Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][CH2:24][CH2:23][O:22][CH3:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COCCCN
Product: COCCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 3-methoxypropylamine (44 mg, 0.49 mmol). The title compound was obtained as a solid (80 mg, 46% yield). 1H NMR (400MHz, d6-DMSO) δ: 8.99 (2H, s), 8.84 (1H, m), 8.42 (1H, s), 3.34 (1H, m), 3.33 (1H, m), 3.23 (5H, m), 1.69 (2H, m). MS m/z: 422.03, 424.03 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1)([O-:20])=[O:19]
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Product: O=[N+]([O-])c1ccccc1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-nitrophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=257.1 [M+H]+.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([C:12](OCC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[NH2:23][C:24]1[CH:25]=[C:26]([CH:42]=[CH:43][C:44]=1[Cl:45])[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:28]>C1(C)C=CC=CC=1>[Cl:45][C:44]1[CH:43]=[CH:42][C:26]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])=[CH:25][C:24]=1[NH:23][C:12](=[O:13])[CH:6]([N:5]1[C:1](=[O:22])[C:2]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:3]2[C:4]1=[O:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)N1C(=O)c2ccccc2C1=O
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(Cl)c(N)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(C(=O)OCC)N2C(=O)c3ccccc3C2=O)c1

Procedure:
Diethyl 2-phthalimidomalonate (15.26 g, 50.0 mmol) and n-dodecyl 3-amino-4-chlorobenzoate (16.99 g, 50.0 mmol) were added to toluene (300 ml) and refluxed under Dean and Stark conditions for 5 days, occasionally removing a small amount of distillate and replenishing the solvent as necessary. The reaction was followed by TLC (1:2 ethyl acetate:60-80° C. petroleum ether), the Rf of the product being between that of the two starting materials. The toluene was removed on the rotary evaporator and on standing the viscous oil solidified. Crystallization from 60-80° C. petroleum ether gave a white solid, 13.92 g, 47%
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.I.I[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=CC=1>ClCCl>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][C:2]4[CH:39]=[N:38][CH:37]=[CH:36][CH:35]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: ICc1cccnc1
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3cc(OCc4cccnc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 3-(Iodomethyl)pyridine hydroiodide (381 mg, 1.1 mmol) was added in portions over a period of 3 hours. The heat source was removed and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-20% CMA in chloroform over 1400 mL and then 20% CMA in chloroform over 600 mL. The resulting solid was recrystallized from acetonitrile to provide 160 mg of 2-propyl-7-[(pyridin-3-yl)methoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 167.0-169.0° C. MS (APCI) m/z 351 (M+H)+; Anal. calcd for C19H18N4OS: C, 65.12; H, 5.18; N, 15.99. Found C, 65.25; H, 5.06; N, 16.03.
Reaction SMILES: [C:1]([Si:5]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[N+:23]([O-])=O)[CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@H](Oc2cc(F)ccc2N)C1
Reaction time: 6 h

Procedure:
A mixture of 9.2 g racemic tert-Butyl-[trans-3-(5-fluoro-2-nitro-phenoxy)cyclohexyloxy]-dimethyl-silane and 0.92 g of Raney Nickel in 200 ml of methanol was hydrogenated at rt under 50 psi for 6 hours. The reaction mixture was filtered and the filtrate concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4].C(O)(=O)C.O>O1CCCC1>[OH:12][CH2:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCC(CO)CC1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To an ice-cold, stirred solution of acid from step 1 (700 mg, 3.8 mmol) in tetrahydrofuran (10 mL) was added borane-dimethyl sulfide complex (2 mL, 4.1 mmol). The reaction mixture was warmed to room temperature for 2 h and a 1:1 mixture of acetic acid/water (10 mL) was added. The resulting mixture was concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 hexanes/ethyl acetate) provided methyl 4-(hydroxymethyl)cyclohexanecarboxylate (560 mg): 1H NMR (500 MHz, CDCl3) δ 3.68 (s, 3H), 3.51-3.46 (m, 2H), 2.59-2.57 (m, 1H), 2.05-2.00 (m, 2H), 1.65-1.55 (m, 5H), 1.31-1.27 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:25]4[CH:26]=[CH:27][C:28](Br)=[CH:29][C:24]=4[O:23][C:22]=3[CH:31]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:48][C:47]2[CH:49]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:51]=[CH:52][C:46]=2[N:45]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:25]4[CH:26]=[CH:27][C:28]([C:50]5[CH:51]=[CH:52][C:46]6[N:45]=[C:44]([CH:40]7[CH2:41][CH2:42][CH2:43][N:39]7[C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[NH:48][C:47]=6[CH:49]=5)=[CH:29][C:24]=4[O:23][C:22]=3[CH:31]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)oc2cc(Br)ccc23)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)oc2cc(-c4ccc5nc(C6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)ccc23)[nH]1
Temperature: 90 °C
Yield: 46.3 %

