Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[C:20]([CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[N:25]=1)O)#[N:21]>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH:22]([C:20]#[N:21])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[N:25]=1)=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: N#CC(O)c1cccc(Oc2cccc(F)c2)n1
Solvent: CCOCC
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OC(C#N)c1cccc(Oc2cccc(F)c2)n1

Procedure:
The acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with cyano[6-(3-fluorophenoxy)-2-pyridyl]methanol in ether as in Example 2 to give cyano[6-(3-fluorophenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[Cl:8][CH:9](CO)[CH:10]([OH:13])CO.S(=O)(=O)(O)O.[OH-].[Ba+2].[OH-]>CC(C)=O.O>[Cl:8][CH:9]([CH:1]1[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]1)[CH2:10][OH:13]
Reactant: OCC(O)C(Cl)CO
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(C(Cl)CO)O1
Reaction time: 2 h

Procedure:
Within 2 hours, 258 ml of 2,2-dimethoxypropane is added dropwise to a stirred and water-cooled solution of 272 g of 3-chloro-1,2,4-butanetriol and 0.5 ml of concentrated sulfuric acid in 1 liter of acetone. The reaction is completed after another 4 hours. The solution is neutralized by the addition of 3.8 g of barium hydroxide, stirred for 30 minutes, filtered off from the solid matter, and concentrated to dryness under vacuum, yielding 2-chloro-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][N:14]=[C:15]=[O:16].Cl>N1C=CC=CC=1>[CH2:11]([O:10][C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:15]([NH:14][CH3:13])=[O:16])=[O:9])[CH3:12]
Reactant: CN=C=O
Reactant: CCOC(=O)c1c(C)nsc1N
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nsc1NC(=O)NC
Temperature: 80 °C

Procedure:
A solution of 5-amino-4-ethoxycarbonyl-3-methylisothiazole (prepared by the method of Goerdeler and Horn, op cit; 3.72 g.) in pyridine (10 ml.) was treated at 80° C. with methyl isocyanate (1.5 ml.) and the mixture was maintained at 80° C. for 6 hours. The mixture was then poured into an excess of dilute aqueous hydrochloric acid to give an off-white precipitate which was filtered off and recrystallised from ethanol to give colourless crystals of 1-(4-ethoxycarbonyl-3-methylisothiazol-5-yl)-3-methylurea (1.6 g.), m.p. 191°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH:20]([CH3:28])[CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH:20]([CH3:28])[CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1OC)CC(C)NC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1cc2c(cc1OC)CN(C(=O)c1cc3ncc(Cl)cn3n1)C(C)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a colorless solid.
Reaction SMILES: O.Cl.Cl.[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:8]=2[CH2:7]1.CN(C)C1CC[C:26]2[O:27]C3C=CC(N)=CC=3[C:25]=2C1.Cl.Cl.C(Cl)(=O)C>>[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:26](=[O:27])[CH3:25])=[CH:13][C:12]=3[C:8]=2[CH2:7]1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Agent: Cl
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc2oc3c(c2c1)CC(N(C)C)CC3
Yield: 76.6 %

Procedure:
Beginning with 9.0 mg (0.029 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine dihydrochloride hemihydrate and 2.8 mg (0.036 mMol) of acetyl chloride, 6.05 mg (77%) of the title compound were recovered by the procedure described in Example 2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[CH3:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(S)cc1C
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethylthiophenol.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:26]=[C:25]4[C:20]([N:21]=[CH:22][C:23]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[N:24]4)=[CH:19][CH:18]=3)[CH:14]=[N:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(#N)C>[N:27]1([C:23]2[CH:22]=[N:21][C:20]3[C:25]([N:24]=2)=[CH:26][C:17]([C:13]2[CH:12]=[C:11]([NH:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:16]=[N:15][CH:14]=2)=[CH:18][CH:19]=3)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=S(=O)(Nc1cncc(-c2ccc3ncc(N4CCNCC4)nc3c2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(7-{5-[(phenylsulfonyl)amino]-3-pyridinyl}-2-quinoxalinyl)-1-piperazinecarboxylate (1.80 mmol) in acetonitrile (4 ml) was added concentrated trifluoroacetic acid (4 ml). The reaction stirred at ambient temperature for 18 hours and was then concentrated to an orange oil. The residue was neutralized with 10% sodium carbonate solution and purified on silica by column chromatography (15% methanol/ethyl acetate). The desired fractions were combined and concentrated to give the title compound (500 mg, 61%) as a tan solid. MS(ES)+ m/e 447.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.Cl>CCOCC>[ClH:1].[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: NCc1ccccn1
Reactant: OCc1cnc2ccc(Cl)nn12
Agent: Cl
Solvent: CCOCC
Product: OCc1cnc2ccc(NCc3ccccn3)nn12
Yield: 20 %

