Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][NH:13][C:14]=3[CH3:16])[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH3:28])[C:14]=3[CH3:16])[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]nc2c1C(c1ccc(Cl)cc1)N(c1ccc(=O)n(C)c1)C2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2c(nn1C)C(=O)N(c1ccc(=O)n(C)c1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)-3-methyl-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (Example 2) (25 mg, 0.070 mmol) in DMF (1 mL) under Ar was added NaH (3.38 mg, 0.085 mmol). The reaction mixture was stirred at rt for 30 min and MeI (6.61 μL, 0.106 mmol) was added. After 1 hr at rt, the reaction mixture was quenched with a saturated aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4, and evaporated. The crude material was purified by preparative HPLC (Gilson gx-281; column: Sunfire C18, 30×100 mm, 5 μm; flow: 30 mL/min; gradient: 5% to 100% B in 20 min; A=0.1% TFA in H2O, B=CH3CN; detection: UV) to afford the title product (10 mg, 0.027 mmol, 38% yield). tR: 3.39 min (HPLC 1); tR: 0.74 min (LC-MS 2); ESI-MS: 369 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3H) 3.34 (s, 3H) 3.83 (s, 3H) 6.10 (s, 1H) 6.30 (d, J=9.8 Hz, 1H) 7.23 (d, J=8.6 Hz, 2H) 7.35 (d, J=8.6 Hz, 2H) 7.44 (dd, J=9.8, 2.7 Hz, 1H) 7.89 (d, J=2.7 Hz, 1H). In addition to the title compound, a second product was isolated during this purification process and is described in Example 4.
Reaction SMILES: [CH3:1]CCCCC.C[Si](C=[N+]=[N-])(C)C.[F:14][C:15]1[C:16]([C:21]([OH:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1>C(O)C.CN(C=O)C>[F:14][C:15]1[C:16]([C:21]([O:23][CH3:1])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ncccc1F
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)c1ncccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A hexane solution (3 mL) of 2 M trimethylsilyldiazomethane was added to a benzene/methanol mixed solvent (1/1, 12 mL) of 3-fluoropyridine-2-carboxylic acid (250 mg), and stirred at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure from the reaction solution, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=40/1) to obtain the entitled compound (238 mg).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C1OCCOCCOCCOCCOCCOC1.[F:30][C:31]([F:45])([F:44])[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O>COCCOCCOC>[F:30][C:31]([F:45])([F:44])[CH2:32][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
Potassium hydroxide pellets (85%, 13.2 g, 0.2 mol) are added to 4-hydroxybenzaldehyde (24.4 g, 0.2 mol) and 18-crown-6 (2.6 g, 5% mol) in diglyme (150 mL). The red reaction mixture is stirred for 16 hours at room temperature and then a solution of 2,2,2-trifluoroethyl-p-toluenesulfonate (50.8 g, 0.2 mol) in diglyme (100 mL) is added over 30 minutes, after which the mixture is allowed to stir at room temperature for 45 minutes. The resulting suspension is then heated at reflux for 24 hours. The mixture is cooled to 10° C. and poured into ice water (1300 mL). The organic materials are extracted with ether (4×200 mL), and the extracts washed with 5% sodium hydroxide (2×100 mL), water (2×100 mL) and saturated sodium chloride (1×100 mL), and dried over MgSO4. Evaporation of the ether gives an amber oil which is purified by high performance liquid chromatography using silica gel on a Waters 500 unit and 50:50 hexane and methylene chloride as eluant to give 12.3 g of the title product with Rf 0.25. Anal. Calcd for C9H7F3O2 (204.15) C, 52.94; H, 3.43. Found C, 52.04; H, 3.59.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1>CN(C)C=O>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:4]([C:3]2[C:2](=[S:1])[NH:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=C(O)c1cccnc1S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-Mercaptonicotinic acid (90 g, 0.58 mol) was suspended in N,N-dimethylformamide (660 mL) under ice-cooling, then carbonyldiimidazole (110 g, 0.70 mol) was added thereto, and the whole was stirred for 2 hours at room temperature. Water (5.4 mL) was added thereto, and the whole was stirred for 40 minutes, and then 3,5-xylidine (76 mL, 0.61 mol) was added thereto and