Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:14]=[C:8]2[CH:9]=[CH:10][C:11](I)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([C:5]1[N:14]=[C:8]2[CH:9]=[CH:10][C:11]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2ccc(I)cn2n1
Reactant: C#Cc1ccccc1
Product: CC(C)(C)c1nc2ccc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, a yellow solid, MS: m/e=276.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridine (example 39, step 4) and phenylacetylene.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][CH:10]([C:16]([CH3:18])=O)[C:11](OCC)=[O:12].S(=O)(=O)(O)O>>[CH3:9][C:10]1[C:11](=[O:12])[O:2][C:1]2[C:8]([C:16]=1[CH3:18])=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=2
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: Cc1c(C)c2ccc(O)cc2oc1=O
Yield: 82.1 %

Procedure:
Resorcinol (5.5 g) and 7.2 g of ethyl 2-methylacetoacetate were stirred at 10° C. for 3 hours in the presence of a catalytic amount concentrated sulfuric acid to give 7.8 g (yield 83%) of 3,4-dimethyl-7-hydroxycoumarin. The product was hydrogenated and dehydrated as in Referential Example 16 to give 5.7 g (78%) of the desired product as a pale brown liquid.
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=1[F:30]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=1[F:30])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)c(F)c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium (0.452 g) in tetrahydrofuran (20 mL), 1-bromo-2,3,4-trifluorobenzene (2.21 mL) was added dropwise at 55° C. over 15 minutes, and the reaction solution was stirred at room temperature for 30 minutes. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.0 g) in tetrahydrofuran (25 mL) at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 4.2 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:12](=O)[C:10]2=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([NH:30][NH2:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:1]1([CH2:7][CH2:8][N:9]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)/[C:12](=[N:31]/[NH:30][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:10]2=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)N(CCC1CCCCC1)C(=O)C2=O
Reactant: NNC(=O)c1ccccc1
Product: COc1ccc2c(c1)N(CCC1CCCCC1)C(=O)/C2=N\NC(=O)c1ccccc1

Procedure:
The title compound was prepared as a yellow solid, using 1-(2-cyclohexylethyl)-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): δ 0.96-1.04 (m, 2H), 1.15-1.38 (m, 4H), 1.59 (dd, 2H), 1.65-1.75 (m, 3H), 1.81 (d, 2H), 3.74 (t, 2H), 3.87 (s, 3H), 6.43 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.96 (br s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCNCC1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C1C=C(N2CCCCC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.90 g, 2.4 mmol) and piperidine (4 ml) in toluene/DMF (2:1; 15 ml) according to method 8a described above.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N1CCOCC1)C.C(OC(Cl)=O)C(C)C.N[C@H](C(N[C@@H](C(NC[C:65]([NH:67][C@H:68]([C:76]([OH:78])=[O:77])[CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=O)=O)C)=O)CC1C=CC(O)=CC=1.[NH2:79][C@H:80]([CH2:85][OH:86])[CH2:81][CH2:82][S:83][CH3:84]>C1COCC1.C(O)(=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([N:67]([CH3:65])[C@H:68]([C:76]([OH:78])=[O:77])[CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH2:79][C@H:80]([CH2:85][OH:86])[CH2:81][CH2:82][S:83][CH3:84]
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: CSCC[C@H](N)CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N(C)[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.17 h

