Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([NH:5][CH:6]=[CH:7][C:8]2=O)=[N:3]1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>>[Cl:14][C:8]1[C:9]2[C:4](=[N:3][N:2]([CH3:1])[CH:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1cc2c(=O)cc[nH]c2n1
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc2c(Cl)ccnc2n1
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of the product of Example 8b (0.177 g, 1.19 mmol) and phosphorus oxychloride (3 mL) was heated under reflux for 30 min and then cooled to room temperature. The reaction mixture was poured over ice, taken to pH 8 by the addition of 1N aqueous sodium hydroxide solution, and extracted with dichloromethane (3×30 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to provide the title compound (0.170 g, 88% yield).
Reaction SMILES: C(OC([O:6][C:7]([CH3:22])([CH:20]=[CH2:21])[C:8]#[C:9][C:10]1(O)[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH:12]=[C:11]1[CH3:18])C)C.[C:23]([OH:26])(=[O:25])[CH3:24]>CCCCCC>[CH3:18][C:11]1[CH:12]([O:26][C:23](=[O:25])[CH3:24])[CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[C:10]=1[C:9]#[C:8][C:7]([CH3:22])([OH:6])[CH:20]=[CH2:21]
Reactant: CC(=O)O
Reactant: C=CC(C)(C#CC1(O)C(C)=CCCC1(C)C)OC(C)OCC
Solvent: CCCCCC
Product: C=CC(C)(O)C#CC1=C(C)C(OC(C)=O)CCC1(C)C

Procedure:
The compound 1-ethoxy-[1-(2,6,6-trimethyl-1-hydroxy-2-cyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-oxy]ethane (9.5 g) in acetic acid (40 ml) was heated at 55° for 11/2 hr and then taken to dryness "in vacuo" (45° at 0.5 mmHg), dissolved in hexane, and chromatographed on silica gel (400 g). Elution with hexane-ether mixtures (4:1 parts by volume and 3:1 parts by volume 500 ml cuts, 2 liters) yielded 1-(2,6,6-trimethyl-3-acetoxycyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-ol (4.3 g) bp 165° (0.09 mmHg).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([NH2:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].O.[C:16]1(C)[C:17](S(O)(=O)=O)=CC=C[CH:21]=1>CC(C)=O>[CH3:21][C:16]1([CH3:17])[NH:14][C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[O:8]1
Reactant: NC(=O)c1ccccc1O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(C)NC(=O)c2ccccc2O1
Reaction time: 24 h

Procedure:
A 500-ml flask was charged with 250 ml of chloroform, 27.4 g (0.2 mol) of salicylamide, 23.2 g (0.4 mol) of acetone and 2.7 g of toluene sulfonic acid monohydrate. The flask was equipped with a Soxhlet extraction vessel containing 36.7 g of molecular sieves (Linde Type 3A, 1/16 inch) in the thimble. The reaction mixture was refluxed for 24 hours. Then fresh sieves were placed in the Soxhlet and 10 g of acetone was added to the reaction mixture. Reflux was continued for 24 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.[CH2:25](I)[CH2:26][CH3:27]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:25][CH2:26][CH3:27])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCCI
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Product: CCCn1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccc1=O

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and propyl iodide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]([O:18]C)=O)=[CH:10][C:11]([CH2:14][OH:15])=[CH:12][CH:13]=1.[C:20]([Li])([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=1[C:16](=[O:18])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: [Li]C(C)(C)C
Reactant: COC(=O)c1cc(CO)ccc1-c1ccccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cc(CO)ccc1-c1ccccc1F
Reaction time: 5 h
Yield: 78 %

Procedure:
To a stirred solution of 66.32C (0.850 g, 3 mmol) in THF (33 mL) at −78° C. was added tert-butyllithium (6 mL, 10 mmol, 1.7M). The reaction was stirred for 5 hours and then a saturated solution of ammonium chloride was added and the mixture was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield 66.32D as a colorless oil (0.670 g, 72% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=3[C:12]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:11]2=3)=[CH:4][CH:3]=1.C[CH2:28][N:29]=C=NCCCN(C)C.Cl.CN.C1COCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([C:19]([NH:29][CH3:28])=[O:20])=[CH:14][C:13]=3[C:12]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:11]2=3)=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN1CCc2c(c3cc(C(=O)O)ccc3n2C#Cc2ccc(F)cc2)C1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)c1c(n2C#Cc2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Fluoro-phenylethynyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid (20 mg, 0.0044 mmol) was dissolved in DMF and EDCI.HCl (42.17 mg, 0.22 mmol) was added. Methyl amine (2.0 M) in THF (0.0446 mL, 0.0089 mmol) was added. The reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC and LCMS. The DMF was evaporated under vacuum and the product purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.05 (s, 1H), 7.82 (d, 1H), 7.62 (m, 3H), 7.20 (t, 2H), 4.40 (m, 1H), 3.70 (m, 1H), 3.38 (m, 4H), 3.20 (s, 3H), 2.90 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:19](=[O:22])(=[O:21])[NH2:20])[C:17]=1Cl)[C:12]([O-:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:30]1([S-])C=CC=C[CH:31]=1.[Na+]>C(O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:19](=[O:22])(=[O:21])[NH2:20])[C:17]=1[S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][CH2:30][CH3:31])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(C(=O)[O-])cc(SCc2ccccc2)c1Cl
Reactant: [S-]c1ccccc1
Reactant: Sc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(SCc2ccccc2)c(Sc2ccccc2)c(S(N)(=O)=O)c1
Reaction time: 20 h