Procedure:
To the solution of 2-[5-(7-Bromo-dibenzofuran-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (124 mg, 0.26 mmol) and 2-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (107 mg, 0.26 mmol) in DME (2.25 ml) and water (0.75 ml) was added potassium carbonate (72 mg, 0.52 mmol), followed by Pd(PPh3)4 (15 mg) and PdCl2(dppf)CH2Cl2 (15 mg). The mixture was heated at 90° C. for 6 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 2-(5-{7-[2-(1-t-butoxycarbonyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-dibenzofuran-3-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (83 mg). m/z: 689.1 (M+1), 687.3 (M−1), 345.0 (M+2)/2.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([C:12]3[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29]C)=[O:28])[CH:18]=4)[N:13]=3)[CH:10]=[CH:11][C:2]1=2.[OH-].[Na+]>CO.O>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([C:12]3[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:27]([OH:29])=[O:28])[CH:18]=4)[N:13]=3)[CH:10]=[CH:11][C:2]1=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCCCO4)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(c1)OCCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of methyl 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140.0 mg, 0.34 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (42.0 mg, 1.03 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (120.0 mg, 84%).
Reaction SMILES: [ClH:1].Cl.Cl.[C:4]([C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[CH2:15][N:16]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[CH:10]=[CH:11][CH:12]=1)(=[NH:6])[NH2:5].Cl.[C:39](=[NH:44])(OCC)[CH3:40].C(N(CC)CC)C.Cl>C(O)C.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:39]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([N:16]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:15]/[CH:14]=[CH:13]/[C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:4](=[NH:5])[NH2:6])[CH:8]=3)=[CH:18][CH:19]=2)[CH2:25][CH2:26]1)(=[NH:44])[CH3:40]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)CCCN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CCCN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 217.8 %

Procedure:
To a solution of ethyl 4-[N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]amino]butyrate trihydrochloride (1378 mg) in ethanol (20 ml) were added ethyl acetimidate hydrochloride (890 mg) and triethylamine (2.01 ml). The resulting mixture was stirred at room temperature for 4 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the mixture was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 25% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in ethanol (20 ml) was added 1M hydrochloric acid (1.0 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 20 ml) was lyophilized to give the title compound (1072 mg, yield 73%) as a pale yellow amorphous solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C@H:15]2[CH2:18][C@H:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16]2)[C:13]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C@H:17]1[CH2:18][C@H:15]([N:14]2[C:13]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [(S)-1-[1-(trans-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl]carbamic acid tert-butyl ester (0.46 g, 1.05 mmol) in DCM (10 mL) was added TFA (4 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting pale red gummy residue dissolved in DCM and loaded onto an SCX-2 (20 g) cartridge. The cartridge washed with DCM then MeOH and then 2M NH3 in MeOH solution. The relevant fractions were concentrated in vacuo to afford the title compound as yellow gum (0.28 g, 80%). LCMS (Method B): RT 2.17 min [M+H]+ 340
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH3:19])=[CH:17][N:18]=[C:14]3[CH:13]([OH:20])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3Cl)[C:10]=2[CH:28]=1.C(O)C.[OH-].[Na+]>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH3:19])=[CH:17][N:18]=[C:14]3[CH:13]([OH:20])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH:28]=1
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2O

Procedure:
A stirred suspension of 294 mg. of 8-chloro-4-hydroxy-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine acetate (1b) in 25 ml. of absolute ethanol under nitrogen is stirred for about 3 hours at room temperature (about 25° C.) with 2.2 ml. of 0.5N aqueous sodium hydroxide, poured into water and extracted with methylene chloride. The extract was dried and concentrated and the residue chromatographed on silica gel, eluting with ethyl acetate to yield 8-chloro-4-hydroxy-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:19])[CH3:18].[NH4+].[Cl-]>C(O)CCC>[CH:17]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCNCC1
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCO
Product: CC(C)N1CCN(c2ccc(-c3ccc(C#N)cc3)nn2)CC1
Yield: 70.1 %