Procedure:
1.23 g of Boc-Tyr-(D)Ala-Gly-OH is dissolved in 30 ml of THF and cooled to 15°. 0.38 ml of ethylmorpholine are added with stirring followed by 0.39 ml of chloroformic acid iso-butyl ester and stirring continued for 10 minutes. A cold solution of 14 g of TFA.H-MePHe-methioninol and 0.45 ml of N-ethylmorpholine in 12 ml of TFA are added with stirring at -15°. The mixture is stirred for 20 hours at 0°, diluted with 250 ml of acetic acid and washed repeatedly with water, 1 N citric acid, 10% KHCO3 and 30% NaCl solution. The liquid is dried over Na2SO4 and evaporated. The residue is purified chromatographically on kieselgel using a mixture of methanol/CH2Cl2 /50% acetic acid, whereby the title compound is obtained. Decomp. 160°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:17])[CH3:16].NC1C=CC(C2C=CC=C(Cl)C=2)=CC=1[C:39](=[O:41])C.C([Mg]Br)C1C=CC=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:18]([C:15]1([CH3:16])[O:17][C:39](=[O:41])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)=[CH:4][C:3]1=2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(O)(Cc1ccccc1)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Agent: Br[Mg]Cc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Yield: 30 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-benzyl-ethanol (prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to procedure described previously, 0.14 g, 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. THF was removed and the residue purified via flash chromatography (silica gel, 35% ethyl acetate/hexane) to give 4-benzyl-6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.045 g, 30%) as an off-white solid: mp 187-188° C.; 1H-NMR (DMSO-d6) δ 10.1 (s, 1H), 7.70 (t, 1H, J=2.3 Hz), 7.6 (d, 1H, J=8.0 Hz), 7.58-7.53 (m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14 Hz), 3.24 (d, 1H, J=14.3 Hz), 3.06 (d, 1H, J=14.3 Hz), 1.68 (s, 3H); MS (ESI) m/z 364 ([M+H]+, 100%); Anal. Calcd. For C22H18ClNO2: C, 72.63; H, 4.99; N, 3.85. Found: C, 71.82; H, 5.09; N, 3.58.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.OC1C=CC=C2C=1N=C(C=O)C=C2.CC([O-])=O.[Na+].Cl.[NH2:32][OH:33]>O1CCOCC1.O>[OH:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH:1]=[N:32][OH:33])[CH:11]=[CH:10]2
Reactant: NO
Reactant: Cc1ccc2cccc(O)c2n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=Cc1ccc2cccc(O)c2n1
Solvent: O
Solvent: C1COCCO1
Product: ON=Cc1ccc2cccc(O)c2n1
Temperature: 80 °C

Procedure:
A solution of 2-methyl-quinolin-8-ol (536 mg, 3.37 mmol) in dioxane (8 mL) was added dropwise over 3 h into a stirred mixture of SeO2 (665 mg, 5.99 mmol) in dioxane (25 mL) at 50-55° C. The resulting mixture was then heated at 80° C. for 16 h, cooled, and the solids filtered off. The filtrate was concentrated and the residue purified by column chromatography on silica (dichloromethane/MeOH, 1:0-40:1). This afforded 8-hydroxy-quinoline-2-carboxaldehyde 4 as a straw-coloured solid (358 mg, 61%). 4: 1H NMR (CDCl3): δ 10.24 (s, 1 H), 8.34 (d, J=8.6, 1 H), 8.22 (br, 1 H), 8.07 (d, J=8.6, 1 H), 7.64 (dd, J=7.5 and 8.0, 1 H), 7.44 (d, J=8.0, 1 H), 7.30 (d, J=7.5, 1 H). The mixture of 4 (100 mg, 0.578 mmol), NaOAc (63 mg, mmol), hydroxylamine hydrochloride (60 mg, 0.863 mmol) and water (5 mL) was heated at 100° C. for 15 min. The precipitate was isolated by filtration. This provided the title oxime (ID 969) D1 as an off-white solid (87 mg, 80%); spectral data of this compound are shown in Table 2.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=CC=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][N:26]1C=C(CN)N=C1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[N:20]=[CH:21][N:26]([CH3:25])[CH:24]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: Cn1cnc(CN)c1
Agent: Cl
Product: Cc1nc(NCc2cn(C)cn2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(1-methyl-1H-imidazol-4-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by crystallization from ethanol (10 mL) to afford the titled compound as the hydrochloride salt as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.25-1.38 (m, 5H), 1.70-1.85 (m, 5H), 1.97 (s, 3H), 2.30 (s, 3H) 2.71 (s, 1H), 3.72 (s, 3H), 4.08 (s, 1H), 4.53 (s, 2H), 7.07 (s, 1H), 7.72 (s, 1H); MS m/z 315.7 (M+1)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)(=O)C.C[O-].[Na+].O>CO>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:18]2[CH:19]=[C:20]([C:21]([F:22])([F:23])[F:24])[N:15]3[N:14]=[CH:13][C:12]([C:10]4[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=4)=[C:16]3[N:17]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)OCc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Reaction time: 17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 4-[5-(4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-ylmethyl acetate (0.16 g, 0.33 mmol) in MeOH (1 ml) was added at room temperature NaOMe (5.4M in MeOH, 0.2 ml). The reaction mixture was stirred for 17 h, poured into water (40 ml) and extracted with dichloromethane (3 times 40 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield the title compound (112 mg, 78%) as an orange solid. MS (ISP) 439.3 [(M+H)+]; mp 2102° C.
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:29]([O:31]C(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.I[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:27][C:25]([F:26])([F:28])[S:22]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:14][C:10]2[N:9]3[C:5](=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:29]1=[O:31])(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N(CCCCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1c2cnc3cccc(n23)CN1CCCCCNS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of 1.75 g (2.87 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 25 ml of chloroform was added dropwise 0.82 ml (5.74 mmol) of iodotrimethylsilane at room temperature. The reaction mixture was stirred for 15 minutes, which was poured into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. This solution was extracted with 150 ml of ethyl acetate. The organic layer was washed with a 1.0N aqueous solution of sodium thiosulfate, then with 100 ml of a saturated aqueous saline solution. The organic layer was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 706 mg of the object product (63.1%, pale yellow solid substance).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.Cl.[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH2:28].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N1CCOCC1)C>CN(C)C=O>[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH:28][C:10](=[O:12])[CH2:9][C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccncc1)C(=O)OCC
Reactant: COC(=O)CN
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)NCC(=O)OC)(Cc1ccncc1)C(=O)OCC
Reaction time: 24 h

