Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH2:15]OS(C)(=O)=O)[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])(=O)=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.COC(C)(C)C>[CH2:21]([N:28]1[CH2:6][CH2:7][C:8]2([CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OCCC1(COS(C)(=O)=O)CCCNC1=O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: O=C1NCCCC12CCN(Cc1ccccc1)C2

Procedure:
A solution of 1 mmol of methanesulphonic acid 3-(2-methanesulphonyloxy-ethyl)-2-oxo-piperidin-3-ylmethyl ester and 3 mmol of benzylamine in 5 ml of dioxane is heated at 60° C. for 30 hours. The reaction mixture is diluted with tert-butyl methyl ether and washed with brine. The organic phase is dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(N(CC)CC)C.[SH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:2][C:3]([NH:5][CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:14]4[NH:18][N:17]=[N:16][N:15]=4)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]23)=[O:4])=[CH:30][CH:31]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Reactant: Sc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(=O)CSc3ccncc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a stirred suspension of 1.0 g (0.0028 mole) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.28 g (0.0028 mole) of triethylamine. The mixture is stirred at ambient temperature until a clear solution is obtained, and then 0.39 g of 4-mercaptopyridine is added. Stirring is continued for a further 4 hours at ambient temperature, and then the solid which has precipitated is filtered off. It is washed with methylene chloride, followed by ether, to give 0.68 g (78% yield) of 6(2-[4-pyridylthio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, m.p. 120° C. (dec.). The infrared spectrum of the product (KBr disc) shows absorption bands at 1790 cm-1 (β-lactam), 1670 cm-1 (amide II). The NMR spectrum (DMSO-d6) shows absorption bands at 9.0-7.0 ppm (multiplet, pyridine hydrogens), 5.9-5.5 ppm (multiplet, C-5 and C-6 hydrogen), 4.0 ppm (singlet, methylene hydrogens), 1.7 ppm (singlet, C-2 methyl hydrogens) and 1.1 (singlet, C-2 methyl hydrogens).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)C.O.CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])/[CH:17]=[CH:35]/[N:36]([CH3:38])[CH3:37])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (3.1 g, 9.2 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated to reflux for 6 days. The mixture was cooled to room temperature, ethylacetate was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (ethyl acetate) provided (2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (3.6 g, 99%) as a tinted oil. 1H NMR (CDCl3): δ 7.73-7.61 (m, 4 H), 7.32 (t, 1 H), 7.14 (t, 2 H), 6.03 (d, 1 H), 5.96 (d, 1 H), 5.05 (d, 1 H), 3.99 (m, 1 H), 5.15-2.42 (broad, 6 H), 2.19-2.08 (m, 2 H), 1.86-1.62 (m, 6 H); 19F NMR (CDCl3) δ −113.75; MS m/z 393 (M+1).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][N:25]([CH3:34])[C@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN[C@H](C(N)=O)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C)[C@H](C(N)=O)C1
Yield: 56.2 %

Procedure:
Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (5) (3.1 g, 6.97 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.93 g, 13.9 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (1.8 g, 56%): 1H NMR Spectrum: (DMSO d6) 1.86-1.91 (m, 3H), 2.07-2.09 (m, 1H), 2.20 (s, 3H), 2.47-2.49 (m, 1H), 2.71-2.81 (m, 2H), 3.96 (s, 3H), 4.82 (m, 1H), 7.02 (s, 1H), 7.23 (s, 1H), 7.26-7.29 (m, 2H), 7.47-7.53 (m, 2H), 7.82 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 460.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[C:3]=1[F:11].[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16]([NH:15][CH:12]([CH3:14])[CH3:13])=[N:10][C:4]=2[C:3]=1[F:11]
Reactant: Nc1cc(Cl)c(Cl)c(F)c1N
Reactant: CC(C)N=C=S
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(F)c(Cl)c(Cl)cc2[nH]1
Yield: 30.9 %

Procedure:
4,5-Dichloro-3-fluoro-1,2-phenylenediamine (3.37 g, 17.28 mmol), isopropyl isothiocyanate (2.10 g, 20.76 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (9.52 g, 22.48 mmol) and pyridine (100 mL) were used according to general procedure I. The title compound was recrystallized from 1,4-dioxane to provide a tan solid (1.40 g, 31%); m.p. 212-215° C.; 1H NMR (DMSO-d6) δ: 11.15 (br s, 1H, NH), 7.21 (s, 1H, Ar—H), 6.99 (d, J=7.8 Hz, 1H, NH), 3.92 (m, 1H, CH), 1.21 (d, J=6.4 Hz, 6H, overlapping CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](O)(=O)[CH2:14][CH:15]([CH3:17])[CH3:16].O>ClCCl>[CH3:16][CH:15]([CH3:17])[CH2:14][C:13]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)CC(=O)O
Reactant: Nc1cnc2ccccc2c1S
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1nc2cnc3ccccc3c2s1
Temperature: 140 °C

