Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][NH2:31]>>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][NH:31][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Reactant: NCCc1ccc2ccccc2c1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccc4ccccc4c3)cc2)cn1
Yield: 50.3 %

Procedure:
Using a method similar to Example 405, using 5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366 g, 0.151 mmol) and 2-naphthalen-2-ylethylamine (0.0286 g, 0.166 mmol) gives the title compound (0.0302 g, 50.3%): TOF MS ES+ 398.2 (M+H)+, HRMS calcd for C2-5H24N3O2 398.1869 (M+H)+, found 398.1833, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min], tR=9.2 min, 98.0% purity.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[OH:27])=[CH:10][CH:9]=1.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH:15]2[O:27][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:10][CH:9]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC3OCCO3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC3OCCO3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In analogy to the procedure described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-[4-([1,3]dioxolan-2-ylmethoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS, 4RS)-4-[4-([1,3]dioxolan-2-ylmethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 520 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:6]1[C:5]2=[O:19].[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:25]([N:12]2[C:7]3=[N:8][C:9]4[C:4]([C:5](=[O:19])[N:6]3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=3)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=4)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CCCC1
Reactant: O=c1c2cc(Cl)ccc2nc2[nH]c3ccccc3n12
Product: O=C(C1CCCC1)n1c2ccccc2n2c(=O)c3cc(Cl)ccc3nc12

Procedure:
6-Cyclopentanoyl-2-chlorobenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazo[2,1-b]quinazolin-12(6H)one and cyclopentanoyl chloride.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[F:28][C:29]1[CH:34]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[C:32]([F:39])=[CH:31][C:30]=1F>C(#N)C>[F:28][C:29]1[CH:34]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[C:32]([F:39])=[CH:31][C:30]=1[O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12]
Reactant: CS(=O)(=O)c1cc(F)c(F)cc1F
Reactant: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2cc(F)c(S(C)(=O)=O)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 1.3 %

Procedure:
Caesium carbonate (523 mg) was added to a solution of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (234 mg) and 1,2,4-trifluoro-5-(methylsulfonyl)benzene (169 mg) in acetonitrile (5 mL) was added. The mixture was heated in a sealed microwave vial to 160° C. for 7000 seconds and left to cool before being filtered and washed with acetonitrile (10 mL). The filtrate was evaporated in vacuo and chromatographed on silica, eluting with 0 to 10% methanol in ethyl acetate. This gave incomplete resolution so the mixture was purified by preparatory HPLC using a gradient of 5 to 95% acetonitrile in water to afford the desired compound (5.1 mg)
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[CH:9]=2)[CH2:4][C:3]21[CH2:26][C:21]1[CH:22]=[N:23][N:24]=[CH:25][C:20]=1[CH2:19]2.C[Si]([N:31]=[C:32]=[N:33][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:14]([C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][C:3]2([CH2:26][C:21]4[CH:22]=[N:23][N:24]=[CH:25][C:20]=4[CH2:19]2)[C:2]3=[N:33][C:32]#[N:31])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(Cc4cnncc4C2)C3)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(-c3cccc(C#N)c3)ccc2CC12Cc1cnncc1C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(1′-oxo-1′,3′,5,7-tetrahydrospiro[cyclopenta[d]pyridazine-6,2′-inden]-6′-yl)benzonitrile (0.0386 g, 0.11 mmol) in CH2Cl2 (5 mL) was added 0.5 mL of 1.0 M TiCl4 in CH2Cl2 at room temperature. After 1.5 h, 0.4 mL of bis(trimethylsilyl)carbodiimide was added to the yellow solution. The resulting mixture was then stirred at room temperature for 20 h. The mixture was quenched with ice, diluted with CH2Cl2, and dried over Na2SO4. After the solvent was removed under reduced pressure, the crude product was directly used in the next step without further purification. LC-MS tR=1.43 min in 3 min chromatography, m/z 362 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Br[C:15]1[S:16][C:17]([S:20][CH3:21])=[N:18][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[CH3:21][S:20][C:17]1[S:16][C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[N:19][N:18]=1
Reactant: CSc1nnc(Br)s1
Reactant: OB(O)c1ccc2cnccc2c1
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: CSc1nnc(-c2ccc3cnccc3c2)s1
Temperature: 90 °C
Yield: 93.5 %

