Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2]>[Pt]=O.CO>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:17]=2)[C:9]2[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC=C(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(F)cccc21
Agent: O=[Pt]
Solvent: CO
Product: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(F)cccc21
Yield: 98.8 %

Procedure:
Inject titanium isopropoxide (1.3 mL, 4.32 mmol) to a mixture of 6-fluor-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (572 mg, 2.16 mmol) and 3,5-bis(trifluoromethyl)benzylamine (972 mg, 3.2 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3-dihydro-benzo[b]azepine-1-carboxylic isopropyl ester (820 mg, 77%). Add methanol (9.3 mL) and platinum oxide (37 mg, 0.16 mmol) to 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3-dihydro-benzo[b]azepine-1-carboxylic isopropyl ester (742 mg, 1.5 mmol) and hydrogenate the mixture at 1 atmosphere and room temperature for 2 h. Filter through celite and remove the solvent under reduced pressure to afford 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (730 mg, quantitative). Add acetic anhydride (0.5 mL, 5.78 mmol) dropwise to a suspension of the amine (190 mg, 0.385 mmol) and pyridine (0.5 mL, 5.78 mmol) in dichloromethane (1.5 mL), stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (141 mg, 68%); MS (ES+): 535 (M+H).
Reaction SMILES: CC1C=C(C=C(C)C=1)C[CH2:6][C:7]([O:9]CC)=S.[O:16]=[C:17]([CH3:35])[CH:18]=[CH:19][C:20]1[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:21]=1[CH2:22]CC(OCC)=S.[O:36]=[C:37]([CH3:55])[CH:38]=[CH:39][C:40]1[C:52]([CH3:53])=[CH:51][C:43]([CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[S:47])=[CH:42][C:41]=1[CH3:54]>>[CH3:34][C:30]1[CH:31]=[C:32]([CH3:33])[C:20]2[CH:19]3[CH2:6][C:7](=[O:9])[CH2:35][C:17](=[O:16])[CH:18]3[S:47][CH2:22][C:21]=2[CH:29]=1.[O:36]=[C:37]([CH3:55])[CH:38]=[CH:39][C:40]1[C:52]([CH3:53])=[CH:51][C:43]([CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[S:47])=[CH:42][C:41]=1[CH3:54]
Reactant: CCOC(=S)CCc1cc(C)cc(C)c1C=CC(C)=O
Reactant: CCOC(=S)CCc1cc(C)cc(C)c1
Agent: CCOC(=S)CCc1cc(C)c(C=CC(C)=O)c(C)c1
Product: Cc1cc(C)c2c(c1)CSC1C(=O)CC(=O)CC21

