Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:31]>CCOCC>[ClH:31].[C:1]1([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(-c2cn[nH]c2)cc1
Yield: 87.4 %

Procedure:
Trityl chloride (1.58 g, 5.67 mmol) was added to a stirred cold (0-5° C.) solution of 4-iodo pyrazole (1 g, 5.15 mmol) and triethylamine (1.04 g, 10.3 mmol) in DCM (12 mL). Stirring was continued at room temperature overnight. Cold water was then added and the product was extracted with DCM and the organic layer was washed with saturated sodium bicarbonate solution followed by brine. The organic phase collected was dried over Na2SO4 and concentrated under reduced pressure The residue was purified by column chromatography (using neutral alumina and 2% EtOAc in hexane as eluent) to afford 1.9 g (84.4% Yield) of 4-iodo-1-trityl-1H-pyrazole. Na2CO3 (727 mg, 6.86 mmol) was added to a stirred solution of 4-iodo-1-trityl-1H-pyrazole (1.5 g, 3.43 mmol) in toluene: H2O (4:1, 20 mL). Pd(PPh3)4 (790 mg, 0.686 mmol) and phenylboronic acid (838 mg, 6.86 mmol) were then added and the reaction mixture was heated to reflux for 2 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated to in vacuo. Purification by column chromatography (using neutral alumina and 5% EtOAc in hexane as eluent) afforded 790 mg (59.4% Yield) of 4-phenyl-1-trityl-1H-pyrazole. 1H NMR (300 MHz, CDCl3): δ 7.96-7.94 (s, 1H), 7.64-7.6 (s, 1H), 7.46-7.4 (d, 2H), 7.36-7.0 (m, 11H), 7.24-7.16 (m, 7H). A solution of 4-phenyl-1-trityl-1H-pyrazole (785 mg, 2.03 mmol) in ether.HCl (15 mL) was stirred for 1 hr. The reaction mixture was then concentrated under reduced pressure and washed with hexane to afford 320 mg (87.4% Yield) of 4-phenyl-1H-pyrazole hydrochloride. 1H NMR (300 MHz, DMSO-d6): δ 8.1-8.08 (s, 2H), 7.64 (d, 2H), 7.38 (t, 2H), 7.22 (t, 1H).
Reaction SMILES: [CH2:1]([OH:13])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:14]#[C:15]CCCCCCCCCCC.[Li]CCCC.C=O>CCOCC>[CH2:1]([OH:13])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:14][CH3:15]
Reactant: C#CCCCCCCCCCCC
Reactant: CCCCCCCCCC#CCO
Agent: C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCCCCC#CCO

Procedure:
2-Tetradecyn-1-ol was prepared as described above for 2-dodecyn-1-ol except that 5.0 g (27 mmole) of 1-tridecyne in 200 ml of ether, 11.6 ml (29 mmole) of n-BuLi, and 874 mg (29 mmole) of paraformaldehyde was used. The reaction afforded a white solid after workup which was crystallized from petroleum ether to yield 4.78 g of white crystals, mp 44-6° C. 1H NMR δ 4.25 (m, 2), 2.20 (m, 2), 1.6-1.2 (m, 20), 0.88 (t, 3, J=7 Hz).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:10]=[CH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:10]=[CH:11][C:12]=1[CH2:13][Br:32])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1O[Si](C)(C)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc(-c2nc3ccccc3o2)ccc1CBr
Temperature: 25 °C

Procedure:
To 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-methylphenyl)-1,3-benzoxazole (1.46 g, 4.3 mmol) in CCl4 (50 mL) was added NBS (770 mg, 4.3 mmol) and benzoyl peroxide (50 mg). The reaction mixture was refluxed for 6 h, cooled to rt, and CCl4 was removed in vacuo. The residue was dissolved in EtOAc (50 mL), washed with H2O (50 mL), dried (MgSO4), filtered and concentrated in vacuo to afford 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-bromomethylphenyl)-1,3-benzoxazole as light yellow solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH:30]=2)[CH:9]=1.C1C(=O)N([Br:58])C(=O)C1>C(#N)C>[CH3:46][Si:45]([CH3:48])([CH3:47])[CH2:44][CH2:43][O:42][CH2:41][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:49])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH:30]=2)[C:9]=1[Br:58]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(C)CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: CC#N
Product: CCOC(=O)C1(C)CC=C(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-methylcyclohex-3-enecarboxylate (Int-18f, 152 mg, 0.212 mmol) was dissolved in acetonitrile (5 mL) and NBS (38 mg, 0.212 mmol) was added. The mixture was stirred at room temperature for 3 h and then concentrated. The residue was purified with a column (silica gel, 0-30% ethyl acetate in hexane) which gave ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-methylcyclohex-3-enecarboxylate (Int-18g) (139 mg). HPLC-MS tR=3.04 min (UV254 nm); mass calculated for formula C39H54BrN5O4Si2 791.3, observed LCMS m/z 792.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[OH:7].Br[C:9]1[S:10][C:11]([C:28]#[N:29])=[C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:18]=2)[N:13]=1>O1CCOCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:17]2[CH:18]=[C:14]([C:12]3[N:13]=[C:9]([O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[S:10][C:11]=3[C:28]#[N:29])[CH:15]=[N:16]2)=[CH:25][CH:24]=1
Reactant: Oc1ccccn1
Reactant: COc1ccc(Cn2cc(-c3nc(Br)sc3C#N)cn2)cc1
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3nc(Oc4ccccn4)sc3C#N)cn2)cc1
Temperature: 25 °C
Yield: 24.8 %