Procedure:
To a stirred mixture or isoquinolin-6-ylboronic acid (83 mg, 0.33 mmol) (prepared as described in US Patent Publication No. US 2007/0173506), 2-bromo-5-(methylthio)-1,3,4-thiadiazole (82 mg, 0.39 mmol) (prepared as described in WO 97/30981) and Pd(PPh3)4 (19 mg, 0.016 mmol) was added dimethoxyethane (5.0 mL) and sodium carbonate (0.41 mM, 2.0 M aq, 0.82 mmol). The mixture was heated at 90° C. under a reflux condenser overnight. After cooling, the mixture was filtered through a short path of Celite and washed with EtOAc (3×10 mL). The combined organic layers were evaporated and purified by flash column chromatography (eluting with a gradient of 1:1 EtOAc in hexanes to pure EtOAc) to provide 6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)isoquinoline (80 mg, 95%) as a pale yellow solid. LCMS (M+H) 260.4 calc. for C12H10N3S2 260.0. 1H NMR (400 MHz, CDCl3): δ ppm 9.33 (d, J=1.17 Hz, 1H) 8.62 (s, 1H) 8.31 (s, 1H) 8.23 (d, J=8.80 Hz, 1H) 8.11 (d, J=8.80 Hz, 1H) 7.74-7.83 (m, 1H) 2.88 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:22][C:23]1[CH:42]=[CH:41][C:26]([CH2:27][NH:28][C:29]([C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[O:30])=[CH:25][CH:24]=1>CN(C=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:29](=[O:30])[C:31]2[CH:36]=[CH:35][C:34]([S:37]([N:9]3[C:10]4=[N:11][CH:12]=[CH:13][CH:14]=[C:15]4[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8]3)(=[O:38])=[O:39])=[CH:33][CH:32]=2)=[CH:41][CH:42]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(-c2c[nH]c3ncccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3cccnc32)cc1
Reaction time: 0.08 h
Yield: 18.5 %

Procedure:
Slowly add 3-phenyl-1H-pyrrolo[2,3-b]pyridine (178 mg, 0.915 mmol, 1.0 eq) as a 2 ml DMF solution to a flask under N2 containing potassium tertbutoxide (108 mg, 0.961 mmol, 1.05 eq) in 1 ml DMF solution. Stir solution for 5 minutes. Slowly add 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (300 mg, 0.915 mmol, 1.0 eq) as a 3 ml DMF solution. Stir reaction for 18 hours at room temperature. Strip reaction of solvent and purify on silica gel chromatography to give N-(4-Fluoro-benzyl)-4-(3-phenyl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzamide (82 mg, 18% yield). Mass Spectrum (m/e): 485.94 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:14][C@H:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: C=CC[C@@H](O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-1-Benzyloxy-4-penten-2-ol (3.13 g) was dissolved in DMF (32 ml), and sodium hydride (60%, 0.91 g) was added in an ice bath. After stirring at the same temperature for 30 minutes, bromoacetaldehyde diethyl acetal (3.03 ml) was added. The mixture was heated to room temperature and stirred for two hours, and then heated to 50° C. and stirred for one hour. After cooling to room temperature, ice was added to the reaction solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound. The mixture containing the recovered raw material was reacted under the same conditions. The title compound was obtained by purification by the same method (total yield: 5.00 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[N:10]([CH3:14])[C:11]([NH2:13])=[O:12])=[CH:4][CH:3]=1.BrBr>CC(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:13][C:11](=[O:12])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CN(/N=C/c1ccc(Br)cc1)C(N)=O
Agent: BrBr
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc(Br)cc2)[nH]c1=O
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of compound 10a (5.80 g, 22.6 mmol) in AcOH (20 mL), was added Br2 (7.30 g, 45.7 mmol) dropwise. The reaction mixture was stirred at 95° C. for 30 min. After cooling to rt, the product was precipitated by addition of Et2O and collected by filtration and washed with Et2O to obtain compound 10b as a yellow solid (5.50 g, 96% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C9H8BrN3O: 254.0 (M+H). Found 254.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[Li+].CC([N-]C(C)C)C.Cl[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]1=[O:7]
Reactant: COC(=O)Cl
Reactant: CN1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1CCN(C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A 250 mL round-bottomed flask was charged with 1-methylpyrrolidin-2-one (5.05 mL, 52.5 mmol), LDA (43.8 mL, 78.8 mmol, 1.8 M), and THF (125 mL). The reaction mixture stirred at −78° C. for 1 hour. Methyl chloroformate (6.06 mL, 78.8 mmol), was added, and the reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (4 hours). Water (125 mL) was added, and the aqueous layer was extracted with EtOAc (3×250 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford the crude product 7.35 g (89%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.37 (s, 3H), 3.28-3.25 (m, 2H), 2.85 (s, 3H), 2.62-2.67 (m, 1H), 2.13-2.22 (m, 1H), 1.99-2.06 (m, 1H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH3:18]>CN(C=O)C>[CH2:17]([N:8]1[C:6]2=[N:7][C:2]([F:1])=[CH:3][CH:4]=[C:5]2[CH:10]=[CH:9]1)[CH3:18]
Reactant: CCBr
Reactant: Fc1ccc2cc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccc2ccc(F)nc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a stirred solution of 6-fluoro-1H-pyrrolo[2,3-b]pyridine (15.00 g, 110.19 mmol) in DMF (100 mL), under a nitrogen atmosphere, is added potassium carbonate (22.84 g, 165.3 mmol), followed by ethyl bromide (12.36 mL, 165.3 mmol). The reaction is heated to 70° C. for 4 h. Further ethyl bromide (3.00 mL, 27.6 mmol) is added and the reaction kept at 70° C. overnight. After cooling further potassium carbonate (8.00 g, 57.9 mmol) and ethyl bromide (3.00 mL, 27.6 mmol) are added, and the reaction heated at 70° C. for 4 h. The reaction is cooled, poured onto brine (ca. 500 mL) and the product extracted with CHCl3 (ca. 2×300 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 70% DCM in hexane to give the title compound as a light yellow oil (16.38 g, 99.77 mmol). MS (m/z): 165 (M+1).
Reaction SMILES: [N:1]([CH2:4][C:5]1([OH:13])[CH2:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6]1)=[N+:2]=[N-:3].[H-].[Na+].[CH3:16]I>O1CCCC1>[N:1]([CH2:4][C:5]1([O:13][CH3:16])[CH2:10][CH2:9][CH2:8][C:7]([CH3:11])([CH3:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: CC1(C)CCCC(O)(CN=[N+]=[N-])C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CN=[N+]=[N-])CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 166B (1.33 g) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 435 mg) in tetrahydrofuran (15 mL) at 0° C. The mixture was stirred for 10 minutes at 0° C. and for 30 minutes at room temperature. CH3I (1.55 g) was added dropwise. The resulting reaction mixture was stirred overnight at room temperature, and then quenched with water (100 mL) and extracted with ethyl acetate (3×50 mL). The extracts were washed with brine, dried (Na2SO4), and filtered. After concentration, the crude material was purified by flash chromatography on silica gel using 0 to 7% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]2[N:18]=[CH:19][N:20]=[CH:21][C:9]=2[C:8]1=[O:22]>O1CCOCC1.N1C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:7]([CH3:6])[C:8](=[O:22])[C:9]2[CH:21]=[N:20][CH:19]=[N:18][C:10]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CN1C(=O)c2cncnc2Nc2ccccc21
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CN1C(=O)c2cncnc2N(C(=O)CCl)c2ccccc21