the resulting mixture was stirred at 60° C. for 16 hours. The mixture was allowed to stand, and then water (1.3 L) was added, and the precipitated solid was filtered off. The solid was dried at 45° C. under reduced pressure to give 130 g of the title Reference Compound as a yellow solid (Yield: 89%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].C(S[CH:10]([C:36]1[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:37]=1)[C:11]1[CH2:16][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13][CH:12]=1)(=O)C>CS(C)=O.C(OCC)(=O)C>[C:1]([S:3][CH:12]1[CH2:13][CH2:14][N:15]([C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][C:11]1=[CH:10][C:36]1[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:37]=1)(=[O:4])[CH3:2]
Reactant: CCOC(=O)CCn1ccc(C(SC(C)=O)C2=CCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1ccc(C=C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
Potassium thioacetate (5.91 g) was added to a solution of 5-((acetylsulfanyl){1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methyl)-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (3.00 g), in dimethyl sulfoxide (30 ml). The mixture was stirred at 80° C. for 4 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, and washed successively with water and a saturated aqueous sodium chloride solution. After the extract was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using ethyl acetate and hexane (1:9 to 2:3) as eluents to afford a crude product of 4-(acetylsulfanyl)-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidine (2.93 g) as a mixture of geometric isomers.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:19]3)[NH:9][C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1>O=P(Cl)(Cl)Cl>[Cl:1][CH:2]1[NH:7][CH:6]=[CH:5][N:4]2[C:10]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:9][C:8]([C:16]3[CH:17]=[C:18]4[C:23]([N:22]=[CH:21][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[N:19]4)=[CH:24][CH:25]=3)=[C:3]12
Reactant: O=C(NC(c1ccc2ncc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1NC=Cn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c21
Temperature: 25 °C

Procedure:
N-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-cyclobutanecarboxamide (56 mg, 0.13 mmol) was heated in POCl3 (5 mL) under Ar at 70° C. for 26 h. Later the reaction was cooled to rt, evaporated under reduced pressure and then high vacuum. A solution of NH3 in i-PrOH (2 M, 10 mL was added to the crude material cooled in an ice-H2O bath under Ar. The mixture was stirred, sonicated and filtered. The solids and the reaction flask were washed with i-PrOH multiple times. The filtrate was concentrated under reduced pressure. The light yellow residue was partitioned between DCM (60 mL) and H2O (20 mL). The aq. layer was extracted with DCM (2×). Combined organic phase was washed with brine and dried (Na2SO4) to afford the title compound as a light yellow solid; NMR (400 MHz, CD3CN) δ 9.40 (s, 1H), 8.36 (s, 1H), 8.32-8.25 (m, 2H), 8.13-8.11 (m, 2H), 7.77 (d, J=4.8 Hz, 1H), 7.63-7.51 (m, 3H), 7.32 (d, J=4.8 Hz, 1H), 3.97 (qund, J=1.2 Hz, 8.4 Hz, 1H), 2.60-2.45 (m, 4H), 2.05-1.95 (m, 2H). MS (ES+): m/z 412.0 (40) [MH+]; HPLC: tR=4.10 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]1([P:7]([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:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=[O:23]>O1CCCC1>[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5 (94 mg, 0.58 mmol), 31 (120 mg, 0.49 mmol), and triphenylphosphine (321 mg, 1.23 mmol) in tetrahydrofuran (10 mL) at 65° C. under nitrogen was added diisopropyl azodicarboxylate (247 mg, 1.23 mmol). The mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give crude 32 (230 mg, contained Ph3PO).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[C:10]2[NH:14][C:13]([C:15]([C:49]3[C:54]([OH:55])=[CH:53][CH:52]=[CH:51][C:50]=3[OH:56])=[C:16]3[N:48]=[C:19]([C:20]([C:40]4[C:45]([OH:46])=[CH:44][CH:43]=[CH:42][C:41]=4[OH:47])=[C:21]4[NH:39][C:24](=[C:25]([C:31]5[C:36]([OH:37])=[CH:35][CH:34]=[CH:33][C:32]=5[OH:38])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2.[C:57]([OH:63])(=O)[C:58]([CH3:61])([CH3:60])[CH3:59]>O1CCCC1.