Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][O:23][C:24]([C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31]Br)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:31][CH2:30][C:29]2[CH:33]=[CH:34][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--see Preparation 8), 4-methoxycarbonylphenethyl bromide (0.53 g--see Preparation 15), anhydrous potassium carbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 1.5 hours. On cooling to room temperature, water (60 ml) was added and the resulting mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.44 g.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH:5](O)[CH2:6][N:7]=[N+:8]=[N-:9])[CH3:2].C(N(S(F)(F)[F:20])CC)C>C1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH:5]([F:20])[CH2:6][N:7]=[N+:8]=[N-:9])[CH3:2]
Reactant: CCOC(OCC)C(O)CN=[N+]=[N-]
Reactant: CCN(CC)S(F)(F)F
Solvent: c1ccccc1
Product: CCOC(OCC)C(F)CN=[N+]=[N-]
Temperature: 25 °C
Yield: 65 %

Procedure:
To a stirring solution of 3-azido-2-hydroxypropanal diethyl acetal (7.32 g, 38.73 mmol) in dry benzene (50 mL) was added diethylaminosulfurtrifluoride (DAST; 20.6 mL) at -78° C. After the addition, the solution was stirred at room temperature for an hour, then heated to 70° C. for 12 hours. The reaction was quenched by the addition of methanol at zero degrees C and diluted with water. After dichloromethane extraction, the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified with silica gel column chromatography (hexane: ether=9:1, volume/volume) to yield 3-azido-2-fluoropropanal diethyl acetal as an oil (65 percent); Rf =0.84 EtOAc: hexane=2:3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O=[Pt]=O.CCO>[C:8]1([CH2:7][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCCCO
Reactant: O=Cc1ccccc1
Agent: O=[Pt]=O
Solvent: CCO
Product: OCCCCNCc1ccccc1

Procedure:
Combine 4-amino-butan-1-o1 (8.9 gm - 0.1 mol), benzaldehyde (10.6 gm - 0.1 mol), EtOH (100 ml) and PtO2 (0.3 gm), and hydrogenate the mixture at 45 lbs./sq.in. until H2 is no longer taken up. Filter, evaporate the solvent (in vacuo) to yield 17.7 gm of the desired compound. Rf is 0.70 (eluted from silica gel with 10% conc. NH3 /CH3OH).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: C1COCCN1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCOCC3)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). Morpholine (0.04 ml; 0.46 mmol; 1.40 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (13) is obtained as white-off solid (15 mg; 19%). 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.46 (s, 3H), 2.96 (m, 4H), 3.67 (m, 4H), 7.33 (d, J=3.8 Hz, 1H), 7.61 (d, J=3.8 Hz, 1H), 12.35 (s, 1H). M−(ESI): 386.17; M+(ESI): 388.46. HPLC, Rt: 3.21 min (purity: 99.7%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]1[CH:11]=[C:10]([C:12](O)=[O:13])[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:8]1)[CH3:6]>CN(C=O)C.C(Cl)Cl>[CH2:5]([N:7]1[CH:11]=[C:10]([C:12]([Cl:3])=[O:13])[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:8]1)[CH3:6]
Reactant: CCn1cc(C(=O)O)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Cl)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reaction time: 16 h

Procedure:
To a solution of thionyl chloride (2.0 mL) and 2 drops of DMF in DCM stirring under nitrogen at RT is added the title compound of Example 3, 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carboxylic acid (0.8 g, 1.65 mmol) in one portion. The resulting suspension is stirred for 16 h. The solution is concentrated and the resulting residue is azeotrophed twice with toluene. It is used as such without any additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[CH:22]=[N:23][O:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[O:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)[CH:26]=[CH:25][C:21]=2[CH:22]=[N:23]1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4cnoc4c3)n2)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5cnoc5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.34 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-benzo[d]isoxazol-6-yl-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(benzo[d]isoxazol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}4-tert-butyl-benzamide.
Reaction SMILES: Cl[N:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][CH:8]=2)[S:3]1.[NH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH:12]1[NH:11][N:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][CH:8]=2)[S:3]1
Reactant: ClN1Nc2cncnc2S1
Reactant: NC1Cc2ccccc2C1
Product: c1ccc2c(c1)CC(NN1Nc3cncnc3S1)C2
Yield: 51.7 %