Procedure:
6.25 g (0.044 mol) of chloroacetyl chloride in 15 ml of absolute dioxan and 4.4 ml of dry pyridine in 15 ml of dioxan are added dropwise simultaneously (at 80° C. and in the course of 20 minutes) to a suspension of 4.6 g (0.020 mol) of 6-methyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 35 ml of absolute dioxan. The mixture is heated at the boil for a further 15 minutes and is then allowed to cool. The supernatant liquid is decanted off from the heavy dark phase, and the latter is washed with methylene chloride; the dioxan and methylene chloride phases are concentrated in vacuo. The oil which remains is dissolved in a little chloroform and filtered through neutral silica gel; the filtrate is evaporated and the residue is recrystallized from isopropanol, yield: 2.8 g, m.p. 176° to 178° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:18])[CH2:16][C:15](=O)[O:14][C:12](=[O:13])[CH2:11]1.C>C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:12](=[O:13])[CH2:11][C:10]([CH3:18])([CH3:9])[CH2:16][C:15]2=[O:14])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC1(C)CC(=O)OC(=O)C1
Solvent: CCO
Product: CC1(C)CC(=O)N(c2ccc(O)cc2)C(=O)C1
Temperature: 165 °C
Yield: 50.2 %

Procedure:
A mixture of 4-aminophenol (3.27 g, 30.0 mmol) and 3,3-dimethylglutaric anhydride (4.26 g, 30.0 mmol) was heated in a round bottom flask at 165° C. for 1 h, followed by heating at 180° C. for 7 h. After cooling to room temperature the solid material was dissolved in hot ethanol, activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was evaporated and the residue was crystallised (water/ethanol) yielding the title compound (3.51 g, 50%, pink solid).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1)#[N:38]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(CCN2CC[C@H](NC(=O)C34CC5CC(CC(C5)C3)C4)C2)cc1
Temperature: 70 °C
Yield: 73.2 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (1.0 g) and 2-(4-cyanophenyl)ethyl p-toluenesulfonate (1.2 g) were dissolved in acetonitrile, and potassium carbonate was added thereto. The mixture was stirred under heating at 70° C. for 5 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue and the mixture was washed with saturated brine. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=30:1). The obtained eluate was concentrated and IPE was added to the obtained residue. The precipitated crystals were collected by filtration to give (S)-N-(1-(2-(4-cyanophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (1.1 g), melting point 104-105° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[O:15]=[C:9]([CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C(=O)Cl
Product: CCOC(=O)C(=O)C1COCCC1=O
Yield: 18.8 %

