Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.CCOC(C)=O>C1COCC1>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C:6]2[C:7]([CH3:9])=[N:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=2)=[O:11])=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
6-(trifluoromethyl)-2-methylpyridine-3-carbonyl chloride (1.68 g, 7.51 mmol) in 3 mL THF was added dropwise to a solution of 4-chloro-3-(pyridine-2-yl)aniline (1.21 g, 5.93 mmol) in THF (15 mL) at 0° C. The solution was stirred for 10 min., poured into EtOAc and washed with saturated aq. NaHCO3 (2×), and brine. The organics were dried (Na2SO4) and concentrated. The crude product was suspended in iPrOAc/Et2O (10 mL, 1:1), stirred at 0° C. for ½ hr, and collected by suction filtration to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide (2.04 g, 5.21 mmol, 88% yield) as a white solid: TLC Rf=0.28 (35% EtOAc/Hex); 1H NMR (CDCl3, 400 MHz) δ 8.88 (bs, 1H), 8.41 (d, 1H), 7.96 (dd, 1H), 7.74 (m, 4H), 7.52 (d, 1H), 7.22 (m, 1H), 2.75 (s, 3H); MS (Q1) 392 (M)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl[CH2:35][CH2:36][CH2:37][S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39]>>[CH3:42][N:41]([CH3:43])[S:38]([CH2:37][CH2:36][CH2:35][O:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)(=[O:40])=[O:39]
Reactant: CN(C)S(=O)(=O)CCCCl
Reactant: O=C(NC1=Nc2c(ccc(OCCCN3CCOCC3)c2O)C2=NCCN12)c1cccnc1
Product: CN(C)S(=O)(=O)CCCOc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-[7-hydroxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Intermediate H) and 3-chloro-N,N-dimethylpropane-1-sulfonamide (Intermediate F). High vacuum drying gave the title compound (15 mg, 15%): HPLC MS RT=0.24 min, MH+=600.4; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 1.07 (6H, t), 2.18-2.27 (4H, m), 3.04-3.13 (2H, m), 3.27-3.36 (4H, q), 3.51 (2H, d), 3.66 (2H, t), 3.98-4.02 (2H, m), 4.21-4.36 (6H, m), 4.56-4.59 (2H, m), 7.49 (1H, d), 8.02 (1H, dd), 8.08 (1H, d), 8.96 (1H, d), 9.04 (1H, dd), 9.50 (1H, d).
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O>C(O)(=O)C>[CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1
Reactant: CN(Cc1ccccc1)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(C(=O)N(C)Cc3ccccc3)cc2S(N)(=O)=O)CC1
Reaction time: 48 h

Procedure:
33.8 Grams of 4-chloro-3-sulfamoylbenzoic acid-N-methylbenzylamide (0.1 mole) were heated with 80 ml of N-methylpiperazine for 4 hours under reflux. Subsequently the solution was introduced into 0.4 l of water, the pH value of the mixture was adjusted to 9.0 by means of glacial acetic acid, and the mixture was then allowed to stand for 2 days at room temperature. The crystalline precipitate was separated and was recrystallized from a mixture of ethanol and water.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8](C#N)[C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:4]([CH3:20])[C:3]=1[CH3:21].Cl.O>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:4]([CH3:20])[C:3]=1[CH3:21]
Reactant: Cc1c(Cl)nnc(C(C#N)c2ccc(F)c(C#N)c2)c1C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cl)nnc(Cc2ccc(F)c(C#N)c2)c1C
Temperature: 25 °C

