyl-piperazine to obtain a 39% yield of 11-[3-(4-allyl-1-piperazinyl)-propionyl]-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 205°-207° C. after crystallization from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:19].OO>CO>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)c1OCc1ccccc1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CO
Product: Cc1cccc(O)c1OCc1ccccc1
Yield: 70 %

Procedure:
2-Benzyloxy-3-methylbenzaldehyde prepared by the above 2-(1) 20.0 g (88.4 mmol) was dissolved in methanol 100 ml and thereto was added sulfuric acid 20.0 g (203 mmol) and then added 30% hydrogen peroxide 30.1 g (265 mmol). The mixture was refluxed for 2 hours. After disappearance of the raw material, the solution was concentrated in vacuo, neutralized with a saturated sodium bicarbonate solution and extracted with methylene chloride. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate) to give 2-benzyloxy-3-methylphenol 13.3 g (yield: 70%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=O)[CH:4]=[C:5](SC)[S:6]C.O.[NH2:14][NH2:15]>C(O)C>[C:2]([C:3]1[N:14]=[N:15][C:5](=[S:6])[CH:4]=1)([CH3:12])([CH3:11])[CH3:1]
Reactant: NN
Reactant: CSC(=CC(=O)C(C)(C)C)SC
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1=CC(=S)N=N1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a stirred solution of 4,4-dimethyl-1,1-bis(methylthio)-1-penten-3-one (18.4 g) in ethanol, was added dropwise with stirring hydrazine hydrate (5.3 g), keeping the temperature below 25°. The reaction mixture was stirred briefly at room temperature, then refluxed for 2 hours. Evaporation of the solvent, and trituration with ether, afforded 3-t-butylpyrazole-5-thione (7.8 g, 20% yield), of melting point 147°-8°.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:9][C:8]1[CH:10]=[CH:11][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCC=O
Reactant: CC(C)Oc1ccc(N)cc1
Product: CCCCNc1ccc(OC(C)C)cc1
Yield: 87.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4-isopropoxyaniline (500 mg, 3.31 mmol) and butyraldehyde (300 μL, 3.31 mmol) were converted to the title compound (600 mg, 83%). 1H NMR (CDCl3) δ 6.88-6.74 (m, 2H), 6.67-6.51 (m, 2H), 4.41-4.30 (m, 1H), 3.08 (t, J=7.0 Hz, 2H), 1.66-1.37 (m, 4H), 1.30 (s, 3H), 1.29 (s, 3H), 0.99-0.87 (m, 3H); MS(ESI+) m/z 208.2 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=2[F:27])[CH2:16][N:15]2[C:28]([C:31]([O:33]C)=O)=[CH:29][N:30]=[C:14]12)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:27][C:21]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=1[C@H:17]1[CH2:16][N:15]2[C:28]([C:31]3([OH:33])[CH2:2][CH2:1]3)=[CH:29][N:30]=[C:14]2[C@H:13]([NH:12][C:10](=[O:11])[O:9][C:5]([CH3:7])([CH3:8])[CH3:6])[CH2:19][CH2:18]1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3(O)CC3)cnc21
Reaction time: 1.5 h
Yield: 42.2 %

Procedure:
Ethylmagnesium bromide (3 M in ether; 0.17 mL, 0.51 mmol) was added dropwise over 15 min to a solution of titanium(IV) isopropoxide (0.08 mL, 0.26 mmol) and methyl (6S,9R)-9-[(tert-butoxycarbonyl)amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine-3-carboxylate (54 mg, 0.13 mmol) in ether (0.9 mL) at 0° C. After 1.5 h, additional titanium(IV) isopropoxide (0.08 mL, 0.26 mmol) and ethylmagnesium bromide (3 M in ether; 0.17 mL, 0.51 mmol) were added. After 1.5 h, the mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed with saturated brine, dried with magnesium sulfate, filtered, and concentrated. Purification by reverse phase HPLC (C-18, 80% water/acetonitrile→40% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (23 mg). MS 420.2 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
Combine methyl-4-bromobenzoate (1.0 g, 4.65 mmol), 2-chlorophenylboronic acid (799 mg, 5.1 mmol), Pd(OAc)2 (51 mg, 0.46 mmol) and sodium carbonate (1.5 g, 13.9 mmol) in dimethylformamide (20 mL) and water (2.0 mL) with stirring. Purge the reaction mixture with argon, add triphenylphosphine (61 mg, 0.23 mmol) and purge again with argon. Place the sealed reaction in an oil bath maintained at 80° C. and allow to stir for 1 hour. Cool the reaction to room temperature, dilute with ethyl acetate and filter through a short plug of celite with additional ethyl acetate. Wash the organics with water, dry over magnesium sulfate, filter and evaporate. Purification by flash column chromatography yields 2′-chlorobiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in tetrahydrofuran (0.25M) and add an equal volume of 1M sodium hydroxide. Stir vigorously at room temperature for 15 hours. Upon completion, acidify the reaction with conc. HCl and extract with ethyl acetate. Evaporation of the solvent yields 762 mg (67%) of the title compound. MS (m/e): 231.1 (M−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[N:13]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)[C:12]2=[S:31])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9]C.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[N:13]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=3)[C:12]2=[S:31])[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: COCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CO)c(F)c1
Temperature: -70 °C
Yield: 7.7 %

Procedure:
The title compound was prepared according to General Method 9. A solution of 4-(3-(3-fluoro-4-(methoxymethyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (80 mg, 0.177 mmol) was dissolved in DCM (3 mL) and stirred at −70° C. BBr3 (0.05 mL, 0.54 mmol) in DCM (3 mL) was added drop wise at −78° C. and the reaction mixture was allowed to warm to and stirred at RT for 2 h. The reaction mixture was poured in ice (20 g) and neutralized with saturated NaHCO3 solution, extracted with ethyl acetate (20 mL×2). The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography to obtain 6 mg of 4-(3-(3-fluoro-4-(hydroxymethyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile, HPLC, Column: YMC POLYMER C18, 4.6×150 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 15 min, hold for 3 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 13.814 min, M+1, 438.