Procedure:
Ethyl (3,5-dimethylbenzyl)thioacetate was converted into an approximately 1:1 mixture of ethyl [2-(3-oxo-but-1-enyl)-3,5-dimethylbenzyl]thioacetate and ethyl [4-(3-oxo-but-1-enyl)-3,5-dimethylbenzyl]thioacetate following essentially the same procedure as that described in Example 6 parts (i) and (ii). The mixture was reacted under the conditions described in Example 6 part (iii) to give 8,10-dimethyl-1,2,3,4,4a,10b-hexahydro-6H-dibenzo[b,d]thiopyran-2,4-dione plus unreacted ethyl [4-(3-oxo-but-1-enyl)-3,5-dimethylbenzyl]thioacetate.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:17][CH2:18][CH2:19][CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCCCCCCCCCCCCOCCCO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 7.1 g (23.7 mmol) of 31 was added 20 mL of DCM and 5.0 mL (36 mmol) of Et3N and the solution was cooled to 0° C. To this cooled solution was added dropwise 2.0 mL (26 mmol) of MsCl and a catalytic amount of DMAP. The reaction was stirred at room temperature overnight. The reaction mixture was then diluted with 50 mL of DCM and washed successively with saturated solution of aq. NaHCO3 (1×), water (1×) and brine (1×), dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude product was then purified by combiflash using hexane/ethyl acetate as eluent to furnish 9 g of target product 32 in quantitative yield.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].Cl.[CH3:18][NH:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([N:19]([OH:20])[CH3:18])=[NH:11]
Reactant: CNO
Reactant: N#Cc1ccccc1N1CCCCS1(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(O)C(=N)c1ccccc1N1CCCCS1(=O)=O
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-benzonitrile and N-methylhydroxylamine hydrochloride (1.67 g, 20 mmol) in 1:1 water/ethanol (70 mL) was added sodium carbonate (1.06 g, 10 mmol) and the resulting mixture stirred at 90° C. for 18 h. After cooling and concentration, the resulting residue was suspended in MeOH/CHCl3 (100 mL, 1:9). The insoluble solids were removed by filtration and concentration of the filtrate gave the crude product as an amber oil (3.5 g) that was carried on without further purification. LCMS calcd for C12H17N3O3S (M+H): 284.35; found: 284.27.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:47][C:48]([NH:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)=[O:25]>>[CH2:44]([O:43][CH:39]([O:40][CH2:41][CH3:42])[C@@H:38]([N:26]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:17])[CH2:47][C:48](=[O:49])[NH:50][C:51]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[CH3:46])[CH3:45]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 67 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[N:21]1.C(N(CC)CC)C.O>CN(C)C=O>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)[N:3]=3)[CH2:34][CH2:33]2)=[O:31])=[N:21]1
Reactant: Clc1nc(-c2ccccn2)ns1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccccn3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
To a solution of 2-(5-chloro-1,2,4-thiadiazol-3-yl)pyridine (104 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 55.7 mg (24.6%) of the desired product. mp 222-223° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10].N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]=[CH2:22])=[O:19]>C(Cl)(Cl)Cl>[CH:21]([O:20][C:18]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[O:19])=[CH2:22]
Reactant: O=C1CCC(=O)N1CCO
Reactant: C=COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=COC(=O)OCCN1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
To a 500 mL 3-neck round bottom flask fitted with a mechanical stirrer, condenser, nitrogen blanket, dropping funnel, ice-saltwater bath, and thermometer were added 5.0 (35.0 mmol) of N-(2-hydroxyethyl) succinimide, 2.8 g (35.0 mmol) of pyridine, and 100 mL chloroform. To the reaction mixture was added 3.7 g (35.0 mmol) of vinyl chloroformate so that the temperature remained below 10° C. After stirring at room temperature for 18 hours the reaction mixture was washed with 100 mL 2N HCl and 100 mL 2N NaOH. The organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting red liquid chromatographed (silica gel, chloroform). The recovered oil totaled 3.0 g (14.1 mmol, 40.2% yield). FTIR (neat, capillary) 1755.10, 1694.90, 1648.77, 1427.00, 1396.38, 1366.15, 1329.97, 1298.34, 1239.58, 1185.85, 1152.26, 1111.20, 1085.92, 1024.25, 1005.00, 946.53, 894.87, 882.46, 848.52, 818.51, 778.99, 700.00, 661.32. NMR (CDCl3) 6.50-6.83 (1H,q), 4.13- 4.66 (2H,m), 3.93-4.13 (2H,m), 3.33-3.66 (2H,m), 2.41 (4H,S). ##STR17##
Reaction SMILES: [CH2:1]([C:3]1([OH:10])[CH2:5][CH:4]1[Si:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].C(N(CC)CC)C.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19].C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:3]1([O:10][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH2:5][CH:4]1[Si:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CCC1(O)CC1[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(OS(=O)(=O)CC)CC1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
2.5 g of 1-ethyl-1-hydroxy-2-(trimethylsilyl)cyclopropane prepared in Section (1) was dissolved in 15 mL of dichloromethane, and 2.3 g of triethylamine was added to the resulting solution. The reaction solution thus prepared was cooled to 0° C., 1.8 g of ethanesulfonylchloride was gradually added thereto and the mixture was vigorously stirred for 1 hour. 5 mL of a saturated NaHCO3 solution was added to the reaction solution, thereby terminating the reaction. An organic layer was separated from the reaction solution, dried over anhydrous magnesium sulfate (MgSO4), and concentrated by solvent distillation at a low temperature of less than 30° C. Although it may be used directly without any further treatment, the resulting concentrate was purified by silica gel chromatography using hexane and ethyl acetate to obtain 1.62 g of 1-ethyl-1-(ethanesulfonyloxy)-2-(trimethylsilyl)cyclopropane as a pure trans isomer. Results of 1H-NMR and 13C-NMR for the trans isomer are given below.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12](Cl)=[O:13])=[C:4]([F:31])[CH:3]=1.[NH3:32]>C1COCC1>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12]([NH2:32])=[O:13])=[C:4]([F:31])[CH:3]=1
Reactant: N
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)Cl)c1Cc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(N)=O)c1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-(2-chloro-5-nitrophenyl)-1H-pyrazole-5-carbonyl chloride (from Step D, theoretically 1.32 mmol) in 10 mL of dry THF was cooled to -50° C. and maintained at that temperature under protection from moisture as ammonia gas was gently bubbled in until saturated. The mixture was allowed to warm slowly to room temperature and stirred overnight. Concentration of the reaction mixture yielded a thick yellow oil, which was purified by flash chromatography on silica gel (elution with 1% and then 3% MeOH in CH2Cl2). Evaporation of the pooled product fractions yielded 625 mg (93%) of the title compound as a slightly yellow solid, mp 145°-147° C.; nearly homogeneous by TLC in 95:5 CH2Cl2 ; mass spectrum (FAB) m/e 509, 511 (M+1)+. 200 MHz 1H NMR (CDCl3) δ0.89 (t, J=7.1 Hz, 3H), 1.35 (m, 2H), 1.59 (m, 2H, partially obscured by H2O peak), 2.58 (t, J=7.7 Hz, 2H), 4.04 (s, 2H), 5.51 (br s, 2H), 6.91 (dd, J≈8, 8 Hz, 1H), 7.25-7.32 (m, 2H), 7.66 (d, J=8.8 Hz, 1H), 8.25 (dd, J=8.8, 2.6 Hz, 1H), 8.41 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH2:8]([NH:10][C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])[CH3:9]
Reactant: CCN
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)C1CCC1
Temperature: 22.5 °C
Reaction time: 0.33 h