Procedure:
Intermediate B1 was suspended in a mixture of acetic acid, conc. aq. HCl and water (1:1:2, 0.07M). The suspension was stirred and heated at reflux for 75 min. The reaction mixture was cooled to RT and the solvents were removed under reduced pressure. To the residue was added saturated aq. NaHCO3 and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel, eluting with PE-EtOAc (10-80% EtOAc) to afford the title compound as a yellow solid. MS (ES) C14H11ClFN3 required: 275, found: 276 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N:21]([CH3:23])[CH3:22])=[CH:13][CH:12]=1)=[O:10].Cl.[NH2:26][OH:27].C[O-].[Na+]>CO>[CH3:22][N:21]([CH3:23])[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([NH:26][OH:27])=[O:2])=[O:10])=[CH:12][CH:13]=1
Reactant: COC(=O)CCCCNC(=O)c1ccc(N(C)C)c2ccccc12
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)c1ccc(C(=O)NCCCCC(=O)NO)c2ccccc12
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
(Method J9B) To the solution of 5-[[[4-(dimethylamino)-1-naphthalenyl]carbonyl]amino]-pentanoic acid methyl ester (3/62) (0.31 g, 0.94 mmol) and hydroxylamine hydrochloride (0.26 g, 3.8 mmol) in absolute methanol was added NaOMe solution made by dissolving Na (0.18 g, 8 mmol) in absolute methanol. A white precipitate immediately appeared. After 0.5 h the reaction was complete (TLC), and the reaction mixture was evaporated, suspended in 1M phosphate buffer (pH 4), and extracted with 3 portions of methylene chloride. The organic phase became turbid, therefore the solvent was removed, and the residue was dried under reduced pressure yielding the crude product (0.27 g). Recrystallisation from acetonitrile gave the title product (0.06 g, 19%) of acceptable purity. Rf 0.50 (CHCl3-MeOH 4:1). M.p. 129° C. 1H NMR (DMSO-d6, TMS) δ: 1.53-1.57 (4H, m), 1.97-2.01 (2H, m), 2.84 (6H, s), 3.32-3.33 (m, overlapped with a signal from DMSO), 7.08 (1H, d, J=8.2 Hz), 7.46-7.56 (3H, m), 8.14-8.24 (2H, m), 8.39 (1H, br t, J=5.2 Hz), 8.69 (1H, br s), 10.37 (1H, br s). HPLC analysis on Symmetry 18 column: impurities <1% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 10:90; detector UV 220 nm; flow rate 1.3 ml/min). Anal. Calcd for C18H23N3O3: C, 65.63; H, 7.04; N, 12.76. Found: C, 65.50; H, 6.90; N, 12.73.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:39]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40]>CN(C=O)C.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:48][C:39]([CH3:41])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:40])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(NC(=O)c1cccc(Oc2ccccc2)c1)c1ccccc1
Reaction time: 0.08 h
Yield: 97.2 %

Procedure:
3-Phenoxybenzoic acid (3.00 g, 14.0 mmol) was dissolved in DMF (45 mL), and the solution was added with EDCI (4.03 g, 21.0 mmol) and HOBT monohydrate (1.07 g, 7.00 mmol) under ice-cooling, followed by stirring at the same temperature for 5 minutes. Then, the mixture was added with cumylamine (4.03 mL, 28.0 mmol) and stirred at room temperature for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by slurry using hexane to obtain 3-phenoxy-N-(1-methyl-1-phenylethyl)benzamide (4.51 g, yield 97%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:4][N:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl>[C:38]([O:1][CH:2]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:4][N:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=1)=[O:19])(=[O:40])[CH3:39]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1N=C(c2cccc(C(F)(F)F)c2)OCC1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 21.0 g 5,6-dihydro-5-hydroxy-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide (prepared in C above), 13.0 ml triethylamine, and 6.5 ml acetic anhydride was stirred at room temperature for 3 h. The mixture was then concentrated under vacuum to produce a solid residue. The solid residue was taken up in 400 ml dichloromethane and washed twice with 100 ml saturated sodium bicarbonate. The organic phase was then dried over sodium sulfate and concentrated under vacuum to produce 5,6-dihydro-5-acetyloxy-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][C:19]([OH:21])=[O:20])=[CH:5]2.[H][H]>CO.[Ni]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]([CH2:18][C:19]([OH:21])=[O:20])[CH2:5]2
Reactant: [H][H]
Reactant: Cc1ccc2nc(-c3ccccc3)c(CC(=O)O)cc2c1
Agent: [Ni]
Solvent: CO
Product: Cc1ccc2c(c1)CC(CC(=O)O)C(c1ccccc1)N2

