Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[I-:18].[Na+].CNC1CCCCC1NC>O1CCOCC1.[Cu]I>[I:18][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: [I-]
Reactant: Fc1ccc(-n2ncc3c(Br)cccc32)cc1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncc3c(I)cccc32)cc1
Temperature: 110 °C
Yield: 95.2 %

Procedure:
4-Bromo-1-(4-fluorophenyl)indazole (291 mg, 1 mmol), copper(I)iodide (9.5 mg, 0.05 mmol), sodium iodide (300 mg, 2 mmol) and (1R,2R)—(N,N′-dimethylcyclohexane-1,2-diamine (14.2 mg, 0.1 mmol) in dioxane (1 ml) were mixed and stirred in argon at 110° C. All starting material was consumed after 24 h. The mixture was cooled and ammonia (5 ml, 28% in water) and water (20 ml) were added followed by extraction with DCM (2×15 ml). The organic phase was concentrated and the crude product was purified by flash chromatography (EtOAc/Heptane) to give the title compound (322 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)=[N:9]2)=[CH:5][CH:4]=1.[Cl-].[NH4+]>O1CCOCC1.O.[Zn]>[NH2:26][C:22]1[CH:21]=[C:20]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=3)[N:9]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc(N)c3)n2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
1.6 g (3.98 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-pyrimidin-2-amine were dissolved in a mixture of 100 ml of dioxane and 30 ml of water and 2.12 g (40 mmol) of ammonium chloride and 1.05 g (16 mmol) of metallic zinc were added successively. The reaction mixture was stirred at 100° C. for 6 hours. The suspension was then filtered through a celite pad and the filtrate evaporated. The residue was partitioned between dichloromethane and aqueous sodium hydrogenocarbonate, dried over sodium sulphate and evaporated again, giving 1 g (67%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>C(O)C.O1CCCC1>[C:21]([C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([OH:25])=[O:3])=[CH:8][CH:9]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)/C=C/c1ccc(C#Cc2cccc(C(C)(C)C)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C#Cc2ccc(/C=C/C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of (E)-3-[4-(3-tert-butyl-phenylethynyl)-phenyl]-acrylic acid ethyl ester (Intermediate 103, 0.015 g, 0.047 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 2M solution of lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 10% aqueous hydrochloric acid and evaporated in vacuo to a solid that was washed with water and hexane and dried to afford the title product as a white solid (0.012 g, 85%). 1H NMR (300 MHz, CDCl3): δ 7.78 (d, 1H, J=16.2 Hz), 7.59–7.26 (m, 8H), 6.47 (d, 1H, J=16.2 Hz), 1.34 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=O.[CH2:17]([NH2:20])[CH2:18][NH2:19]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]12[NH:20][CH2:17][CH2:18][N:19]1[C:10](=[O:12])[C:9]1[C:8]2=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1C(=O)c1cccs1
Reactant: NCCN
Product: O=C1c2ccccc2C2(c3cccs3)NCCN12