Procedure:
Cyclobutanecarbonyl chloride (4.0 mL, 35 mmol) was added slowly to an ice-cooled solution of ethylamine [20 mL, 2M solution in tetrahydrofuran (THF)] and triethylamine (4.85 mL, 35 mmol) in anhydrous methylene chloride (25 mL) at 0-5° C. under nitrogen. After stirring for 20 min the mixture was warmed to 20-25° C. and stirred for an additional 5-7 h. The reaction was quenched by pouring the mixture into 5-10% aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and the solvent was evaporated to give cyclobutanecarboxylic acid ethylamide as a pale yellow liquid, which solidified upon standing at RT.
Reaction SMILES: C1N=C2N([C@@H]3[O:14][C@H](COP(OP(OP(O)(O)=O)(O)=O)(O)=O)[C@@H](O)C3)C=NC2=C(N)N=1.P(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[P:59]([O:71][CH2:72][C@H:73]1[O:77][C@@H:76]([N:78]2[C:88]3N=C(N)N[C:82](=[O:83])[C:81]=3[N:80]=[CH:79]2)[CH2:75][C@@H:74]1[OH:89])([O:62][P:63]([O:66][P:67]([OH:70])([OH:69])=[O:68])([OH:65])=[O:64])(=[O:61])[OH:60]>>[CH:81]1[C:82](=[O:83])[NH:80][C:79](=[O:14])[N:78]([C@@H:76]2[O:77][C@H:73]([CH2:72][O:71][P:59]([O:62][P:63]([O:66][P:67]([OH:69])([OH:70])=[O:68])([OH:65])=[O:64])([OH:60])=[O:61])[C@@H:74]([OH:89])[CH2:75]2)[CH:88]=1
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Agent: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1

Procedure:
200 μM each dATP, dCTP, and dGTP
Reaction SMILES: C([O-])=O.[NH4+].C(O)=O.[N+:8]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][CH:12]=1)([O-])=O>CO.[Pd]>[NH2:8][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][CH:12]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)CCC2
Reaction time: 0.5 h

Procedure:
Ammonium formate (2 g), Pd/C (5%; 1 g), and formic acid (0.5 g; cat.) were added in that order to a solution of 7-nitro-1-tetralone (1.95 g; 10 mmol) in methanol (50 mL), and the mixture was stirred for 30 minutes. The solution was filtered, and the filtrate was concentrated. The remainder was soaked with methylene chloride (50+25 mL), and the mixture was filtered and concentrated. Yield 1.4 g (88%).
Reaction SMILES: II.C1[O:14][CH:6]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)OC1.[Cl-].[Li+].Cl[CH:18]=[C:19]([Cl:21])[CH3:20].[Cl-].[NH4+]>C1COCC1.[Cu]Cl>[Cl:21][C:19](=[CH2:18])[CH2:20][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[O:14])=[CH:12][CH:11]=1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: CC(Cl)=CCl
Agent: Cl[Cu]
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(Cl)Cc1ccc(C=O)cc1
Reaction time: 1 h