Procedure:
1.00 g (3.61 mmol) of 13 was taken up in 80 ml of methanol, 1 g of Raney Ni (water-wet) was added, and the mixture was hydrogenated overnight at 50° C. at a hydrogen pressure of 5 bar. The catalyst was filtered off, the filtrate was evaporated to dryness, and the residue was purified by column chromatography (ethyl acetate/cyclohexane), giving a yellowish solid, which was identified as the racemic cis-compound 14.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.CS(C)=O.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15][CH2:14]1>C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:20][CH2:19][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: NCC1CCOCC1
Reactant: Clc1cncc(Cl)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1cncc(NCC2CCOCC2)n1
Temperature: 75 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
A mixture of 2,6-dichloropyrazine (950 mg, 6.38 mmol), DMSO (14 ml), TEA (1.067 ml, 7.65 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (771 mg, 6.70 mmol) was stirred at 75° C. for 6 hours, and the reaction progress was followed by LCMS. The crude reaction mixture was cooled to ambient temperature, diluted with 300 ml of ethyl acetate, washed with 1M NaOH soln.(1×), water (1×), saturated salt soln. (1×), dried with sodium sulfate, filtered, and concentrated to constant mass, giving 1185 mg of titled compound as free base, used without further purification. LCMS (m/z): 228.0 (MH+), retention time=0.73 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][Cl:26])=[O:23]>C(OCC)C>[C:22](=[O:23])([O:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[O:24][CH2:25][Cl:26]
Reactant: O=C(Cl)OCCl
Reactant: O=C(CCCO)OCc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CCCOC(=O)OCCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of benzyl 4-hydroxybutanoate (synthesized by the procedure described in Weber et al., J. Med. Chem, 1991, 34, 2692-2701, 5.0 g) in diethyl ether (100 ml), pyridine (2.3 ml) was added under a nitrogen atmosphere, and chloromethyl chloroformate (3.7 g) was added dropwise at −10 ° C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered with glass filter and then the filtrate was washed with water and a saturated sodium chloride aqueous solution successively. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure, and thus the residue was subjected to silica gel column chromatography and eluted with acetone/hexane (1:1 v/v) to obtain chloromethyl (3-benzyloxycarbonylpropyl) carbonate (7.25 g) as a colorless oily product.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH3:20][CH:19]([NH:22][CH2:15][CH:14]([OH:16])[CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:18][CH:17]=1)[CH3:21]
Reactant: CC(C)N
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: CC(C)NCC(O)COc1ccc(CCOCC2CC2)cc1

Procedure:
reacting 1-{4-[2-(Cyclopropylmethoxy)ethyl]phenoxy}-2,3-epoxypropane with isopropylamine to produce Betaxolol; and
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[S:15][CH2:16][CH:17]([CH3:19])[CH3:18])=O.COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[S:15][CH2:16][CH:17]([CH3:19])[CH3:18])/[C:36](=[O:37])[N:38]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CC(C)CSc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CSc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-isobutylsulfanyl-quinoline-3-carbonitrile (example 65b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isobutylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 369 (MH+).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.C=O.CC1(C)O[C:18](=O)[CH2:17][C:16](=[O:21])[O:15]1.O>C(#N)C>[N:1]1[CH:2]=[C:3]([CH2:18][CH2:17][C:16]([OH:21])=[O:15])[N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: c1cn2c(n1)CCCCC2
Agent: C=O
Solvent: CC#N
Solvent: O
Product: O=C(O)CCc1cnc2n1CCCCC2

Procedure:
To a solution of 6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine in acetonitrile are added aqueous formaldehyde solution and 2,2-dimethyl-1,3-dioxane-4,6-dione with stirring and the mixture is heated for 4 hours. After the completion of the reaction, the reaction mixture is poured into water and the mixture is extracted with chloroform, washed with water, and dried over magnesium sulfate. The solution is concentrated under reduced pressure and the resulting 2,2-dimethyl-5-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-ylmethyl)-1,3-dioxane-4,6-dione is dissolved in pyridine with sting. Water and copper powder are added and the mixture is refluxed under heating for 3 hours. After the completion of the reaction, the reaction mixture is filtered while it is hot and the solvent is evaporated under reduced pressure to give 3-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)propionic acid. To a solution of this compound in dimethylformamide are added 4-(4-chlorophenyl)piperidine, triethylamine and cyanophosphonic acid diester and the mixture is stirred at room temperature. After the completion of the reaction, the reaction mixture is poured into water and the mixture is extracted with chloroform, washed with water, and dried over magnesium sulfate. The solution is concentrated under reduced pressure and the resulting 1-(4-(4-chlorophenyl)piperidin-1-yl)-3-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)propan-1-one is dissolved in tetrahydrofuran and lithium aluminum hydride is added under ice-cooling with stirring and the mixture is stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture is poured into water and the mixture is extracted with chloroform, washed with water, and dried over magnesium sulfate. The solution is concentrated under reduced pressure and the obtained residue is subjected to silica gel column chromatography to give 3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])[O:14][CH3:15])=[CH:20][CH:19]=1)#[N:16]
Reactant: COc1ccc(F)c(C(OC)C(=O)O)c1
Reactant: N#Cc1ccc(CN)cc1
Product: COc1ccc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1