Procedure:
3-Aminoquinoline-4-thiol (4.6 g) was added to polyphosphoric acid (80 g). Isovaleric acid (3.5 mL) was added and the reaction mixture was heated at 140° C. for 2 hours. The reaction mixture was poured into a mixture of ice and water (300 mL). The mixture was filtered through a layer of Celite® filter aid to remove some insoluble material. The filtrate was made alkaline with 50% sodium hydroxide while cooling with ice and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide an oil. The oil was dissolved in dichloromethane and then placed on a layer of silica gel and eluted with 1:1 ethyl acetate:hexanes. The eluant was concentrated under vacuum to provide 2-(2-methylpropyl)thiazolo[4,5-c]quinoline.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.N[C@H](C(O)=O)CC(C)C.C(N(C(C)C)CC)(C)C.[O:42](C(OC(C)(C)C)=O)[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=O>O1CCOCC1>[C:46]([O:45][C:43]([NH:12][C:13]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:42])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)CC1(N)CCOCC1
Agent: CC(C)C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CC1(NC(=O)OC(C)(C)C)CCOCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of methyl 2-(4-aminotetrahydro-2H-pyran-4-yl)acetate p-toluenesulfonic acid salt (prepared in the similar manner as described in Bioorg. Med. Chem. Leu. 2006, 16, 2699-2704, 1.0 g, 2.9 mmol) in anhydrous dioxane (5 mL) was sequentially added diisopropylethylamine (1 mL, 5.8 mmol) and (BOC)2O (1.26 g, 5.8 mmol) at room temperature. Upon completion of addition, the reaction mixture was stirred at room temperature for 60 h, concentrated under reduced pressure and partitioned between ethyl acetate (30 mL) and 1N HCl (10 mL). The ethyl acetate layer was washed with 1N NaOH (10 mL), brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (1.0 g) as an oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43](I)[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[C:10][C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][N:37]=[C:36]2[NH:35][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[C:20]([Cl:19])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester is prepared by adding prop-2-ynyl-carbamic acid tert-butyl ester (0.978 g, 6.31 mmol), diisopropylamine (1.77 ml, 12.63 mmol), Pd(PPh3)2Cl2 (210 mg, 0.30 mmol) and CuI (57 mg, 0.30 mmol) to a stirred solution of [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine (3.11 g, 5.74 mmol) in THF (40 ml). After stirring the reaction mixture at rt under N2 for 3 h, the THF is removed under reduced pressured and methylene chloride is added. The organic layer is washed with NH4Cl (sat) and brine, and dried (Na2SO4). The solvent is evaporated and the residual solid is used without further purification.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:47]=[CH:46][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:42]=[C:41]([CH3:43])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[C@H:32]([OH:44])[C@@H:31]2[OH:45])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[Si:48](Cl)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:42]=[C:41]([CH3:43])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[C@H:32]([O:44][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@@H:31]2[OH:45])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:12]2[CH:46]=[CH:47][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
Anhydrous pyridine (9.9 mL) was added to a solution of 5′-O-(4,4′-dimethoxitrityl)-5-methyluridine (6.9 g) and AgNO3 (2.51 g) in dry THF (123 mL) and stirred at room temperature for 20 min under an argon atmosphere. Followed by addition of tert-butyldimethylsilyl chloride (2.51 g) in dry THF (6 mL) and stirred at the same temperature for 2-3 h. The solids were filtered off and the filtrate was concentrated to a crude residue which was applied to a column of silica gel eluted with hexane-ethyl acetate (3:1) to give a pure title compound (7.04 g) as an amorphous solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=O)(C)(C)C.[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16]>C(Cl)Cl>[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[NH:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1CNC1
Reaction time: 1.25 h