Procedure:
Dry Mg (0.58 g) under dry N2 in a flask is covered with THF (5 ml) and a crystal of I2 added. 5 ml of a solution of 4-bromobenzaldehyde ethylene acetal (5.0 g) in THF (25 ml) is added and kept until it becomes warm, when it is cooled to 15°, and the remainder of the acetal added over 15 min, then stirred for an additional 1 hour. A mixture of ground lithium chloride (0.35 g) and copper (I) chloride (0.70 g) dissolved in THF is prepared, treated with 1,2-dichloropropene (CH2Cl.CCl=CH2) (4.5 g) and cooled to -20°. The above Grignard solution (under moisture excluding conditions) is then added to this solution during 5 min, and allowed to warm to 20° with stirring for 16 hours. Saturated aqueous ammonium chloride is added and the organic layer evaporated under reduced pressure to a small residue, which is dissolved in THF (100 ml), cooled to -100°, treated with 3N HCl (50 ml), then stirred at 20° for 1 hour. The product is partitioned between ether and water, and the ether layer washed with NaHCO3, H2O NaCl, dried (MgSO4) and the residue chromatographed on florisil. The fraction eluted by 15% ether in petrol is collected and purified by preparative HPLC. Yield 0.50 g (13%) nD20 1.5571.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[C:28]([C:33](O)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:33]([C:28]4[C:27]([CH3:26])=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1cccnc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ncccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-methylpyridine-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:34].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:34].[ClH:34].[CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)c2ccccc2n1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2ccc(N)cc2)c2ccccc2n1

Procedure:
The 2-methyl-N-(4-nitrophenyl)quinol-4-amine (13) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: CO[C:3]([C:5]1(C)[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[C:9]([Br:16])[C:8]=2[CH2:7][CH2:6]1)=O.Cl>>[Br:16][C:9]1[C:8]2[CH2:7][CH2:6][CH:5]([CH3:3])[C:14](=[O:15])[C:13]=2[CH:12]=[N:11][CH:10]=1
Reactant: COC(=O)C1(C)CCc2c(Br)cncc2C1=O
Agent: Cl
Product: CC1CCc2c(Br)cncc2C1=O
Yield: 90.1 %

Procedure:
(rac)-4-Bromo-7-methyl-8-oxo-5,6,7,8-tetrahydro-isoquinoline-7-carboxylic acid methyl ester (3.3 g, 11.0 mmol) was dissolved in aq. 6 N HCl (28.0 mL, 168 mmol) and heated at reflux for 2.5 h. The acidic solution was concentrated in vacuo, re-suspended in water (ca. 25 mL), cooled in an ice-water bath, and basified with 6 N aq. KOH solution. The aqueous solution was then washed with Et2O (2×) and CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (2.38 g, 90% yield) as a brown solid. MS: 240.1 & 242.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>C(O)CCC>[C:14]1([C:4]2[N:3]=[C:2]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=3)[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ccc(N)cc1
Reactant: Clc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Solvent: CCCCO
Product: CSc1ccc(Nc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1

Procedure:
4-Chloro-2,6-diphenyl-pyrimidine (0.4 g, 1.5 mmol) was reacted with 4-methylsulfanyl-phenylamine (0.22 g, 1.6 mmol) in a solvent n-butanol (10 mL) at reflux temperature for 12 hours to yield (2,6-diphenyl-pyrimidin-4-yl)-(4-methylsulfanyl-phenyl)-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH:9][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:40][CH:39]=2)[CH:8]=1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)cc1)C2
Yield: 65.3 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (312 mg) and 4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (1.0 g) according to an analogous synthetic method to Example 110, the title compound (360 mg) was obtained.
Reaction SMILES: O.[S-2].[Na+].[Na+].[S].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=1[N+:24]([O-:26])=[O:25])[CH3:7].[Na+].[Cl-]>O>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[N+:24]([O-:26])=[O:25])[CH3:7]
Reactant: CCOc1ccccc1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [S-2]
Solvent: O
Product: CCOc1ccccc1-c1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A clear orange-red solution of polysulfide (120 ml, 7.5 eq.), previously prepared by heating sodium sulfide monohydrate (10 g), sulfur (1.04 g) and water (160 ml), was added dropwise at 90° C. over 45 minutes to a suspension of 2′-ethoxy-2,4-dinitro-biphenyl (1.2 g, 4.0 mmol) in water (40 ml). The red-brown solution was heated at reflux for 1.5 h. The mixture was cooled to room temperature, and solid NaCl (5 g) was added. The solution was extracted with CH2Cl2 (3×50 mL), and the combined organic extracts was concentrated to provide 2′-ethoxy-2-nitrobiphenyl-4-yl amine (0.98 g, 95%) that was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.26 (m, 2H), 7.17 (d, J=2.7 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.00 (t, J=6.9 Hz, 1H), 6.83 (m, 2H), 3.91 (q, J=6.9 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H); HPLC ret. time 2.81 min, 10-100% CH3CN, 5 min gradient; ESI-MS 259.1 m/z (MH+).