Procedure:
Using 2-chloro-1-thia-2,3,5,7-tetraazaindene (50 mg, 0.29 mmol) (see J. Org. Chem. 26, 4961 (1961), J. Chem. Soc. (C) 1856 (1967)) and 2-aminoindan (120 mg, 0.90 mmol), a similar procedure to Production Example 190 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (41 mg, 0.15 mmol) having the following physical properties:
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][N:12]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:31][CH2:30]2)=[CH:25][C:24]=1[F:40])[C:13]([C:15]1[C:16](Cl)=[N:17][CH:18]=[N:19][C:20]=1[Cl:21])=[O:14])(C(C)(C)C)(C)C>O1CCOCC1.CO>[Cl:21][C:20]1[C:15]2[C:13](=[O:14])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:30][CH2:31][CH:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][CH2:34]4)=[CH:25][C:24]=3[F:40])[CH2:11][CH2:10][O:9][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: COC(=O)CC1CCC(c2ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c3c(Cl)ncnc3Cl)c(F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC1CCC(c2ccc(N3CCOc4ncnc(Cl)c4C3=O)c(F)c2)CC1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
The title compound of Preparation 4 was prepared as follows. 4M HCl in dioxane (0.5 mL) was added to a solution of methyl 2-(4-(4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidine-5-carboxamido)-3-fluorophenyl)cyclohexyl)acetate (30 mg, 0.05 mmol) in methanol (1 mL). The mixture was stirred at 23° C. for 30 minutes. The reaction mixture was concentrated to remove solvent. The residue was dissolved in acetonitrile (1 mL) and NEt3 (0.05 mL) was added to it. The reaction mixture was stirred at 80° C. for 18 hours. EtOAc (15 mL) and water (15 mL) were added to reaction mixture. The organic layer was separated and dried over MgSO4 and concentrated. The crude material was purified by a 4 g silica gel column eluted with 30-50% EtOAc in heptane to give methyl 2-(4-(4-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-3-fluorophenyl)cyclohexyl)acetate a colorless oil (20 mg). m/z=448.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH:7]=[CH:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(OCC)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][Br:36]
Reactant: BrC(Br)(Br)Br
Reactant: OCC=CCOCc1cc(Br)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Br)cc1COC/C=C\CBr
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 100 ml round bottom flask 4-(2-fluoro-5-bromobenzyloxy)but-2-en-1-ol (2.145 g, 7.80 mmol) was dissolved in diethyl ether under a nitrogen atmosphere. Triphenylphosphine (2.66 g, 10.1 mmol) and then carbon tetrabromide (3.36 g, 10.1 mmol) were added to the reaction mixture. The resulting mixture was stirred for six hours at ambient temperature. A white precipitate formed during the stirring. The progress of the reaction was monitored by thin layer chromatography. The solution was filtered and the filtrate was evaporated to give a thick oil. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2Br)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:28](=[O:30])=[O:29]>CCOCC>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[C:28]([OH:30])=[O:29])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(F)ccc2Br)CC1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(F)ccc2C(=O)O)CC1
Temperature: -78 °C
Yield: 78 %

Procedure:
A 1.6M solution of butyllithium in hexanes (2.5 mL, 4.0 mmol) was added in three portions over 2 hours into a solution of 4-(2-bromo-5-fluoro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.34 mmol) in anhydrous Et2O cooled at −78° C. After one additional hour at −78° C., an excess of dry ice was added and the cooling bath was removed. The reaction mixture was allowed to warm up to RT and was concentrated under vacuum. The residue was taken up with a saturated aqueous solution of NH4Cl and extracted with EtOAc (3×). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum to give the title compound as a yellow oil (391 mg, 78%), used without further purification. HPLC (max plot) 92.1%; Rt 2.47 min. UPLC/MS: (MS+) 339.3 ([M+H]+), (MS−) 337.4 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:3].[BH3-]C#[N:25].[Na+]>CO>[CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH2:25])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(C=O)cc1
Agent: [Na+]
Solvent: CO
Product: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.5 g of 4′-formyl-biphenyl-2-sulfonic acid dimethylaminomethyleneamide prepared according to H. Jendralla et al. (Liebigs Ann. 1995, 1253–7) in 15 ml MeOH were treated with 208.6 mg NaCNBH3 and the reaction was stirred for 4 hours at RT. The pH was adjusted to 4.0, the reaction was filtered, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluting with a gradient of 10–20% MeOH in DCM.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.CO[C:12](=N)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1.O.Cl>CO>[CH3:24][O:23][C:17]1[CH:16]=[C:15](/[CH:14]=[CH:13]/[C:12]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: Nc1ccccc1N
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C/c2nc3ccccc3[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of 1,2-phenylenediamine (0.63 g; 5.8 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (1.5 g; 5.8 mmol) in methanol (35 mL) was stirred at ambient temperature for 18 hours. The methanol solution was concentrated to dryness. The residue was recrystallized from MeOH-Diethyl Ether to obtain 1.3 g (67% yield) of the title compound as a mono-hydrochloride, hydrate, yellow solid, m.p. 248° C. dec. Anal. Calcd. for C17H16N2O2 HCl H2O: C, 60.98, H, 5.12; N, 8.37. Found: C, 60.78; H, 5.12; N, 8.45. Mass Spectrum: (EI; M+) m/z 280..1H-NMR (DMSO-d6; 400 MHz) δ15.2 (broad s, 1H), 8.18-8.2 (d, 1H), 7.76-7.8 (m, 2H), 7.45-7.54 (m, 2H), 7.32 (d 1H), 7.2-7.3 (m, 3H), 7.08-7.12 (d, 1H), 3.83 (s, 3H), 3.86 ppm (s, 3H).
Reaction SMILES: C[N:2]1[CH2:12][CH:11](C2C=CC=C(N=C=S)C=2)[C:10]2[CH:9]=[C:8]([OH:22])[C:7](Cl)=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:24]([OH:30])(C(F)(F)F)=[O:25]>O.C(#N)C>[CH2:4]([O:22][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:2]([C@H:3]([CH3:4])[C:24]([OH:30])=[O:25])[CH:12]=[CH:11]2)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2cccc(N=C=S)c2)C1
Reactant: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: C[C@H](C(=O)O)n1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.12 h