Procedure:
9.27 g of 4-(4-pyridyl)-3,3-bisethoxycarbonylbutyric acid are dissolved in 600 ml of dimethylformamide. 3.69 g of glycine methyl ester hydrochloride, 8.78 g of TOTU and 11.5 ml of N-ethylmorpholine are then added successively. The mixture is stirred for 24 h and the solvent is then stripped off in vacuo. The oily residue is chromatographed on silica gel using ethyl acetate. The fractions containing the product are combined and concentrated.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])[C:5]1=[O:30])([CH3:3])[CH3:2]>Cl.CO>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[O:14])[C:5]1=[O:30])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Solvent: CO
Product: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Yield: 75 %

Procedure:
A solution of tert-butyl 4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidine-1-carboxylate (3.992 g, 9.58 mmol) in 50 ml 10% hydrochloric acid in methanol and 10 ml concentrated hydrochloric acid was stirred at room temperature for 18 hours. The mixture was then concentrated and basified with aqueous Na2CO3, extracted with CHCl3 (100 ml) for 3 times. The combined extract was dried and concentrated. Flash chromatography of the residue (NH-silica gel, elutent: CH2Cl2/methanol=100/1) afforded a colorless oil 2.272 g (75%) as the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:20][CH2:21][CH:22]([C:25]([N:27]3[CH2:28][CH2:29][N:30]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=4)[CH2:31][CH2:32]3)=[O:26])[CH2:23][CH2:24]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1nccc(Cl)n1
Reactant: O=C(C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nccc(N2CCN(C(=O)C3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)n1
Yield: 67.1 %