Procedure:
Prepared from (6-chloroimidazo[1,2-b]pyridazin-3-yl)methanol (7) and 2-(aminomethyl)pyridine according to general procedure 4 (StepB). The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (48 mg, 20%) as a yellow solid; 1H NMR (300 MHz, CD3OD) δ 8.49 (d, J=4.2 Hz, 1H), 7.77 (dt, J=1.7, 9.4 Hz, 1H), 7.61-7.52 (m, 2H), 7.35 (s, 1H), 7.31-7.26 (m, 1H), 6.77 (d, J=9.7 Hz, 1H), 4.74 (s, 2H), 4.67 (s, 2H); 13C NMR (75 MHz, CD3OD) δ 160.2, 154.9, 149.6, 138.8, 137.8, 129.8, 129.5, 125.9, 123.7, 123.6, 114.2, 53.8, 47.6; HPLC tR=7.0 min (Synergi), 96.1%; ES-MS: (M+H)=256 m/z.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[C:18]([C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22])#[N:19]>>[C:18]([C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)#[N:19]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(C#N)c(N)c1
Product: Cc1ccc(C#N)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-cyano-5-methylaniline (38 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (8 mg, 12%). 1H NMR (CDCl3): 9.62–9.61 (m, 1H), 8.75–8.69 (m, 2H), 8.08 (s, 1H), 7.62 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.46–7.41 (m, 1H), 7.12 (dd, J=0.9, 8.1 Hz, 1H), 7.00 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:25][C:24]1[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: Cc1cccnc1CCl
Agent: Cl
Product: Cc1cc(C#Cc2cn(Cc3ncccc3C)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=303.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloromethyl-3-methyl-pyridine hydrochloride.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[OH:11][C:12]1[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([OH:18])[CH:17]=1>O>[OH:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[C:13]=1[CH:3]=[O:4]
Reactant: Oc1cc(O)cc(F)c1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(O)cc(O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
Dimethylformamide (12.7 g) was added to vigorously stirred phosphorous oxychloride (14.4 g) at 0° C. The reaction mixture was stirred at this temperature for 30 minutes, then 3,5-dihydroxyfluorobenzene (6 g) was added. The sticky red syrup was allowed to warm to room temperature and stirred for 2 hours, then left to stand for 14 hours. Water (100 ml) was added and the mixture extracted three times with ethyl acetate (100 ml). The combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2, v/v). Fractions homogeneous in the required product were combined and evaporated to give an orange solid which was triturated with ethyl acetate to give the title compound (2 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][C:26](=O)[CH2:27][N:28]([C:36]([O:38][CH2:39]C2C=CC=CC=2)=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16]C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:39]([O:38][C:36]([N:28]([CH2:27][C:26]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:14]([O:15][CH2:16][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:13]=2)[CH2:23][CH2:24][N:25]=1)[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN(C(=O)OCc1ccccc1)c1ccc(Cl)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(OCc1ccccc1)N(CC1=NCCc2cc(OCc3ccccc3)c(OCc3ccccc3)cc21)c1ccc(Cl)cc1
Yield: 197.4 %

Procedure:
A mixture of N-[2-(3,4-dibenzyloxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-chloroanilino)acetamide (7.3 g), phosphorus oxychloride (2.3 g) and anhydrous benzene (73 ml) was refluxed for four hours. The reaction mixture was concentrated to dryness under reduced pressure and to the residue was added a diluted aqueous ammonia solution, and then the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off to give 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-3,4-dihydroisoquinoline (7.0 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17]Br)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][O:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1ccc(Br)nc1
Temperature: 40 °C
Reaction time: 20 h
Yield: 90.3 %

