Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-(bromomethyl)-2-(trifluoromethyl)benzene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (87%) as a colorless solid: mp 137-138° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.6 Hz, 1H), 7.52-7.33 (m, 2H), 7.22-7.13 (m, 3H), 7.07-7.00 (m, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.08 (d, J=17.1 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.23-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 127.9 (q, 2JC-F=30.8 Hz), 127.6, 126.8, 126.4 (q, 5JC-F=5.8 Hz), 124.4 (q, 1JC-F=273.8 Hz), 124.1, 123.8, 120.8, 111.6, 109.2, 99.6, 80.3, 64.5, 64.0, 58.2, 40.6 (q, J=3.4 Hz); MS (ES+) m/z 454.0 (M+1). Anal. Calcd. for C26H18F3NO4: C, 66.22; H, 4.00; N, 3.09. Found: C, 66.16; H, 4.11; N, 3.07.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[C:12]([O:16][CH2:17][O:18][CH3:19])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)#[CH:21]>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:21]#[C:20][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:12]([O:16][CH2:17][O:18][CH3:19])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: COCOc1cnc(OCc2ccccc2)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: COCOc1cnc(OCc2ccccc2)cc1C#Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine (3.0 g, 8.08 mmol), copper (I) iodide (92 mg, 0.485 mmol), PdCl2(PPh3)2 (284 mg, 0.404 mmol), 1-ethynyl-4-fluorobenzene (1.07 g, 8.89 mmol) were combined in dioxane (40 mL) and TEA (40 mL), degassed and stirred at 80° C. for 1.5 hrs. The mixture was diluted with EtOAc and washed with sat NaCl and H2O. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(benzyloxy)-4-((4-fluorophenyl)ethynyl)-5-(methoxymethoxy)pyridine (2.52 g, 6.93 mmol, 86% yield) consistent by LCMS. LC-MS retention time: 2.71 min; m/z (MH+): 364. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:42]([C:41]5[CH:45]=[CH:46][C:38]([C:37]([O:36][CH3:35])=[O:47])=[CH:39][CH:40]=5)=[O:43])[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (50.5 mg, 0.1 mmol) in dichloromethane (5 mL) was added terephthalic acid monomethyl ester (18 mg, 0.1 mmol) and triethyl amine (30 μL, 0.2 mmol). The resulting mixture was then cooled down on an ice-water bath before the addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbo-diimide hydrochloride (19 mg, 0.1 mmol) and 4-dimethylaminopyridine (catalytic amount). After being stirred overnight at ambient temperature, the reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate as amorphous solid (65 mg, quant.). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=8.2 Hz, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.41 (d, J=7.3 Hz, 2H), 7.34-7.24 (m, 4H), 7.21-7.15 (m, 2H), 4.66 (br, 1H), 4.26-4.21 (m, 1H), 3.97 (s, 3H), 3.52-3.30 (m, 5H), 2.60 (s, 3H), 2.40 (br, 3H), 2.21-2.17 (br, 1H), 1.99-1.79 (m, 10H), 1.68-1.66 (m, 2H). HRMS m/z (M+H)+ calcd: 591.3335, obsd: 591.3320.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: COCCNc1nc2ccc(OC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCCOC)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (312 mg, 1.3 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added 3-(chloromethyl)-6-methoxy-N-(2-methoxyethyl)quinolin-2-amine hydrochloride SLA 47064B (400 mg, 1.3 mmol) and a 2 N aq. LiOH solution (1.26 mL, 2.52 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to room temperature, THF was removed at 40° C. under vacuum and the residue was then taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH3CN:H2O:TFA=100:0:0.05 to 50:50:0.05) gave 6,7-dimethoxy-4-((6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at room temperature and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 76 as a brown solid (39.5 mg, 5% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1.S(OC)(O[CH3:30])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH3:30])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1
Reactant: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and dimethyl sulphate with sodium carbonate in acetone there is obtained 1-(4-chloro-2-fluoro-5-methoxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone. m.p. 123°-125° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:39][CH:36]3[CH2:38][CH2:37]3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: BrCC1CC1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Product: COc1ccc(CC2c3cc(OCC4CC4)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with cyclopropylmethyl bromide
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[OH:23][C:24]1([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[OH:23][C:24]1([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:29]1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4n[nH]c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH2:14])[CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:5]2.Cl[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:14][CH2:13][CH2:12][N:7]1[CH:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH2:8]1
Reactant: Clc1ccccn1
Reactant: NCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(CC2Cc3cc(F)ccc3CN2CCNc2ccccn2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
40 mg of 2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 180-b), 17 mg of 2-chloropyridine, and 36 mg of potassium carbonate were dissolved in 0.4 mL of DMF, followed by stirring at 120° C. overnight. After completion of the reaction, the reaction liquid was left to be cooled, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:ammonia saturated methanol=10:1) to obtain 6 mg (yield 13%) of a title compound as a light yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(F)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(F)cc2)n1

Procedure:
218 mg (87.5%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-fluorophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (155.9 mg, 0.568 mmol), 1-(2-fluorophenyl)piperazine (106 mL, 0.852 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)Cl>[Br:18][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[Cl:1])[NH:8][N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ncc12
Solvent: ClC(Cl)Cl
Product: Clc1ncnc2[nH]nc(Br)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a suspension of 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (1.1 g, 7.1 mmol) in CHCl3 (50 mL) was added NBS (1.49 g, 8.4 mmol) The mixture was stirred at room temperature for 5 hours, cooled to 0 C and the solids were isolated by vacuum filtration, rinsed with cold CHCl3, and air dried. The solid was purified by column chromatography on silica (50% EtOAc/hexanes) to give 3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.3, 77%.)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH:23][C:8](=[O:10])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CN1CCN(CCCN)CC1
Product: CN1CCN(CCCNC(=O)CN2CCCC2=O)CC1