Procedure:
(RS)-(2-Fluoro-5-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-5-methoxy-phenyl)-2-methoxy-acetamide. Colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl[C:13]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:14].Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCC(=O)Cl
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CCCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Chlorobenzene (8.13 ml, 79.9 mmol) was dissolved in 100 ml of 1,2-dichloroethane, and 21.3 g (160 mmol) of aluminum trichloride and 12.15 ml (87.9 mmol) of methyl 4-(chloroformyl)butyrate were added thereto, followed by stirring the mixture at room temperature overnight. The reaction solution was poured into hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica-gel column chromatography (eluent: a mixture of 4% ethyl acetate and hexane) to obtain 15.8 g of the above-mentioned compound (yield 82%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: BrCC1CCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC5CCCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 61.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and bromomethyl cyclohexane (122 mg, 0.690 mmol) gave 2-[5-(4-cyclohexylmethyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (75 mg, 63%). MS (ESI) m/z 531.4 (M+H)+
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]([OH:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC1C=CC=CC=1C>[C:8]([OH:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:1]([OH:6])(=[O:7])[CH2:2][CH2:3][C:4]([OH:15])=[O:5]
Reactant: O=C1CCC(=O)O1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(O)CCC(=O)O
Temperature: 165 °C
Reaction time: 6 h

Procedure:
A 1 liter reaction flask was provided with a mechanical agitator, a thermometer and a Dean Stark arrangement. 261.06 g (1.960 mol, 2.8 equivalents) of di-isopropanolamine (type S, BASF); 69.69 g (0.696 mol, 1 equivalent) of succinic acid anhydride (Aldrich); and 540.88 g (4.429 mol, 6.4 equivalents) benzoic acid (Aldrich) were placed in the flask. A small quantity of o-xylene, about 60 ml, was added as entraining agent to remove the liberated water. The reaction mixture was kept under a nitrogen atmosphere and heated for 1 hour at 165° C., where after the reaction temperature was raised to 180° C. After 6 hours the temperature was reduced to 160° C. and the flask was evacuated to remove the o-xylene. It was possible to draw off the reaction mixture after about 1 hour. Analysis showed that the number-averaged molecular weight (Mn) was 583 and the weight-averaged molecular weight (Mw) was 733. The ratio between Mw and Mn (1.26) showed that there was a mixture of compounds formed. The reaction scheme as shown in FIG. 4 indicates what compounds may form during the reaction between di-isopropanolamine, benzoic acid and succinic acid (it should be noted that the reaction product as shown in the reaction scheme of FIG. 4 is the most probable structure of the resulting compounds). The reaction shows the formation of a mono-disperse compound. The ratio in respect of reactants as indicated in the formula belongs to a chosen value for n. This ratio need not necessarily be identical to the ratio for the overall reaction, where in fact a mixture of compounds with different values for n is formed. In the reaction according to this experiment, a ratio has been chosen which is equal to 2.82:6.36:1 (di-isopropanolamine:benzoic acid:succinic acid anhydride). This means that there are 3×2.82=8.46 mol equivalents of reactive NH/OH groups in the amine, as against 6.36+2×1.00=8.36 mol equivalents of acid groups in the benzoic acid and anhydride. There is therefore only a very small excess (about 1%) of di-isopropanolamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[N:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[CH2:15]([CH2:17][NH2:18])[OH:16].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:18][CH2:17][CH2:15][OH:16])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cnc2cccnc2c1NCCO
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A solution of 3-nitro[1,5]naphthyridin-4-ol (9.14 g, 43.7 mmol) dissolved in 300 mL of CH2Cl2 was treated with ethanolamine (7.9 mL, 130 mmol) and the mixture was stirred under N2. After 3 hours, the reaction mixture was concentrated to give a yellow solid. The yellow solid was treated with 200 mL of H2O and the suspension was heated to reflux, with stirring, for 10 minutes. The mixture was cooled in an ice bath. The resulting yellow solid was isolated by filtration, washed with cold H2O and dried with suction to give 2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (10.02 g) as fine yellow crystals.