Procedure:
According to Scheme 7, Step 5: To the reaction mixture of pyridin-2-ol (1.05 mmol, 100 mg) and 2-bromo-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrile (1.16 mmol, 434 mg) in dioxane (8 mL) was added Ag2O (3.16 mmol, 733 mg). The resulting mixture was stirred at reflux overnight. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC PE/EtOAc (1:1) to give 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile (0.26 mmol, 153 mg, 37%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[NH:11][C:10](=[O:19])[C:9]([C:20]([OH:22])=O)=[CH:8]2)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[NH:11][C:10](=[O:19])[C:9]([C:20]([Cl:25])=[O:22])=[CH:8]2)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)[nH]c2cc1OC(C)=O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)[nH]c2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-1,2-dihydro-2-oxoquinoline-3-carboxylic acid (100 mg), thionyl chloride (70 μL), and dimethylformamide (one drop) was heated under reflux for 4.5 hours in 50 mL of benzene, and the solvent was distilled off. Benzene (30 mL) was added to the residue and the benzene was distilled off again, followed by vacuum drying, to yield 6,7-diacetoxy-1,2-dihydro-2-oxoquinoline-3-carbonyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=O)[CH2:15][CH3:16])[C:9](=[O:18])[CH2:8]2)=[CH:5][CH:4]=[N:3]1.[Cl:19]/[CH:20]=[CH:21]/[CH2:22][O:23][NH2:24]>>[Cl:19][CH:20]=[CH:21][CH2:22][O:23]/[N:24]=[C:14](/[CH:10]1[C:11](=[O:13])[CH2:12][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:8][C:9]1=[O:18])\[CH2:15][CH3:16]
Reactant: NOC/C=C/Cl
Reactant: CCC(=O)C1C(=O)CC(c2ccnn2C)CC1=O
Product: CC/C(=N\OCC=CCl)C1C(=O)CC(c2ccnn2C)CC1=O

Procedure:
To 5 ml of an ethanolic solution of 0.35 g (1.4 mmols) of 5-(1-methyl-1H-pyrazol-5-yl)-2-propionylcyclohexane-1,3-dione was added 3.8 ml (1.4 mmols) of 0.38 mol ethanolic solution of (E)-3-chloro-2-propenyloxyamine. The mixture was reacted for 10 hours with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=b 1:2) to give 0.25 g of the product.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.O[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[OH:1][CH2:2][C:3]1([CH2:6][O:7][N:9]2[C:13](=[O:14])[C:12]3[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCC1(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCC1(CO)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56.9 %

Procedure:
(1-Hydroxymethyl-cyclopropyl)-methanol (4.08 g, 0.04 mol), N-hydroxyphthalimide (6.53 g, 0.04 mol) and triphenylphosphine (10.50 g, 0.04 mol) were combined in anhydrous tetrahydrofuran (100 mL) and stirred at 0° C. for 1.5 hours. Diethyl azodicarboxylate (6.97 g, 0.04 mol) was added at 0° C. and the reaction mixture was stirred at room temperature overnight. Repeated concentration of the reaction mixture from chloroform and filtration of the resulting precipitate (triphenylphosphine oxide) afforded the crude product which was further purified by silica gel chromatography. Elution with hexane/ethyl acetate (3:2) provided 2-(1-Hydroxymethyl-cyclopropylmethoxy)-isoindole-1,3-dione (5.63 g, 57% yield) as a white solid: 1H NMR (400 MHz; CDCl3) δ 7.82-7.85 (2H, m), 7.74-7.78 (2H, m), 4.19 (2H, s), 3.72 (2H, s), 0.63 (4H, s)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:11](=O)[NH:10][CH2:9][C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:7][C:6]=2[C:5]([CH3:22])=[N:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:11](=[S:32])[NH:10][CH2:9][C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:7][C:6]=2[C:5]([CH3:22])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)c2c1C(=O)NCC(c1ccc(OC)cc1)=N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCn1nc(C)c2c1C(=S)NCC(c1ccc(OC)cc1)=N2
Yield: 86 %