Procedure:
From 8.5 g. of ethyl 2-oxo-1-pyrrolidineacetate and 10.2 g. of 3-(4-methyl-1-piperazinyl)propylamine [J.A.C.S. 82, 2386 (1960)], following the procedure of Example 9, there is obtained N-[3-(4-methyl-1-piperazinyl)propyl]-2-oxo-1-pyrrolidineacetamide; m.p. 93° C. after recrystallization from cyclohexane.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[N:20]=[C:19]1[NH2:33]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[N:20]=[C:19]1[NH2:33])=[NH:5]
Reactant: Nc1nc(-c2ccc3ccccc3c2)cn1N
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: Cl
Solvent: CC(C)O
Product: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc3ccccc3c2)nc1N
Temperature: 120 °C
Reaction time: 24 h

Procedure:
7 ml of concentrated hydrochloric acid are added, with stirring, to a mixture of 2.01 g (9.8 mmol) of 4-(N-hydroxyarnidino)-2,3-dihydro-1H-inden-1-one oxime, 2.2 g (9.8 mmol) of 1,2-diamino-4-(2-naphthyl)-imidazole (see J. Heterocycl. Chem. 11, 327-329 (1974)) and 25 ml of isopropanol, and the mixture is stirred at 120° C. for 24 hours. The mixture is cooled to 20° C., filtered and washed with isopropanol, and the filtration product is taken up in 60 ml of methylene chloride. The suspension is stirred at room temperature for 15 hours and is then filtered, and the crystallizate is washed with methylene chloride. In that manner there is obtained the title compound, m.p. 265°-270° C., 1H-NMR (DMSO/D2O): δ=8.32 (s, 1H); 8.29 (d, 1H); 8.19 (s, 1H); 8.04 (d, 1H); 7.88-7.98 (m, 3H); 7.81 (d, 1H); 7.53-7.68 (m, 3H); 3.38 (s, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:32]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:33]C([O-])=O.Cl>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH2:33][C:32]([O:38][CH2:39][CH3:40])=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of 2.65 g (10 mmoles) of 6-benzyloxycarbonylaminohexanoic acid and 1.62 g (10 mmoles) of commercial 1,1'-carbonyldiimidazole in 25 ml of anhydrous tetrahydrofuran was stirred for 15 minutes at room temperature. To the reaction mixture was added a suspension of 6.18 g (40 mmoles) of a white powder of magnesium enolate of monoethyl malonate (prepared from 5.28 g of monoethyl malonate and 972 mg of magnesium) in 50 ml of anhydrous tetrahydrofuran. The mixture was stirred for 2 hours at room temperature. After addition of 50 ml of 1N hydrochloric acid and stirring for 10 minutes, the reaction mixture was extracted 3 times with 50 ml of chloroform. The chloroform layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline, then dried over anhydrous sodium sulfate and freed from the solvent by distillation. The residue was passed through a column of 100 g "Silica Gel 60" (Merck & Co.) and eluted with chloroform (20 g fraction size). Fractions No. 43 to No. 105 were combined and evaporated to dryness to yield 2.35 g (70% yield) of ethyl 8-benzyloxycarbonylamino-3-ketooctanoate.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27]([N:42]3[CH2:41][CH2:40][CH:39]([C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)[CH2:44][CH2:43]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(F)ccc1F
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 35.9 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2,5-difluorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1.38 g, 3.04 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.70 g, 3.88 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.64 g, 43%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:26][C@H:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH3:25])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 47.3 %

Procedure:
2.4 g of 2,4,6-trichloropyrimidine was dissolved in 24 ml of tetrahydrofuran, and 2.0 ml of triethylamine was added at room temperature, and a solution of 2.0 g of (S)-(−)-1-(4-fluorophenyl)ethylamine in 12 mL of tetrahydrofuran was added dropwise, and then the mixture was stirred at room temperature for 9.5 hours. The reaction mixture was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 1.77 g of the objective compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CS(C)=O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 59.1 %

Procedure:
A mixture of 20 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 28.5 g of N-methylpiperazine and 120 ml of anhydrous dimethylsulphoxide is heated at 135°-140° C. for 2.5 hours. The solvent is distilled off under a fine vacuum and the residue is suspended in about 50 ml of water. The solid is filtered off with suction, rinsed with water, dried over calcium chloride in a vacuum drying cabinet at 80° C. and recrystallized from glycol monomethyl ether. 14.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 248°-250° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:13])=[O:12].Br[CH2:15][C:16]#[CH:17].C1COCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([CH2:17][C:16]#[CH:15])(=[O:13])=[O:12]
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Solvent: C1CCOC1
Solvent: O
Product: C#CCS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Yield: 73.2 %

Procedure:
110.7 g (0.5 mol) of 2-chloro-5-nitrobenzenesulfinic acid were dissolved in 500 ml of water at pH 6.5 and the solution was added to a solution of 65.5 g (0.55 mol) of 3-bromoprop-1-yne and 100 ml of THF. The reaction mixture was then heated to 40°-50° C. After the reaction had ended (check by TLC), the reaction product was extracted with 1.5 l of ethyl acetate, and the organic phase was neutralized and dried over sodium sulfate. The solvent was evaporated off to leave 95 g of 2-chloro-5-nitro-1-(prop-1-yn-3-ylsulfonyl)benzene (melting point 238°-241° C.). ##STR28##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][CH2:19][O:20][CH3:21])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][CH2:19][O:20][CH3:21])[CH:17]=2)=[N:31]\[OH:32])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COCCn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2C)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-(2-methoxy-ethyl)-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless amorphous solid, MS (ESI+): m/z=469.2 [M+H]+.