Procedure:
A mixture of ethyk 3-benzylthio-4-chloro-5-sulfamylbenzoate (0.77 g), thiophenol (0.36 ml), and dry ethanol (15 ml) containing 3millimoles of sodium thiophenolate is refulxed for 20 hours. After cooling the precipitate is collected by filtration to yield ethyl 3-benzylthio-4-phenylthio-5-sulfamylbenzoate with a melting point of 151° - 152°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[N:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1cncc(F)c1
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cncc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 5-fluoropyridin-3-ol: MS (ESI) m/z 282 (M+H)+.
Reaction SMILES: BrCCC1C=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14](CCBr)=[C:13]([Cl:20])[C:12]=2[Cl:21])=C(Cl)C=1Cl.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[ClH:20].[Cl:21][C:12]1[C:13]([Cl:20])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:7][CH2:8][NH:27][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Clc1c(CCBr)ccc(Oc2ccc(CCBr)c(Cl)c2Cl)c1Cl
Product: CC(C)NCCOc1cccc(Cl)c1Cl
Product: Cl
Yield: 62.7 %

Procedure:
Following the procedure of Example 11, 2-bromoethyl-2,3-dichlorophenyl ether was reacted with isopropyl amine (excess) and the reaction mixture processed to give an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride salt, m.p. 161°-163.5° C. in 62.7% yield.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[C:26]([O:30][C:31](ON=C(C1C=CC=CC=1)C#N)=[O:32])([CH3:29])([CH3:28])[CH3:27]>O1CCOCC1.O>[C:26]([O:30][C:31]([NH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CCOC(=O)C(N)CCc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(CCc1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 2-amino-4-(o-nitrophenyl)butyrate (17.4 g) in 50% aqueous dioxane (130 ml) is added triethylamine (10.5 g) and 2-(tert-butyloxycarbonyloxyimino-2-phenylacetonitrile (18.7 g). The reaction mixture is stirred at room temperature for 4 hours and then diluted with water (300 ml). The mixture is extracted with ether (2×150 ml) and the aqueous phase acidified with ice-cold 2N hydrochloric acid and extracted with ethyl acetate (2×250 ml). The ethyl acetate layers are combined, washed with water (150 ml) and dried over sodium sulfate. The solvent is removed under reduced pressure to give ethyl 2-t-butyloxycarbonylamino-4-(o-nitrophenyl)butyrate, used without further purification.
Reaction SMILES: NO.C(Cl)CCl.[CH:7]1[CH:8]=[CH:9][C:10]2N(O)N=[N:13][C:11]=2[CH:12]=1.C(N[C@H:25]([C:30]([OH:32])=[O:31])[CH2:26][CH:27](C)C)(OC(C)(C)C)=O>C(Cl)Cl.C(OCC)(=O)C>[N:13]1[C:11]2[C:10](=[CH:9][CH:8]=[CH:7][CH:12]=2)[CH:27]=[CH:26][C:25]=1[C:30]([OH:32])=[O:31]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: NO
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(O)c1ccc2ccccc2n1
Temperature: 25 °C
Yield: 212 %

Procedure:
To a solution of the amino alcohol of Example 1e (720 mg, 2.72 mmol) in CH2Cl2 was added EDC (521 mg), HOBt (368 mg) and N-Boc-leucine (630 mg). The reaction was maintained at room temperature until complete consumption of the starting material was observed by TLC analysis. The reaction was diluted with ethyl acetate and washed with 1N HCl, sat. K2CO3, water, brine, dried (MgSO4), filtered and concentrated. Column chromatography of the residue (3% methanol:dichloromethane) gave 1.0 g of the title compound: MS(EI) 478 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)P(=O)(N(C)C)N(C)C>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Na]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(OCc1ccccc1)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt are dissolved in 75 parts of hexamethylphosphoric triamide while heating to 110° C. After cooling to 20° C, 3.4 parts of (chloromethyl)benzene are added dropwise. Upon completion, stirring is continued for 18 hours at room temperature. The reaction mixture is poured onto 300 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding phenylmethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 76.7° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:16]([N:18](CC)CC)C.CN>O1CCCC1>[CH3:16][NH:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Yield: 97.5 %