Procedure:
Reverse Phase HPLC conditions: Column: YMC-Pack ProC18 (AS-300), 50×4.6 mm (I.D.), S-5 μm, 12 nm (No. 040506614); Mobile Phase: A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile; Gradient: 90-5% A (10-95% B) in 7 min.; Flow rate: 4.0 mL/min; Detector (UV): 220 nm. Retention time of title compound: 3.53 min.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH:10][NH2:11])[CH:5]=1.C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C>C(O)C>[NH2:21][C:20]1[N:10]([C:6]2[CH:5]=[C:4]([O:3][CH:2]([F:1])[F:12])[N:8]([CH3:9])[N:7]=2)[N:11]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: Cn1nc(NN)cc1OC(F)F
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: Cn1nc(-n2ncc(C#N)c2N)cc1OC(F)F

Procedure:
22.5 g (0.13 mol) 5-Difluoromethoxy-3-hydrazino-1-methylpyrazole was dissolved in 310 ml ethanol and treated with 15.4 g (0.13 mol) ethoxymethylenemalononitrile. After the mixture had been heated under reflux for one hour it was cooled. The precipitate was suction filtered and washed with a small amount of ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[S:11][CH2:10][CH2:9][C:8]2=[O:13].[BH4-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[S:11][CH2:10][CH2:9][CH:8]2[OH:13]
Reactant: COc1cccc2c1SCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c1SCCC2O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
89 mmol of 8-methoxy-4-thiochromanone are dissolved in 70 ml of a mixture of methanol and tetrahydrofuran (3/4). 134 mmol of sodium borohydride dissolved in 50 ml of aqueous methanol (50%) are added. After stirring for 1 hour at room temperature and then extracting with methylene chloride, the resulting product is recrystallised from a mixture of methanol and diethyl ether (1/10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][CH:31]([CH3:35])[CH2:32][CH2:33]O.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][CH:31]([CH3:35])[CH2:32][CH2:33][O:24][C:23]([C:18]1([C:20]([O:22][CH2:2][CH2:3][CH:4]([CH3:8])[CH3:5])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(C)CCO
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)CCOC(=O)C1(C(=O)OCCC(C)C)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-methylbutanol accord-ing to the procedure of Example 1 as an off-white foam (HCl salt); 1H NMR (CDCl3) δ 0.90 (d, 12H), 1.35 (d, 2H), 1.55-1.80 (m, 6H), 2.70-2.85 (m, 1H), 3.45-3.55 (m, 3H), 4.30 (t, 4H), 5.45 (bd, 1H), 5.65 (bs, 1H), 6.70-6.80 (m, 1 H), 6.80-6.90 (m, 3H), 7.25-7.35 (m, 3H), 7.43 (s, 1H), 8.74 (bs, 1H), 10.08 (bs, 1H); IR (KBr): 3303 cm-1 (--OH), 1765 cm-1 (C=O); MS (ES) m/z 562.4 (MH+); [α]D25 -24° (c, 1.0, CHCl3). Anal. Calcd. for C30H40ClNO7 ·HCl: C, 60.20; H, 6.74; N, 2.34; Cl, 11.85. Found: C, 59.98; H, 7.04; N, 2.24; Cl, 12.09.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=2[NH2:14])[CH2:4][CH2:3]1.O.[N:21]#[C:22]Br.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:12]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=3[N:14]=[C:22]2[NH2:21])[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCNc2ccc(Cl)cc2N)CC1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(CCCn2c(N)nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 2-[3-(4-methyl-1-piperazinyl)propylamino]-5-chloroaniline (70 g., 0.248 mole) in 350 ml. of water and 150 ml. ethanol was added, with stirring, 59.0 g. (0.557 mole) of cyanogen bromide in portions over 1 hour. The temperature was maintained at 40°-50° C. After the addition was completed the mixture was allowed to cool to room temperature and stirred overnight. After pouring into 1500 ml. ice water and making strongly alkaline with 20% NaOH, the precipitated solid was collected on a Buchner funnel, washed with water and dried in the vacuum oven to obtain 45.0 g. (59% yield) of crude 1-[3-(4-methyl-1-piperazinyl)propyl]-2-amino-5-chlorobenzimidazole, m.p. 223°-227° C. A portion was recrystallized from acetone as colorless needles, m.p. 228°-229.5° C.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]3[C:14]([C:5]2=[N:4][N:3]=1)=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3.[O-:22][CH2:23][CH3:24].[Na+]>C(O)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]1=[N:4][N:3]=[C:2]([O:22][CH2:23][CH3:24])[N:6]1[N:7]=[C:8]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC[O-]
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)nn1c(Cl)nnc21
Agent: [Na+]
Solvent: CCO
Product: CCOc1nnc2c3ccc(Cl)cc3c(-c3ccccc3)nn12
Temperature: 100 °C