Procedure:
A mixture of 6-bromopyridin-3-ol (1.50 g), tert-butyl(2-bromoethyl)carbamate (2.32 g), cesium carbonate (3.65) and N,N-dimethylformamide (30 mL) was stirred at 40° C. for 20 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.47 g).
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]CC)=[O:36])[CH:30]=2)=[O:27])[C:9]1=[O:40])=[O:6])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]([NH:25][C:26](=[O:27])[NH:28][C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]([OH:37])=[O:36])[C:9]1=[O:40])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea (500 mg) was dissolved in methanol (20 ml), the solution of lithium hydroxide monohydrate (191 mg) in water (10 ml) was added, the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, after acidification with 1N hydrochloric acid, the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and recrystallized from ethanol and isopropyl ether, to thereby obtain 380 mg of the titled compound (Yield: 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:12]=[C:13]([CH2:15][O:16][CH3:24])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(CO)cn2c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of inert gas, a suspension of 1.2 g of 8-benzyloxy-6-hydroxymethyl-2,3-dimethylimidazo[1,2-a]pyridine in 12 ml of dimethylformamide is admixed with 0.36 g of 60% sodium hydride in paraffin, and the mixture is stirred at room temperature for 30 minutes, until the generation of gas has ceased, and then, at room temperature, admixed with 0.56 ml of methyl iodide. After a reaction time of one hour, the mixture is poured into 100 ml of ice-water and extracted three times with in each case 100 ml of ethyl acetate. The organic phases are combined and washed with water. The solvent is removed in vacuo and the oily residue is chromatographed on silica gel (mobile phase: methylene chloridelmethanol=100/1). This gives 0.34 g of the title compound of melting point 107° C. (diethyl ether).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][NH:27]C.[CH3:29][CH:30]1[CH2:39][CH2:38][C:37]2[C:32]3=[C:33]([C:40]([C:42]([OH:44])=O)=[CH:41][N:31]13)[CH:34]=[CH:35][CH:36]=2>C(#N)C>[CH3:1][C:2]1[N:6]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[N:4][C:3]=1[CH2:26][NH:27][C:42]([C:40]1[C:33]2=[C:32]3[C:37](=[CH:36][CH:35]=[CH:34]2)[CH2:38][CH2:39][CH:30]([CH3:29])[N:31]3[CH:41]=1)=[O:44]
Reactant: CNCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Reactant: CC1CCc2cccc3c(C(=O)O)cn1c23
Solvent: CC#N
Product: Cc1c(CNC(=O)c2cn3c4c(cccc24)CCC3C)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 12 h

Procedure:
A mixture of 3.4 g (9.3 mmol) of 5-methyl-4-(methylamino) methyl-1-triphenylmethyl-1H-imidazole, 2.0 g (9.3 mmol) of 4-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid, and 2.06 g (10 mmol) of N,N-dicyclohexylcarbodiimide in 100 ml of acetonitrile was stirred for 12 hours under nitrogen. The precipitate was sucked off and the filtrate was evaporated in vacuo. The residue was dissolved in ethylacetate and washed with 2 N sodium hydroxide and saturated saline respectively, and then evaporated in vacuo. The residue was chromatographed on silicagel using methylene chloride/methanol (95/5) as an eluent. After evaporating the desired fractions 3.6 g of N-methyl, N-[(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl]-4-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxamide were obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[N:6][CH:5]=[N:4]1)[CH3:2].Cl[C:11]1[C:12]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:13][C:14]2[N:15]([C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:18][N:19]=2)[N:16]=1.[H-].[Na+]>CN(C=O)C.O>[CH3:30][C:27]([C:12]1[C:11]([O:9][CH2:8][C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][N:6]=2)=[N:16][N:15]2[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:18][N:19]=[C:14]2[CH:13]=1)([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Reactant: CCn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a solution of (2-ethyl-2H-1,2,4-triazol-3-yl)methanol (0.094 g, 0.74 mmol) and 6-chloro-7-(1,1-dimethylethyl)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (0.15 g. 0.49 mmol) in DMF (10 ml) was added sodium hydride (0.024 g of a 60% dispersion in oil, 1.1 mol eq.) and the reaction mixture was stirred at room temperature for 30 minutes. After this time, the reaction mixture was diluted with water (80 ml) and the solid that precipitated was collected by filtration and washed several times with water in the sinter funnel. The solid was recrystallised from ethyl acetate/hexane to give pure title compound (0.085 g, 44%). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.40-1.47 (12H, m), 4.14 (2H, t, J=7.3 Hz), 5.26 (2H, s), 7.26-7.38 (2H, m), 7.53-7.58 (1H, m), 7.86-7.90 (1H, m), 7.93 (1H, s), 7.99 (1H, s); MS (ES+) m/e 396 [MH]+. Anal. Found C, 61.02; H, 5.45; N, 24.75%. C20H22FN7O requires C, 60.75; H, 5.61; N, 24.79%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH2:9])[CH:3]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][C:17](=[O:19])[CH3:18])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc(Br)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.5 %