Procedure:
The method described in Part A of Example 4 was used to treat 2,4-dichloro-3-nitroquinoline (10.0 g, 40.8 mmol) with triethylamine (8.53 mL, 61.2 mmol) and methylamine (20.41 mL of a 2 M solution in tetrahydrofuran, 40.82 mmol) to provide 9.45 g of N-methyl-2-chloro-3-nitroquinolin-4-amine as a yellow powder.
Reaction SMILES: [CH:1]#[C:2][CH:3](O)[CH2:4][CH3:5].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.NC1C=CC=CC=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].ClCCl>[CH2:2]([C:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:4]=1[CH3:5])[CH3:1]
Reactant: Nc1ccccc1
Reactant: C#CC(O)CC
Agent: [Ru]
Agent: Cl
Agent: [C-]#[O+]
Solvent: ClCCl
Product: CCc1c(C)[nH]c2ccccc12
Temperature: 140 °C
Reaction time: 7.5 h
Yield: 111.2 %

Procedure:
1-Pentine-3-ol (0.757 g, 9 mmol), aniline (0.559 g, 6 mmol), Ru3(CO)12 (16.0 mg, 0.025 mmol) and aniline hydrochloride (0.130 g, 1.0 mmol) were placed in a 10 ml round-bottomed flask, and the mixture was stirred at 140° C. for 7.5 hours. After cooling, dichloromethane (3 mL) was added, and the organic layer was washed twice with 1 M hydrochloric acid (2 mL) and once with water (2 mL). The organic layer was dried over sodium sulfate, and the solvent was distilled away, whereby a 9.3:1 mixture of 2-ethyl-3-methyl indole and 3-ethyl-2-methyl indole (1.06 g; 6.67 mmol; yield, 95%) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[CH2:17]([O:10][C:9]1[C:2]([Br:1])=[C:3]([CH:6]=[CH:7][C:8]=1[O:11][CH3:12])[CH:4]=[O:5])[CH:16]=[CH2:15]
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1c(OC)ccc(C=O)c1Br
Reaction time: 0.5 h

Procedure:
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (1.68 g) was dissolved in DMF (17 ml), and sodium hydride (0.209 g) was added thereto under ice-cooling, followed by stirring for 30 minutes. Allyl bromide (0.944 ml) was added to the mixture, followed by stirring at 60° C. for one hour. After being allowed to stand for cooling, water was added to the mixture and the precipitated solid was collected by filtration. The obtained crude crystals were recrystallized from isopropanol to give Compound IIe-a (1.30 g, 66%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[N:10][CH:11]=[C:6]2[CH2:5][NH:4][C:3]1=[O:24].FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][N:2]1[C:7]2=[N:8][C:9]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:17][CH:18]=3)=[N:10][CH:11]=[C:6]2[CH:5]=[N:4][C:3]1=[O:24]
Reactant: CN1C(=O)NCc2cnc(Nc3ccc(-n4cccn4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cn1c(=O)ncc2cnc(Nc3ccc(-n4cccn4)cc3)nc21
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Prepared from 200 mg (0.46 mmol) of 1-methyl-7-[4-(pyrazol-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 309 mg (2.76 mmol) of potassium tert-butoxide in 15 mL of tetrahydrofuran. The reaction mixture is stirred overnight. After the workup, the semi-solid is triturated in diethyl ether, and the powder is collected and dried to give 102 mg (65%) of the title compound: mp>290° C. (dec).
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.Br[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1>>[CH3:27][C:24]1[N:25]=[CH:26][C:21]([CH2:20][CH2:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:17])=[CH:10][CH:11]=2)[NH2:16])=[CH:22][CH:23]=1
Reactant: Cc1ccc(NN)cc1
Reactant: Cc1ccc(CCBr)cn1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by General Method 1. Triethylamine (13.0 mL, 94.5 mmol) was added dropwise to p-tolylhydrazine hydrochloride (5.0 g, 31.5 mmol) over a period of 5-10 min. The reaction mixture was stirred for additional 10 min. 5-(2-bromoethyl)-2-methylpyridine (6.3 g, 31.5 mmol) was added dropwise at 25° C. over a period of 10-15 min. The reaction mixture was stirred at RT for 1 h and the subsequently heated at 90° C. for 2-3 h at which point the reaction was found complete by TLC and LC-MS. Reaction mixture was concentrated under reduced pressure and diluted with water (50 mL) and extracted with ethyl acetate (100 mL×2). The organic layer was separated, dried (Na2SO4) and concentrated to obtain crude product as dark brown oil (16.7 g). Purification of crude product by column chromatography (silica gel, 100-200 mesh, eluent: 0-40% ethyl acetate-Hexane) furnished 1.92 g of pure product as brown liquid. Yield: 25%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:10]=1)=[O:4].[OH-].[Na+].Cl>C(O)(C)(C)C.O>[C:28]([O:27][C:25]([NH:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:13]=[C:8]4[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(=O)O)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 70 °C