Procedure:
2-Methyl-4-chloro-pyrimidine (0.34 g) was added to a suspension of 1-(4-bromophenylsulphonyl)-4-(1-piperazinylcarbonyl)piperidine (1.0 g) in ethanol (10 ml) and 1(triethylamine (0.5 ml). The reaction was heated under reflux for 2 hours, cooled and the solvent removed by evaporation. The reaction mixture was purified by filtration column chromatography (silica, gradient elution dichloromethane to 10% methanol in dichloromethane) to give 1-(4-bromophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl]piperidine as a solid (0.82 g) mpt 239-240° C.; NMR (CDCl3) 1.75-2.0 (m, 5H), 2.5 (m, 2H), 3.45-3.8 (m, 10H), 6.3 (m, 1H), 7.65 (m, 4H), 8.2 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N+:33]=1[O-:42].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:34][N+:33]=3[O-:42])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)c[n+]3[O-])cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 35 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 2-amino-5-(trifluoromethyl)pyridine 1-oxide (Intermediate-41, 0.096 g, 0.600 mmol), THF (5.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.12 (s, 2H), 7.32 (m, 2H), 7.41 (m, 1H), 7.52 (s, 1H), 7.80 (d, J=9.3 Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 8.94 (s, 1H), 9.50 (s, 1H), 11.21 (s, 1H), 12.30 (s, 1H); MS [M+H]+: 536.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])=[C:14]3[N:26]2[CH2:42][CH2:41][C:29]3([CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH2:28][CH2:27]2)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([CH:23]2[CH2:24][CH2:25]2)=[O:22])=[C:14]3[N:26]2[CH2:42][CH2:41][C:29]3([CH2:33][NH:32][CH2:31][CH2:30]3)[CH2:28][CH2:27]2)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8]
Reactant: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC5(CCN(C(=O)OC(C)(C)C)C5)CC4)c3c2)cc(Cl)c1O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC5(CCNC5)CC4)c3c2)cc(Cl)c1O
Yield: 37.7 %

Procedure:
Following general procedure A-2, tert-butyl 8-[6-(3-chloro-4-hydroxy-5-methoxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-yl]-2,8-diazaspiro[4,5]decane-2-carboxylate (110 mg, 0.097 mmol) was reacted with TFA (2 mL) to afford the desired product (18 mg, 38%) as a green solid: 1H NMR (300 MHz, CD3OD) δ 8.79 (s, 1H), 8.29 (s, 1H), 8.02 (s, 2H), 7.30 (d, J=2.1 Hz, 1H), 7.23 (d, J=2.1 Hz, 1H), 3.98 (s, 4H), 3.08 (s, 2H), 2.65-2.52 (m, 1H), 2.03-1.81 (m, 7H), 1.37-1.16 (m, 8H); ESI MS m/z 492 [C28H30ClN3O3+H]+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@:10]21[C:51]1[S:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[CH2:52]O)[C:43]=1[CH2:42][CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:55].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@:10]21[C:51]1[S:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[CH2:52][Cl:55])[C:43]=1[CH2:42][CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cccc2c3c(sc12)[C@@]1(OCC3)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1cccc2c3c(sc12)[C@@]1(OCC3)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 56.2 %

Procedure:
To a solution of (1S,3′R,4′S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-3,3′,4,4′,5′,6′-hexahydro-8-hydroxymethyl-spiro[2-oxa-9-thia-fluorene-1,2′-[2H]pyran] (72 mg, 0.10 mmol) in dichloromethane (1 mL) were added carbon tetrachloride (48 μL, 0.5 mmol) and triphenylphosphine (131 mg, 0.5 mmol). The resultant solution was then stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:2)), to thereby obtain the titled compound (42 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].C([NH+](CC)CC)C.Cl>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]2[NH:26][N:25]=[N:24][N:18]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C#N)nn1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: CCCOc1ccc(Br)cc1CN(CC)c1ccc(-c2nnn[nH]2)nn1
Temperature: 110 °C
Yield: 86.4 %

Procedure:
6-[N-(5-Bromo-2-propoxybenzyl)-N-ethylamino]-3-cyanopyridazine (reference example 18) (1.0 g, 2.67 mmol), was dissolved in DMA (15 ml) and treated with sodium azide (520 mg, 8.0 mmol) followed by triethylammonium chloride (550 mg, 4.0 mmol) and the mixture heated at 110° C. for 3 hours. The solution was poured 2M hydrochloric acid (50 ml), extracted with ethyl acetate and dichloromethane (100 ml of each) and the combined extracts washed with water (3×100 ml), dried over MgSO4 and concentrated in vacuo. Addition of ether and hexane precipitated a solid which was triturated with acetonitrile/toluene to give the title compound (965mg, 87%).