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:57]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])[C:3]=1[C:9]1[C:10]2[NH:14][C:13]([C:15]([C:49]3[C:50]([O:56][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[CH:51][CH:52]=[CH:53][C:54]=3[O:55][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[C:16]3[N:48]=[C:19]([C:20]([C:40]4[C:45]([O:46][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[CH:44][CH:43]=[CH:42][C:41]=4[O:47][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[C:21]4[NH:39][C:24](=[C:25]([C:31]5[C:32]([O:38][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])=[CH:33][CH:34]=[CH:35][C:36]=5[O:37][C:57](=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59])[C:26]5[CH:27]=[CH:28][C:29]=1[N:30]=5)[CH:23]=[CH:22]4)[CH:18]=[CH:17]3)=[CH:12][CH:11]=2)(=[O:63])[C:58]([CH3:61])([CH3:60])[CH3:59]
Reactant: Oc1cccc(O)c1-c1c2nc(c(-c3c(O)cccc3O)c3ccc([nH]3)c(-c3c(O)cccc3O)c3nc(c(-c4c(O)cccc4O)c4ccc1[nH]4)C=C3)C=C2
Reactant: CC(C)(C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1cccc(OC(=O)C(C)(C)C)c1-c1c2nc(c(-c3c(OC(=O)C(C)(C)C)cccc3OC(=O)C(C)(C)C)c3ccc([nH]3)c(-c3c(OC(=O)C(C)(C)C)cccc3OC(=O)C(C)(C)C)c3nc(c(-c4c(OC(=O)C(C)(C)C)cccc4OC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2

Procedure:
50 ml of a solution of 1.0 g of 5,10,15,20-tetra(2',6'-dihydroxyphenyl)porphyrin in dry tetrahydrofuran was refluxed at the boiling point in an atmosphere of nitrogen. 5.0 g of anhydrous pivalic acid and then 0.17 g of 4-dimethylaminopyridine were added to the solution, and the mixture was heated under reflux for about 20 hours. The reaction solution was evaporated and the residue obtained was dissolved in 250 ml of chloroform. The chloroform solution was washed with dilute hydrochloric acid and with water. The solution was dehydrated by using anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness. The residue obtained was fractionated and purified by chromatography on a column of silica gel (chloroform / ether (10/1) (volume/volume)). The object fractionated was collected and evaporated to dryness under reduced pressure. Thus, 5,10,15,20-tetra(2',6'-dipivaloyloxyphenyl)porphyrin was obtained as violet needle crystals. Yield: 1.15g (60%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([Cl:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of 5-(6-chloro-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (144) (41 mg, 0.166 mmol) in 2 ml DCM was added 2,6-difluorobenzoyl chloride (42 μl, 2 eq) followed by addition of DIEA (145 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (330 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(6-chloro(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (145) (52.7 mg, yield: 82.1%, purity>95%) as white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[SH:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][S:39][C:40]4[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=4)=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCSc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-propyl-urea, 80 mg), potassium carbonate (138 mg), and 4-mercaptopyridine (22 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 60 mg (yield 72%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:3]([O:6][C:7]([C:9]([CH2:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5]
Reactant: N#Cc1ccc(CCBr)cc1
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC(=O)OCC)(CCc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27923.2 %

Procedure:
6.37 g (159.27 mmol; content 60%) of sodium hydride are added in portions to a solution of 45.23 g (144.79 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonylheptanedioate from Example 82A in 250 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 30 min. The reaction solution is then cooled to 0° C. and, after addition of 36.50 g (173.75 mmol) of 4-(2-bromoethyl)benzonitrile from Example 8A in 250 ml DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1-4:1→1:1). 17.85 g (40.43 mol, 28% yield) of a colorless solid are obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([F:17])=[C:15]([F:18])[CH:14]=[C:13]([F:19])[C:12]=3[F:20])[N:9]=[CH:10][C:3]=12.[O:21]1CC[O:23][BH:22]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:20][C:12]1[C:13]([F:19])=[CH:14][C:15]([F:18])=[C:16]([F:17])[C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:22]([OH:23])[OH:21])=[C:3]2[CH:10]=[N:9]1