Procedure:
Condense o-(2-thienoyl)benzoic acid with ethylenediamine by the procedure of Example 1 to obtain 9b-(2-thienyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one and reduce with lithium aluminum hydride as described in Example 1 to obtain 1,2,3,4,5,6-hexahydro-1-(2-thienyl)-2,5-benzodiazocine, m.p. 148° C. The dihydrochloride melts at 241° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: COc1cccc(N)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1cccc(Nc2ncc3c(n2)CCN(C(=O)c2cccnc2)C3)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3-methoxyaniline (0.012 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 51.7% yield (0.017 g, 0.047 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26](O)=[O:27])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1N=C[N:32](C(N2C=NC=C2)=O)C=1.C([O-])(=O)C.[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26](=[O:27])[NH2:32])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c(CCC(=O)O)ccc2-c2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-n2c(CCC(N)=O)ccc2-c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-[2-(2-carboxy-ethyl)-5-phenyl-pyrrol-1yl]-benzoic acid tert-butyl ester (1.33 mmol, 1.0 eq.) in THF (10 ml) was added CDI (1,1′ carbonyldiimidazole, 1.60 mmol, 1.2 eq). The mixture was stirred at 45° C. for 2 h. To the reaction mixture was then added ammonium acetate (1.72 mmol, 1.3 eq.). The mixture was stirred at 45° C. for 16 hours.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
Degassed DMF (argon sparged, 100 mL) was added to Intermediate 1b (8.00 g, 31.3 mmol) and [N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium (Strem Chemicals Inc.; 594 mg, 0.93 mmol). Triethylamine (8.66 mL, 62.6 mmol) was added slowly to ice cold formic acid (2.34 mL, 62.6 mmol) and stirred for 20 min; this was then added to the DMF solution. The reaction was heated to 60° C. for 18 h. After cooling, the mixture was partitioned between DCM (200 mL) and water (600 mL). The aqueous layer was extracted DCM (3×) and the combined organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, using 0-100% EtOAc in cyclohexane, afforded the title compound (7.10 g, 27.4 mmol, 88%). 1H NMR (400 MHz, CDCl3): 1.88-1.92 (1H, d, J=4.8 Hz), 1.98-2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H, br s), 7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[O:22][CH3:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 77.7 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (660 mg, 2.4 mmol) and 2-methoxybenzoyl chloride (0.7 mL, 4.7 mmol) in THF (20 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methoxy-benzamide as a white solid (760 mg, 78% yield): mp, 286–287° C.; 1H NMR (DMSO-d6) (at 340K) δ 2.09–2.14 (m, 1H, CHH), 2.55–2.66 (m, 2H, CH2), 2.85–2.98 (m, 1H, CHH), 4.14 (s, 3H, OCH3), 5.19 (dd, J=5.5, 12.9 Hz, 1H, NCH), 7.17 (t, J=7.2 Hz, 1H, Ar), 7.30 (d, J=8.3 Hz, 1H, Ar), 7.61–7.68 (m, 2H, Ar), 7.89 (t, J=7.7 Hz, 1H, Ar), 8.12 (dd, J=1.8, 7.9 Hz, 1H Ar), 9.03 (d, J=8.5 Hz, 1H, Ar), 11.17 (s, 1H, NH), 11.64 (s, 1H, NH); 13C NMR (DMSO-d6) (at 340K) δ 22.09, 31.02, 49.29, 56.19, 112.65, 116.31, 117.93, 120.66, 121.14, 125.52, 131.59, 131.75, 134.34, 136.22, 137.00, 157.64, 163.82, 166.69, 168.15, 169.43, 172.32; Anal Calcd for C21H17N3O6: C, 61.92; H, 4.21; N, 10.31. Found: C, 62.05; H, 4.10; N, 10.38.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:28]([NH:35][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 120.8 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), benzylamine (18.2 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 45.2 mg (76%) of the title compound as a TFA salt (1.5 H2O, 2.1 TFA, effective MW=711.98). 1H NMR (DMSO-d6): δ 9.86 (1H, s), 9.14 (1H, t, J=5.4), 8.73 (1H, d, J=4.8), 8.29 (4H, m), 7.56 (1H, d, J=7.0), 7.74 (2H, m), 7.89 (2H, m), 7.31 (5H, m), 7.16 (1H, d, J=7.8), 6.93 (1H, t, J=7.3), 4.46 (2H, d, J=6.1). ESIMS (M+H+): 446.5.
Reaction SMILES: O.Cl.[O:3]=[C:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(OCC)C.Cl[C:16]([O:18][CH2:19][Cl:20])=[O:17].[OH-].[Na+]>O>[Cl:20][CH2:19][O:18][C:16]([N:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)=[O:17]
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)OCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C1CCN(C(=O)OCCl)CC1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 1 g of 4-oxopiperidine hydrochloride monohydrate in 0.7 ml of water was added 2.2 ml of diethyl ether, and the mixture was stirred at 0° C. Chloromethyl chloroformate (0.3 ml) was added dropwise, and the mixture was stirred at 0° C. for 5 minutes. Next, 0.8 ml of a 17N aqueous sodium hydroxide solution and 0.3 ml of chloromethyl chloroformate were divided into three portions and alternately added dropwise, and the resulting mixture was stirred at 0° C. for additional 20 minutes. The reaction mixture was diluted with 5 ml of a saturated aqueous saline, and extracted three times with 5 ml of diethyl ether. The organic layer thus obtained was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 1.7 g (100%) of 1-chloromethoxycarbonyl-4-oxopiperidine.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Zr+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH3:10][Si:11]1([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)[CH2:14][CH2:13][CH2:12]1.[Li]>ClCCl>[Cl-:1].[Cl-:1].[CH3:10][Si:11]1([C:15]2[CH:23]([Zr+2:9][CH:4]3[CH:8]=[CH:7][CH:6]=[CH:5]3)[C:18]3[C:17]([CH:16]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][CH2:14]1
Reactant: C[Si]1(C2C=Cc3ccccc32)CCC1
Reactant: [Zr+3]C1C=CC=C1
Agent: [Cl-]
Agent: [Li]
Solvent: ClCCl
Product: C[Si]1(C2=Cc3ccccc3C2[Zr+2]C2C=CC=C2)CCC1
Reaction time: 8 h
Yield: 144.1 %