Procedure:
To a solution of 4-(6-chloro-pyridazin-3-yl)-benzonitrile (20 g, 92.8 mmol) in 1-butanol (150 mL) was added 1-isopropyl-piperazine hydrochloride (29.8 g, 148.5 mmol) and NH4Cl (4.96 g, 92.8 mmol). The reaction mixture was heated at reflux for 48 h and then concentrated under reduced pressure. The residue was dissolved into a 10% solution of citric acid in water and filtered. Solid K2CO3 was added to the filtrate until pH 9. The precipitate was isolated and washed with water to give 4-[6-(4-isopropyl-piperazin-1-yl)-pyridazin-3-yl]-benzonitrile (20 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:41][C:42]1[CH:47]=[C:46](I)[CH:45]=[CH:44][N:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:41][C:42]1[CH:47]=[C:46]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)[CH:45]=[CH:44][N:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Clc1cc(I)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
Bis-(4-methoxybenzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (1.65 g, 3.05 mmol) was suspended in dimethylformamide (20 ml), followed by addition of 2-chloro-4-iodopyridine (805 mg, 3.36 mmol), palladium acetate (35 mg, 0.156 mmol), triphenyl phosphine (81 mg, 0.309 mmol) and potassium phosphate (1.95 g, 14.1 mmol), and argon gas was blown for 10 minutes while irradiating ultrasonic wave. The reaction mixture was stirred at 100° C. for 1 hour, and cooled to room temperature, followed by addition of water (50 ml). The mixture was extracted with ethyl acetate (100 ml) and dichloromethane (100 ml), and the combined organic layers were washed with brine, followed by drying over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1), followed by suspension of the residue in ethyl acetate/hexane (10 ml/50 ml). The precipitate was filtered, and washed with hexane, followed by drying under reduced pressure, to obtain {5-[7-(2-chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine as a yellow powder (1.75 g, 88%).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.CN(C)C=O>[Cu]I.O.C(OCC)(=O)C>[C:14]1([N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=[C:2]([C:28]#[C:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3]2=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#Cc1ccccc1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(C#Cc2ccccc2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 50 °C
Yield: 6.6 %

Procedure:
100 mg of 3-bromo-1-phenyl-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one, 55 mg of phenylacetylene, 1 mg of copper (I) iodide and 4 mg of dichlorobis(triphenylphosphine) palladium were added to a mixed solvent of 1.5 ml of triethylamine and 1 ml of dimethylformamide, and stirred at 50° C. in a nitrogen atmosphere for a night. The reaction mixture was distributed into the ethyl acetate and water layers. The organic layer was washed with water, dried and concentrated, and the residue was refined by silica gel chromatography (ethyl acetate/hexane-based solvent), to obtain 7 mg of the subject compound.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:29][CH:28]2[CH2:30][CH:24]3[CH2:25][CH:26]([CH2:31][CH:22]1[CH2:23]3)[CH2:27]2.Cl>O.C1(C)C=CC=CC=1>[CH:24]12[CH2:30][CH:28]3[CH2:27][CH:26]([CH2:31][CH:22]([N:21]([CH2:20][CH2:19][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:8]#[N:9])[CH2:29]3)[CH2:23]1)[CH2:25]2
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: ClCCN1CC2CC3CC(C2)CC1C3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(CCN1CC2CC3CC(C2)CC1C3)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 18 parts of α-phenylbenzeneacetonitrile in 140 parts of dry toluene is added, with stirring under nitrogen, approximately 4 parts of a 57% dispersion of sodium hydride in oil. The resultant mixture is heated to 90° and stirred thereat under nitrogen for 3/4 hr. The yellow-green flocculent suspension which eventuates is cooled to around 65°, whereupon 20 parts of 4-(2-chloroethyl)-4-azatricyclo[4.3.1.13,8 ]undecane [preparable by mixing the hydrochloride thereof (U.S. Pat. No. 3,845,038) with excess aqueous sodium carbonate, extracting the mixture with toluene, and consecutively washing the extract with water, drying it over anhydrous sodium sulfate, filtering out the drying agent, and removing the solvent by vacuum distillation] in 85 parts of dry toluene is introduced, with stirring, during 15 minutes. The mixture thus obtained is stirred for 2 hours at 90°-100°. The yellow-orange solution which results is cooled to room temperature, at which point 20 parts of water is stirred in. Aqueous and organic phases are separated, the aqueous phase is extracted with toluene and then discarded, and the extract and organic phases are combined and thereupon consecutively washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is stripped of solvent by vacuum distillation, affording 4-[4-azatricyclo(4.3,1.13,8)undecan-4-yl]-2,2-diphenylbutanenitrile as the residue. The product has the formula ##STR9##
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>C(O)(C)C>[ClH:2].[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:10][CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:26]([F:31])[CH:25]=1
Reactant: Clc1ncnc2cc(OCCCN3CCOCC3)ccc12
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: Fc1cc(Cl)ccc1Nc1ncnc2cc(OCCCN3CCOCC3)ccc12
Yield: 11.2 %

Procedure:
A mixture of 4-chloro-7-(3-morpholinopropoxy)quinazoline hydrochloride (238 mg, 0.69 mmol) and 4-chloro-2-fluoroaniline (145 mg, 1 mmol) in isopropanol (5 ml) was heated at reflux for 1 hour. The solvent was removed by evaporation and the residue partitioned between water and ethyl acetate and the aqueous layer adjusted to pH8 with sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/acetonitrile/methanol (60/30/10 followed by 60/20/20). The resulting semi-purified solid was repurified by chromatography on neutral alumina eluting with methylene chloridelmetlhanol (95/5). The resulting white solid was dissolved in methylene chloride and 4 M ethereal hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation, and the residue triturated by the addition of methylene chloride followed by methanol and ether. The precipitated solid was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(3-morpholinopropoxy)quinazoline hydrochloride (35 mg, 10%).