Procedure:
(R1=methyl; R2=ethyl; R3=4-methoxyphenyl) 2.2 g (7.4 mmol) of 1-ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one are refluxed in toluene with 6 g (14.8 mmol) of Lawesson's reagent to give 2 g (87%) of an expected compound of type E (see Scheme 1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Cl-:15].[Ca+2].[Cl-]>C(#N)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: [Cl-]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Ca+2]
Solvent: CC#N
Product: O=C(O)CCCCCCCCCCCl
Yield: 102.1 %

Procedure:
To 11-bromoundecanoic acid (1 g) dissolved in acetonitrile (50 ml) were added calcium chloride (2 g) and tetra-n-butylammonium chloride (1.2 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and then distributed into ethyl acetate-water, and the ethyl acetate layer was dried over anhydrous sodium sulfate to give 11-chloroundecanoic acid (0.85 g). After a 230 mg portion of 11-bromoundecanoic acid thus obtained, para-nitrophenol (145 mg) and N,N'-dicyclohexylcarbodiimide (215 mg) in N,N-dimethylformamide (DMF) was stirred for 12 hours, precipitates were removed by filtration and DMF was removed by distillation to give an active ester. To the active ester of 11-chloroundecanoic acid dissolved in DMF (20 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (400 mg) and triethylamine (1.2 ml), and the mixture was stirred for 12 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK133 in the yield of 103 mg.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:17])=[CH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)CC>[N+:18]([C:12]1[CH:13]=[N:14][C:15]2[C:10]([C:11]=1[OH:17])=[CH:9][CH:8]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:16]=2)([O-:20])=[O:19]
Reactant: Oc1ccnc2cc(-c3ccccc3)ccc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1O
Temperature: 129 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
A stirred suspension of 7-phenylquinolin-4-ol (84.9 g, 384 mmol) in propionic acid (850 mL) was heated to 129° C. Nitric acid (70%, 45.0 g) was added dropwise over 25 min, during which the temperature dropped to 124° C. The reaction was stirred an additional 3 h at that temperature and then cooled to 5° C. on an ice bath. The resulting solid was collected by filtration, washed with ice cold ethanol (until washings were nearly colorless) and dried at 70° C. in a vacuum oven overnight to obtain 83.2 g of 3-nitro-7-phenylquinolin-4-ol as a beige powder.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[CH:29][C:28]=1[C:37](O)=[O:38].FC(F)(F)C(O)=O>ClCCl>[CH2:19]([N:18]([C:37]([C:28]1[CH:29]=[N:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1)=[O:38])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: O=C(O)c1cnc2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and quinoxaline-2-carboxylic acid as starting materials and by an operation similar to that of Example 312-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1.[CH:27]1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:5][CH:4]=1
Reactant: CNC(=O)c1ccc2ncc(C(=O)O)c(Nc3ccc(OC)cc3)c2c1
Reactant: On1nnc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CO
Product: CNC(=O)c1ccc2ncc(C(=O)OC)c(Nc3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a suspension of 0.1 g of 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)-quinoline-3-carboxylic acid in dichloromethane EDC.HCl (1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride, 0.161 g), HOBt (N-hydroxybenzotriazole, 0.042 g), DMAP (4-dimethylaminopyridine, 0.17 g) and 20 mL of methanol were added and the reaction mixture was stirred at room temperature for 3 h. After aqueous work up, the reaction mixture was extracted, concentrated and dried over anhydrous sodium sulfate to afford the crude product which was later purified by column chromatography to afford 0.062 g (60%) of methyl 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)quinoline-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ 11.51 (s, 1H, —NH—), 9.12 (s, 1H, aromatic), 8.38-8.15 (m, 2H, aromatic), 8.10 (s, 1H, aromatic), 7.23 (d, 2H, J=9 Hz, aromatic), 7.02 (d, 2H, J=9 Hz, aromatic), 4.02 (s, 3H, —OCH3), 3.90 (s, 3H, —OCH3), 2.92 (s, 3H, —NCH3); LC-MS (m/z) 365.9 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[CH3:7])(=[O:3])[CH3:2].[CH3:9][N:10]([CH3:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]([CH3:18])[CH3:9])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CN(C)c1ccc(O)cc1
Reactant: CC(=O)OCC(C)Br
Product: CC(=O)OCCCOc1ccc(N(C)C)cc1

Procedure:
3-(4-(Dimethylamino)phenoxy)propyl acetate (47A) was prepared following a similar procedure as that described in example 39, except 2-bromopropyl acetate was used instead of 2-bromoethyl acetate and 4-(dimethylamino)phenol was used instead of 3-(dimethylamino)phenol in step 1 of example 39.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccc(Nc2cc(Cl)ncn2)cc1
Yield: 76 %