Procedure:
5 g (19.03 mmol) of cyclopentadienylzirconium trichloride (CpZrCl3) was placed into a flask with 20 mL of dichloromethane to form suspension. 3.92 g (19.03 mmol) of lithium 1-(1-methyl-1-silacyclobutyl)indene was also placed into another flask with 20 mL of dichloromethane to form suspension. The suspension of CpZrCl3 in the first flask was slowly added into the suspension of lithium 1-(1-methyl-1-silacyclobutyl)indene in the second flask, and then the remained reactant in the first flask was washed with 10 mL of dichloromethane and added into the second flask. After repeating the washing and addition process for three times, the reaction mixture was stirred overnight. After the completion of reaction, LiCl was filtered and removed from the formed yellowish solution with 11G4 filter. The solvent was then evaporated from the filtrate under vacuum and the remaining volatile material was also removed under vacuum at 50° C. overnight. The concentrate was then sublimated at 130° C. in the presence of 50μ Hg to obtain 5.85 g (72% of yield) of pure ((1-methyl-1-silacyclobutyl)-indenyl)(cyclopentadienyl)zirconium dichloride having the following 1H NMR (CDCl3, ppm) data: δ7.95 (d, 1H), 7.92 (d, 1H), 7.42-7.28 (m, 2H), 7.14 (d, 1H), 6.84 (d, 1H), 6.10 (s, 5H, C5H5), 2.38-2.15 (m, 2H), 1.57-1.27 (m, 4H), 0.74 (s, 3H).
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][CH:10]2[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccnc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(CC2CCNCC2)c1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of 1-(1,1-dimethylethyloxycarbonyl)-4-(3-pyridylmethyl)piperidine (500 mg, 1.80 mmol) in chloroform (14 mL) was cooled to 0° C. and treated with trifluoroacetic acid (5 mL, 65.14 mmol). The resulting mixture was stirred for 1 h and then made basic by addition of aqueous sodium hydroxide. The organic extracts were separated and the aqueous was reextracted three more times with chloroform. The chloroform extracts were combined, dried over sodium sulfate, filtered and concentrated on a rotary evaporator to give the title compound as a colorless oil (300 mg, 1.70 mmol, 95%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])[N:19]=[C:18]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])[CH2:17]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:38][Mg]Cl>O1CCCC1>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH:16]([C:12]2[CH:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:38])[CH3:2])=[CH:9][CH:8]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:17][C:18]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:31])([F:32])[F:33])[OH:29])=[N:19]1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(-c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)cc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
To a mixture of 5-(4′-acetyl-biphenyl-3-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (25.0 mg, 0.05 mmol) prepared in Example 225 in tetrahydrofuran (1.0 mL), was slowly added methylmagnesium chloride (in 3.0 M tetrahydrofuran, 77.0 uL, 0.23 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 5 hours, quenched with a saturated solution of ammonium chloride at 0° C., and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 20.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.CC1N=C([N+]([O-])=O)[C:14]([OH:20])=[CH:13]C=1.[H-].[Na+].ClCC(OC)=O>CS(C)=O>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:13][C:14](=[O:20])[NH:1][C:2]=2[N:3]=1
Reactant: Cc1ccc(O)c(N)n1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: COC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c(n1)NC(=O)CO2
Temperature: 100 °C