Procedure:
Ethyl 2-oxo-2-(4-oxotetrahydro-2H-pyran-3-yl)acetate (272 mg, 19%) was synthesised from tetrahydro-4H-pyran-4-one (1 ml, 10.83 mmol) and ethyl 2-chloro-2-oxoacetate (0.808 ml, 7.22 mmol) by the general procedure for the preparation of diketones. MS (ES−) m/z 199.1 (M−H)−
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[NH2:20][C@@H:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23]>C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:20][C@@H:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCC[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and methyl (S)-2-aminopentanoate hydrochloride (prepared from (S)-2-aminopentanoic acid (Novabiochem) using General Procedure H), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.4 in 9:1 CHCl3/MeOH).
Reaction SMILES: O1CCCC1.[Si]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]2([OH:44])[CH2:26][CH2:25][N:24]([CH2:27][C:28]34[CH2:43][CH:35]([C:36]5[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][C:41]=53)[C:34]3[C:29]4=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[CH:18]=[N:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]2[CH:35]3[CH2:43][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][C:21]([C:17]5[CH:18]=[N:19][CH:20]=[C:15]([CH2:14][OH:13])[CH:16]=5)([OH:44])[CH2:26][CH2:25]4)([C:29]4[C:34]3=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:41]=2[CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
A tetrahydrofuran solution (15 mL) of 4-(5-(tert-butyldimethylsilyl)oxymethyl-3-pyridyl)-1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidin-4-ol (1.70 g, 3.04 mmol) was cooled to 0° C. under nitrogen and treated with tetrabutylammonium fluoride (1.0N in tetrahydrofuran, 3.20 mL, 3.20 mmol, 1.05 eq). The reaction was warmed to room temperature and stirred at that temperature for 3 h. Water (15 mL) was added and the resulting aqueous phase was extracted with ethyl acetate (3×15 mL). Combined organic extracts were dried over anhydrous sodium sulfate, filtered, and reduced to an oil. This procedure resulted in 1.20 g (89%) of the title compound. TLC analysis (Rf 0.11, 5% methanol in diethyl ether). No additional purification was required. 1H NMR (CDCl3, 250 MHz) 8.62 (s, 1H), 8.42 (s, 1H), 7.84 (s, 1H), 7.21 (m, 4H), 6.94 (m, 3H), 4.69 (s, 2H), 4.27 (s, 1H), 3.44 (s, 2H), 2.90 (m, 2H), 2.74 (m, 2H), 2.62 (d, J=1.3 Hz, 2H), 2.11 (m, 2H), 1.76 (m, 2H) MS (CI, CH4) m/z 447 (M+1,100), 449 (32), 475 (M+29,19), 429 (71), 431 (25) The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (room temperature, 10 pascal, 18 h) to yield a white solid, mp 235°-240° C. (dec).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][C@H:11]([C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:15]=2[N:14]=1)[CH3:12]>C(OCC)(=O)C.C(=O)([O-])O.[Na+].[Pd]>[F:28][C:25]1[CH:26]=[CH:27][C:15]2[N:14]=[C:13]([C@@H:11]([NH:10][C:3]3[C:4](=[O:9])[N:5]([CH3:8])[N:6]=[CH:7][CH:2]=3)[CH3:12])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16]=2[CH:24]=1
Reactant: C[C@H](Nc1c(Cl)cnn(C)c1=O)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ccnn(C)c1=O)c1nc2ccc(F)cc2n1-c1ccccc1
Reaction time: 3 h
Yield: 55 %

Procedure:
5-Chloro-4-[(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamino]-2-methyl-2H-pyridazin-3-one (0.06 g, 0.15 mmol) in ethyl acetate (5 mL) and sat. aq sodium hydrogen carbonate (1 mL) was hydrogenated over 10% palladium on carbon (20 mg) at room temperature and pressure for 3 h. The reaction mix was filtered, evaporated to dryness and purified by column chromatography (Si—PCC, gradient 50-100% EtOAc in DCM). Fractions containing the product were evaporated and freeze dried to give 326 as a white solid, (30 mg, 55%). LCMS (Method C): RT 4.0 min [M+H]+ 364.09. 1H NMR δ (ppm) (DMSO-d): 7.76 (1H, dd, J=8.83, 4.84 Hz), 7.58-7.56 (5H, m), 7.44 (1H, d, J=4.98 Hz), 7.13 (1H, ddd, J=9.9, 8.9, 2.5 Hz), 6.85 (1H, dd, J=8.90, 2.47 Hz), 6.74 (1H, d, J=7.91 Hz), 5.90 (1H, d, J=5.04 Hz), 4.81 (1H, dq, J=7.12 Hz), 3.59 (3H, s), 1.49 (3H, d, J=6.65 Hz)