Reactant: Fc1cc(F)c(F)c(-n2ncc3c(I)ccnc32)c1F
Reactant: B1OCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1c(F)c(F)cc(F)c1F
Temperature: 105 °C

Procedure:
To a 48 mL pressure bottle under N2 was added the compound from Intermediate 69A (1.1 g, 2.8 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (1.17 g, 4.61 mmol), potassium acetate (1.15 g, 11.72 mmol), and anhydrous DMSO (8 mL). Argon was bubbled into the reaction mixture for 5 min and then PdCl2(dppf).CH2Cl2 (71 mg, 0.097 mmol) was added. The reaction mixture was flushed with argon, securely capped, and heated at 105° C. for 75 min. After adding 30 mg more palladium catalyst and 60 mg more 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane, the reaction mixture was heated at 115° C. in an oil bath for an additional 75 min to give the desired intermediate. LC/MS (Condition B): ret. T=3.2 min, (M+H)+ 312.03.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:19][CH2:20][N:15]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16][CH2:17]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: CC(C)(C)OC(=O)NN1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 63.9 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (29.8 g, 137 mmol) and tert-butyl piperazin-1-ylcarbamate (28.9 g, 144 mmol) gave tert-butyl (S)-{4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-yl}carbamate (36.68 g, yield 64%) as a white powder in the same manner as in Example 496.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[ClH:33]>C(O)(C)C.C1(C)C=CC=CC=1>[ClH:33].[CH2:14]([NH:21][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COc1ccc2c(c1)CC(NCc1ccccc1)CC2
Temperature: 25 °C

Procedure:
A mixture of 8 g of 7-methoxy-2-tetralone, 4.8 g of benzylamine, 150 ml of anhydrous toluene and 100 mg of p.toluenesulfonic acid is refluxed for three hours. The mixture is evaporated to dryness, the oily residue is taken up with 100 ml of methanol and to the solution thus obtained 8.5 g of sodium borohydride are cautiously added at 0°-5° C. The mixture is left under stirring at room temperature for a night, then added with 50 ml of water and left under stirring for 30 minutes. The solvent is evaporated, the residue is taken up with 30 ml of water and 10 ml of a concentrated solution of ammonium hydroxide. After extraction with 200 ml of ethyl acetate, the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. A dark coloured oil is obtained, which is purified by flash chromatography using a mixture ethyl acetate/methanol 95/5 as an eluent. The base so obtained is converted into its hydrochloride by solution in 40 ml of isopropanol and addition of isopropanol saturated with hydrogen chloride to give 11.4 g of 2-benzylamino-7-methoxytetraline hydrochloride; m.p. 265°-267° C. (dec.).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH3:29][N:30]([CH3:44])[C:31]([CH3:43])([CH3:42])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[CH3:29][N:30]([CH3:44])[C:31]([CH3:43])([CH3:42])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:36][CH:35]=1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(C)(C)COc1ccc(C=O)cc1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N(C)C)cc2)c1
Yield: 73.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (34 mg) and 4-(2-dimethylamino-2-methylpropoxy)benzaldehyde (100 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (33 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][C:18]([CH3:24])([CH2:22][CH3:23])[C:19](O)=[O:20]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:19](=[O:20])[C:18]([CH3:24])([CH3:17])[CH2:22][CH3:23])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: CCC(C)(C)C(=O)O
Product: CCC(NC(=O)C(C)(C)CC)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 58A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 78 mg (0.67 mmol) 2,2-dimethylbutanoic acid and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.