Procedure:
A solution of 2-amino-6-methyl-pyridin-3-ol (5.7 g, 46 mmol) (prepared by reduction of 6-methyl-2-nitro-pyridin-3-ol according to the procedure of J. Kaminski et al, [J. Med. Chem, 30 (11), 2031 (1987)1 in dimethylsulphoxide (60 ml) was treated with sodium hydride (44 mmol) under argon. After 0.25 hours methyl chloroacetate (4 mL, 5 g, 46 mmol) was added and the mixture heated at 100° C. for 3.5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL), then partitioned between dichloromethane and water. The organic extracts were dried and evaporated and the residue was chromatographed eluting with 0-20% ethyl acetate in dichloromethane affording the product as a white crystalline solid (4.7 g, 62%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:13]([NH:15][C:16]([NH2:18])=[NH:17])#N>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[NH:10][C:5]=2[CH:4]=1
Reactant: N#CNC(=N)N
Reactant: Nc1ccc(C(F)(F)F)cc1N
Product: N=C(N)Nc1nc2ccc(C(F)(F)F)cc2[nH]1

Procedure:
4-Trifluoromethyl -o- phenylenediamine (25.46g) and cyanoguanidine (12.40g) were reacted together in a manner analogous to that of Example 2 to yield 5-Trifluoromethyl-2-guanidinobenzimidazole is a red gummy solid which when dissolved in 5N hydrochloroic acid and evaporated to dryness yielded the dihydrochloride (25.01g) as a brown solid, m.p. 206°-209°C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCCC>[Br:18][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Reaction time: 20 h

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.76 g, 25.0 mmol) was dissolved in dry tetrahydrofuran (100 mL) and carbon tetrabromide (9.12 g, 27.5 mmol). A solution of triphenyl phosphine (6.62 g, 25.3 mmol) in dry tetrahydrofuran (25 mL) was added dropwise, and the mixture was stirred for 20 hours. The reaction was diluted with n-hexane (100 mL) and washed with a saturated NaHCO3 solution, water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes 1:4 gave the title compound. MS (DCI) m/z 295 (M+H)+.
Reaction SMILES: COC(=O)[C@@H:4]([CH:24]([CH3:35])[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)[NH:5][C:6](=[O:23])[C@@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[NH:8][C:9](OC(C)(C)C)=[O:10]>FC(F)(F)C(O)=O>[CH3:34][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C@H:24]([C@H:4]2[NH:5][C:6](=[O:23])[C@@H:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:8][C:9]2=[O:10])[CH3:35])=[CH:26]1
Reactant: COC(=O)[C@H](NC(=O)[C@@H](Cc1ccccn1)NC(=O)OC(C)(C)C)C(C)c1cn(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1cn(C)c2ccccc12)[C@H]1NC(=O)[C@@H](Cc2ccccn2)NC1=O
Reaction time: 0.5 h

Procedure:
A mixture of Nα -[N-t-butoxycarbonyl-3-(2-pyridyl)-D-alanyl]-1,β-dimethyl-D-tryptophan methyl ester (10.54 g) and trifluoroacetic acid (80 ml) was stirred on an ice bath for 30 minutes. After removal of the solvent, resultant crude residue was dissolved in ethanol (150 ml) and saturated ammonia in ethanol (150 ml) was added to the solution and resultant mixture was stirred for 16 hours at ambient temperature. After evaporation of the solvent, chloroform (200 ml) was added to the mixture. The insoluble material was filtered off and again solvent was evaporated in vacuo to give an oil which was chromatographed on silica gel (250 g, chloroform-methanol 20:1 as eluent) to afford (3R,6R)-3-[(R)-1-(1-methylindol-3-yl)ethyl]-6-(2-pyridylmethyl)piperazine-2,5-dione.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[C:19](=O)(O)[O-].[Na+]>CO>[CH3:19][O:12][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCO2
Yield: 97.8 %

Procedure:
A solution of 19.6 g (109 mmol) of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (J. Chem. Soc., 3445, 1957) in 400 mL of MeOH containing 4 mL of H2SO4 was refluxed overnight. Sodium bicarbonate (18 g) was added, the solvent was removed and the residue was triturated several times with Et2O. The washes were combined, filtered through anhyd MgSO4 and evaporated to yield 20.7 g of the title compound as a pale yellow oil: mass spectrum (electron impact, m/e): 194.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([O:49][CH3:50])[C:35]=1[OH:51]>>[Cl:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:20][CH2:19]2)[CH:37]=[C:36]([O:49][CH3:50])[C:35]=1[OH:51]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N(C)C(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}(methyl)carbamate (68 mg, 0.135 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (58 mg, 0.203 mmol) to afford the crude product (90 mg) as a brown oil: ESI MS m/z 580 [C32H38ClN3O5+H]+.