Procedure:
A mixture of 3,8-dichloro-6-phenyl-1,2,4-triazolo[3,4-a]phthalazine (5 g), sodium ethoxide (1.3 g) and absolute ethanol (40 ml) is poured into a steel bomb and heated to 100° C. for 8 hours. Then the mixture is cooled and concentrated to dryness. The obtained residue is triturated with water, filtered and crystallized from ethanol/chloroform yielding 3.3 g of the compound of the title. M.p. 226°-28° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:36])=[C:23]([C:26]4[O:27][C:28]([CH:31]5OCC[O:32]5)=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>C1COCC1>[ClH:37].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:36])=[C:23]([C:26]4[O:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C2OCCO2)o1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cc2F)o1
Reaction time: 1.5 h
Yield: 61 %

Procedure:
Prepared according to Procedure C from a stirred solution of (4-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine (0.51 grams, 1.1 mmol) in 20 ml of THF was added 5 ml of 1 N HCl. After stirring for 90 minutes, the resultant suspension was filtered and washed with diethyl ether (200 ml) to yield, after drying under vacuum, a yellow solid (0.32 grams, 61% yield). δ1H NMR (400 MHz, DMSO-6) 11.52(s, 1H), 9.70(s, 1H), 9.25(d, 1H), 8.76(s, 1H), 7.76(m, 2H), 7.55(d, 2H), 7.45(d, 2H), 7.33(m, 4H), 7.11(d, 2H), 5.14(s, 2H). ESI-MS m/z 440(M+1).
Reaction SMILES: [CH3:1][C:2]([C:32]([O:34]C)=[O:33])([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[NH:3][C:4]([O:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)=[O:5].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][C:2]([C:32]([OH:34])=[O:33])([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:23]=1)[NH:3][C:4]([O:6][CH:7]1[CH:8]2[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]1[CH2:15]3)[CH2:16]2)=[O:5]
Reactant: COC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC1C2CC3CC(C2)CC1C3
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(Cc1ccc(OCc2ccccc2)cc1)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To a stirred solution of methyl α-methyl-O-(phenylmethyl)-N-[(tricyclo[3.3.1.13,7 ]dec-2-yloxy)-carbonyl]-DL-tyrosinate (1.10 g, 0.0023 mol) in 8.8 mL dioxane and 4.4 mL water, lithium hydroxide monohydrate (0.145 g, 0.003 mmol, 1.5 eq) was added. This reaction mixture was then stirred for 48 hours at room temperature. The reaction mixture was then concentrated in vacuo and the resulting white syrup was diluted with 20 mL H2O. Thisbasic solution (pH 13) was then acidified (pH 2) with 1 mL 10% HCl, upon which white solid precipitated. This acidified aqueous suspension was thenextracted three times each with ether. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the desired product (0.78 g, 0.0016 mmol, 73%). MS: 464.3 (MH+); 463.3 (M+).