Procedure:
3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester 9b (0.73 g, 4.2 mmole) was dissolved in CH2Cl2 (2 ml) and trifluoroacetic acid (2 ml). CAUTION: The deprotection generated a rapid evolution of gas. The clear solution was stirred for 75 minutes and the solvent was removed, in vacuo, to a clear oil (1.4 g, >100%): 1H-NMR (DMSO-d6, 400 MHz) δ 8.63 (2H, br. s), 4.55–4.48 (1H, m), 4.09–4.02 (2H, m), 3.76–3.68 (2H, m).
Reaction SMILES: C([Mg]Br)C.C1COCC1.[CH2:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:11]#[CH:12].[CH2:20]([O:22][CH:23](OCC)[O:24][CH2:25][CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][CH:23]([O:24][CH2:25][CH3:26])[C:12]#[C:11][CH2:10][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: C#CCOC1CCCCO1
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(C#CCOC1CCCCO1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A 1M solution of ethylmagnesium bromide in THF (200 ml, 0.2 mol) was treated with 29 ml (0.2 mol) of a solution of 3,4,5,6-tetrahydro-2-(2-propynyloxy)-2H-pyran in toluene, while maintaining ambient temperature through use of a cool water bath. The resulting solution was stirred for 4 h and treated with 47 ml (0.28 mol) of a solution of triethylorthoformate in toluene, while maintaining ambient temperature with a cool water bath. The resulting solution was heated to 85° C. for 8 h, allowing the removal of THF by distillation. After being allowed to cool, the resulting solution was poured into 500 ml of ice-water containing 29 g of NH4OAc, extracted with two portions of ether, added over K2CO3, and concentrated in vacuo. The residue was distilled at ca. 0.5 mm Hg pressure (b.p. 103°-108° C.) to provide 39.5 g (79%) of the desired compound. 1H NMR (CDCl3) δ 1.24 (t, J=7 Hz, 6H), 1.5-1.9 (m, 6H), 3.5-3.65 (m, 3H), 3.7-3.9 (m, 3H), 4.32 (AA', 2H), 4.81 (m, 1H), 5.31 (m, 1H). Mass spectrum: (M+NH4)+ =260.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=O.O.NN.[OH-].[K+]>C(O)COCCO>[NH:14]1[C:15]2[C:11](=[C:10]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: O=C(c1ccccc1O)c1cccc2[nH]ccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Oc1ccccc1Cc1cccc2[nH]ccc12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 22.74 g of the product of Step D of Example 3, 49.4 ml of hydrazine monohydrate, 96 ml of diethylene glycol and 38.4 ml of 38% caustic potassium hydroxide was stirred for 30 minutes at 140° C. and after the mixture was heated to 210° C., the water and hydrazine hydrate were distilled off. Stirring was continued for one hour at 210° C. and the mixture was allowed to return to ambient temperature and poured into 300 ml of a saturated aqueous soluton of sodium chloride. Extraction took place with ethyl acetate and the extracts were evaporated to dryness under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride) to obtain 20.55 g of the desired product melting at 139° C. which was used as is for the following step.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH2:29][CH3:30]>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:28][CH2:29][CH3:30])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(OC)ccc(-c2cccc3c2CCC3=O)c1OC
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (116 mg, 0.843 mmol) and propyl bromide (103 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 33.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[NH:14][C@@H:15]([CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][C:17](O)=[O:18])([O-:3])=[O:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[O:31]1[CH2:32][CH2:33][N:28]([C:17](=[O:18])[CH2:16][C@@H:15]([NH:14][C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:20][S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a mixture of Example 10D (0.75 g) and morpholine (0.318 g) in N,N-dimethylformamide (5 mL) were added N,N-dimethylpyridin-4-amine (0.445 g) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.699 g). The mixture was stirred overnight, diluted with ethyl acetate and washed with 5% aqueous HCl and water. The organic layer was dried over Na2SO4 and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:36]([F:37])=[CH:35][C:34](O)=[CH:33][C:32]=1[F:39].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:32]([F:39])=[CH:33][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:35][C:36]=1[F:37]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1c(F)cc(O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1c(F)cc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1F

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 2,6-difluoro-4-hydroxy-benzoic acid methyl ester and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. Light yellow oil (85%). MS (Turbo Spray): m/z=561.2 [M+H].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH2:18][F:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH2:18][F:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](OCCCF)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCCCF)nc1Cl
Yield: 116.7 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-butoxypiperidine-1-carboxylate obtained in Example (127d) (0.84 g, 3.0 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.41 g, 2 mmol), WSC hydrochloride (0.77 g, 4 mmol), HOBt (0.41 g, 3 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 1.01 g of the title compound as a colorless solid (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.N>O>[C:7]1([N:5]2[N:6]3[C:16](=[O:15])[CH:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:1]=[C:2]3[CH:3]=[CH:4]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1ccn(-c2ccccc2)n1
Agent: N
Solvent: O
Product: O=c1cc(-c2ccccc2)nc2ccn(-c3ccccc3)n12
Reaction time: 1.5 h

Procedure:
A mixture of 10 g. of 5-amino-2-phenylpyrazole (0.063 mol.),12.1 g. of benzoylacetic acid ethyl ester (0.063 mol.) and 50 g. of polyphosphoric acid is heated at 110°-120° with stirring for 90 minutes. After cooling, 200 ml. of water and then concentrated aqueous ammonia is added under external cooling to adjust the mixture to pH 9. The collected 1,5-diphenylpyrazolo[1,5-a]pyrimidin-7(1H)-one is washed with water and dried at 70°, yield: 17 g. (94%); m.p. 194°-200°. A sample, recrystallized from absolute ethanol, melts at 205°-207°.