Procedure:
A mixture of 4,6-dichloropyrimidine (3.0 g), 4-aminophenol (2.2 g) and triethylamine (6 ml) in ethanol.(50 ml) was refluxed for 2 hours. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 6-chloro-4-(4'-hydroxyanilino)pyrimidine in 76% yield, m.p. 241-244° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([OH:15])=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([OH:15])=[N:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2nnc(O)o2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2nnc(O)o2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a flask, is dissolved 5-(4-nitrophenyl)-1,3,4-oxadiazol-2-ol (4.50 g; 21.72 mmol; 1 eq.) in MeOH (150 ml) under inert atmosphere. Palladium 10% on charcoal (2.31 g; 2.17 mmol; 0.10 eq.) is added and the reaction mixture is stirred 5 minutes at rt. The mixture is then put under atmospheric pressure of hydrogen. The reaction is completed after 2 hours. The mixture is filtrated on celite and rinced with MeOH. The solvents are evaporated under vacuo, affording 5-(4-aminophenyl)-1,3,4-oxadiazol-2-ol as a white powder (2.34 g; 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][N:13]=[N:12]1.[H-].[Na+].I[CH2:20][CH3:21]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:20][CH3:21])[N:13]=[N:12]1
Reactant: COc1cc(-n2nn[nH]c2=O)c(Cl)cc1F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCn1nnn(-c2cc(OC)c(F)cc2Cl)c1=O
Yield: 85.6 %

Procedure:
In the manner of Example 2, Step F, the reaction of 1.33 g (0.0054 mole) of 1-(2-chloro-4-fluoro-5-methoxyphenyl)-1,4-dihydro-5H-tetrazol-5-one with 0.26 g (0.0054 mole) of sodium hydride and 1.6 g (0.01 mole) of iodoethane in 60 mL of dimethylsulfoxide produced 1.26 g of 1-(2-chloro-4-fluoro-5-methoxyphenyl)-1,4-dihydro-4-ethyl-5H-tetrazol-5-one, compound 105, 79°-80° C. Compound 106 was prepared in a similar manner.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][CH2:23][CH2:24][C:25]([OH:32])([CH2:29][CH:30]=[CH2:31])[CH2:26][CH:27]=[CH2:28])[CH3:21])=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH2:29]([C:25]1([CH2:26][CH:27]=[CH2:28])[O:32][C:2](=[O:4])[N:22]([C@H:20]([C:17]2[CH:16]=[CH:15][C:14]([Br:13])=[CH:19][CH:18]=2)[CH3:21])[CH2:23][CH2:24]1)[CH:30]=[CH2:31]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CC=C)CCN[C@@H](C)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC1(CC=C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphosgene (6.90 g) is added to a solution of 4-{2-[(S)-1-(4-bromo-phenyl)-ethylamino]-ethyl}-hepta-1,6-dien-4-ol (7.86 g) and ethyl-diisopropyl-amine (4 mL) in dichloromethane (150 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature overnight. Water is added and the organic phase is then separated. The organic phase is dried (Na2SO4) and concentrated to give the crude title compound that is used without further purification. Yield: 8.65 g (ca. 90% pure); LC (method 1): tR=4.03 min; Mass spectrum (ESI+): m/z=364/366 (Br) [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([CH3:18])[N:3]=1.[S-2:19].[Na+].[Na+]>CN(C=O)C>[CH3:18][C:4]1[C:5]([C:16]#[N:17])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:7]([C:8]#[N:9])=[C:2]([SH:19])[N:3]=1
Reactant: [S-2]
Reactant: Cc1nc(Cl)c(C#N)c(C2CCCCO2)c1C#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(S)c(C#N)c(C2CCCCO2)c1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
471 mg (1.35 mmol) of the compound from Example 40A are initially charged in 4 ml of dry DMF, and 126 mg (1.62 mmol) of sodium sulfide are added. The reaction mixture is stirred at RT for 12 h. The solvent is then removed on a rotary evaporator and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 200:1→5:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:15]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:15])[C:9]1=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CC1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
300 mg (1.61 mmol) of 2-oxo-pyrrolidin-1-carboxylic acid t-butyl ester was dissolved in tetrahydrofuran and then cooled to −78° C. To the resulting solution, was dropwise added a solution of 1.7 mL (1.7 mmol) of 1.0 M lithium bis(trimethylsilyl)amide tetrahydrofuran, followed by stirring for 1 hour. 0.19 mL (3.05 mmol) of iodomethane was dropwise added thereto. Thereafter, the temperature was gradually raised to −30° C. for 2 hours. 50 mL of ethyl acetate was added to the solution, and the reaction solution was washed with aqueous ammonium chloride, and an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 130 mg (0.65 mmol) of the title compound in a yield of 40%.