Procedure:
Into a 500-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (4-bromopyridin-2-yl)methanamine (compound 39.1, 4.5 g, 24.1 mmol) in dichloromethane (160 mL). Triethylamine (6.72 mL, 48.2 mmol) and acetic anhydride (2.29 mL, 24.2 mmol) were carefully added and the resulting solution was stirred at room temperature for 12 h. The volatiles were removed under reduced pressure and the residue was slowly quenched with water (200 mL). The pH of the solution was slowly adjusted to 9-12 with aqueous sodium carbonate (3 M) and the aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane/methanol (100:1-10:1) as the eluent to yield 4.0 g (73%) of the title compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2.[OH:26]O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2)=[O:26]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCSc3cc(Cl)ccc3Cl)ccc2N1
Solvent: CC(=O)O
Product: O=C1CCc2cc(OCCCCS(=O)c3cc(Cl)ccc3Cl)ccc2N1
Temperature: 25 °C

Procedure:
A suspension of 5.55 gm (0.014 mol) of 6-[4-(2,5-dichlorophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril in 40 ml of glacial acetic acid was admixed with 1.19 ml of an aqueous 40.06% solution of hydrogen peroxide (0.014 mol) dissolved in 1.5 ml of glacial acetic acid, and the mixture was stirred at room temperature. The suspension cleared, and an almost clear solution was obtained. After 70 hours white crystals separated out, which were suction-filtered off and recrystallized from ethanol.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CS(C)=O.O>[CH2:25]([N:28]([C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: CCCNCCC
Reactant: Cc1cc(C)c(-c2c3nc(C)cc(Cl)c3n3ccccc23)c(C)c1
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCC)c1cc(C)nc2c(-c3c(C)cc(C)cc3C)c3ccccn3c12
Temperature: 130 °C
Yield: 86.8 %

Procedure:
A mixture of 4-chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrido[2,3-b]indolizine (10.0 g; 30 mmol) and dipropylamine (15 mL; 1 mol) in DMSO (30 mL) is heated at 130° C. under nitrogen atmosphere for two days. The mixture is cooled to room temperature, diluted with water (ca. 300 mL), and extracted with ether (100 mL×2). The combined organics are washed successively with saturated ammonium chloride and saturated brine, dried (Na2SO4), filtered, and concentrated. The concentrate is chromatographed (first with 5% ethyl acetate in hexane and then with 10% triethylamine in hexane) to give 10.4 g of the title compound (compound 1, Table 1) as a fluorescent yellow foam (87%): 1H nmr (400 MHz, CDCl3) d 0.90 (t, 6 H), 1.6 (br, 4 H), 2.02 (s, 6 H), 2.37 (s, 3 H), 2.62 (s, 3 H), 3.2 (br, 4 H), 6.52 (t, 1 H), 6.73 (s, 1 H), 6.89 (t, 1 H), 7.00 (s, 2 H), 7.06 (d, 1 H), 8.98 (d, 1 H).