Procedure:
2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (0.76 g) was suspended in tert-butanol (19.2 mL) and treated with dilute aqueous sodium hydroxide solution (1M, 6.1 mL). The mixture was heated to 70° C. for 3.5 h. On cooling the reaction was diluted with water and the pH adjusted to 5 with dilute aqueous hydrochloric acid. The resulting emulsion was extracted with ethyl acetate and the organic extract washed with brine, dried and concentrated in vacuo to give the crude title compound which was used without further purification.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].[OH:24][CH2:25][CH2:26][NH:27][NH2:28]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:28][N:27]2[CH2:26][CH2:25][OH:24])=[CH:14][CH:15]=1
Reactant: NNCCO
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: OCCn1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Yield: 14 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2 mmol) and 2-hydroxyethylhydrazine (0.085 g, 1.0 mmol) to give 0.020 g of product as a white solid
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[CH3:16][C:17]([NH2:21])([C:19]#[CH:20])[CH3:18].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:8][C:6](=[CH2:7])[CH2:5][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:3][CH2:2][NH:21][C:17]([CH3:18])([C:19]#[CH:20])[CH3:16]
Reactant: C#CC(C)(C)N
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(C)(C)NCCC(O)(CC(=C)C)c1ccccc1
Temperature: 80 °C
Yield: 42.6 %

Procedure:
A stirred mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (550 mg, 2.45 mmol), 1,1-dimethylpropargylamine (204 mg, 2.45 mmol), KI (447 mg, 2.7 mmol), i-Pr2NEt (05 mL, 2.7 mmol) and dry DMF (3 mL) was heated at 80° C. in an oil bath for 24 h. The mixture was concentrated to leave a brown oil which was purified by chromatography on a 12-g silica cartridge eluted with a 0-10% MeOH in CH2Cl2 gradient to afford 5-methyl-1-(2-methylbut-3-yn-2-ylamino)-3-phenylhex-5-en-3-ol (283 mg, 42%) as a brown solid which was used in the next step without further purification. LC-MS Method 1 tR=1.08 min, m/z=272.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[OH:25][C:26]1[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[N:3]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: Cc1ncccc1O
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2cccnc2C)n1

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 3-hydroxy-2-methylpyridine in analogy to example 3. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 34% yield.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[S:12]([OH:19])([O:15][CH2:16][CH2:17][NH2:18])(=[O:14])=[O:13]>CO.[OH-].[Na+]>[S:12]([OH:19])([O:15][CH2:16][CH2:17][NH:18][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])=[O:13]
Reactant: c1ccc(CCC2CO2)cc1
Reactant: NCCOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(O)OCCNCC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1,2-epoxy-4-phenylbutane (1.48 g.) and 2-aminoethyl hydrogen sulphate (7.05 g.) in methanol (7.5 ml.) and sodium hydroxide solution (18N, 2.8 ml.) is stirred at ambient temperature for 2 hours. The 2-(2-hydroxy-4-phenylbutyl)aminoethyl hydrogen sulphate formed as intermediate is not isolated but is cyclised in situ as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[N:27]([C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[C:28]([CH3:31])=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:36][C:35]3[CH:34]=[CH:33][C:32]([N:27]4[C:28]([CH3:31])=[CH:29][CH:30]=[C:26]4[CH3:25])=[CH:39][CH:38]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1ccc(C)n1-c1ccc(C=O)cc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(-n4c(C)ccc4C)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione to 4-(2,5-Dimethyl-pyrrol-1-yl)-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (DMSO-d6): δ 1.32-1.66 (br m, 8H), 1.89 (m, 2H), 1.90 (s, 6H), 2.30 (m, 1H), 2.52 (m, 2H), 2.61 (d, 1H, J=17.7 Hz), 2.79 (d, 1H, J=17.7 Hz), 3.57 (d, 1H, J=14.4 Hz), 3.65 (d, 1H, J=14.4 Hz), 3.80 (s, 3H), 5.77 (s, 2H), 7.01 (t, 1H, J=8.6 Hz), 7.10 (t, 1H, J=8.4 Hz), 7.10 (d, 2H, J=8.3 Hz), 7.21 (s, 1H), 7.31 (d, 2H, J=8.1 Hz), 10.91 (s, 1H) Anal. Calcd. For C32H36N0O4Cl.0.5H2O: C, 70.77; H, 6.887; N, 2.58. Found: C, 70.92; H, 6.79; N, 2.54.