Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>[O-2].[O-2].[Mn+4].O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=1
Reactant: COc1nc2ccc(C(O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1.08 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (2.3 g, 4.98 mmol, Intermediate 12: step a) was added 1,4-dioxane (80 mL) to give a suspension at room temperature. The flask was fitted with a reflux condenser and heated briefly to 50° C. which resulted in a homogeneous solution. Then, activated manganese dioxide (1.73 g, 19.9 mmol) was introduced and the temperature was raised to 80° C. After 65 minutes, the reaction mixture was filtered through Celite® and rinsed with warm THF. The effluent was concentrated to dryness to provide the title compound as a white solid.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[NH2:5]/[C:6](=[N:18]\[OH:19])/[C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:9])[CH3:8]>CN(C=O)C>[CH3:1][C:2]1[O:19][N:18]=[C:6]([C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])([CH3:9])[CH3:8])[N:5]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NC(C)(C)/C(N)=N/O
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(C)NC(=O)OC(C)(C)C)no1
Temperature: 120 °C
Reaction time: 10 h
Yield: 79.8 %

Procedure:
To a solution of acetic acid (1.8 g) in DMF (50 mL) was added N,N′-carbonyldiimidazole (CAN 530-62-1, 4.865 g, mmol). The solution was stirred at ambient temperature for 0.5 h. (Z)-tert-butyl 1-amino-1-(hydroxyimino)-2-methylpropan-2-ylcarbamate (6.07 g) was added and the reaction mixture was stirred at 120° C. for 10 h. Removal of the solvent under reduced pressure left a yellow oil which was purified by column chromatography (silica gel 120 g, eluting with 30% ethyl acetate in petroleum ether) to give the title compound (5.38 g, 80%) as colorless oil; MS: m/e=264.1 [M+Na]+.
Reaction SMILES: C(O)(C)C.[CH2:5]([C:8]1[C:9]([Cl:18])=[N:10][C:11]2[N:12]([N:15]=[CH:16][CH:17]=2)[C:13]=1Cl)[CH:6]=[CH2:7].[CH3:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>C(N(CC)CC)C>[CH2:5]([C:8]1[C:9]([Cl:18])=[N:10][C:11]2[N:12]([N:15]=[CH:16][CH:17]=2)[C:13]=1[NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH3:19])=[CH:23][CH:24]=1)[CH:6]=[CH2:7]
Reactant: C=CCc1c(Cl)nc2ccnn2c1Cl
Reactant: CCOc1ccc(N)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C=CCc1c(Cl)nc2ccnn2c1Nc1ccc(OCC)cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To an isopropanol (52 mL) solution containing 6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.98 g), triethylamine (12.7 mL) and phenethidine (4.30 g) were added, and this mixture was stirred at 40° C. for 5 hr. After the reaction, the solvent was distilled off. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated to obtain the title compound (8.62 g).
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]([CH3:15])=[N:8][C:7](O)=[C:6]2O.C(N(CC)CC)C.C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Ru].C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C@H:9]([CH3:15])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(C)nc(O)c(O)c2cc1OC
Agent: [Ru]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1cc2c(cc1OC)[C@H](C)NCC2
Yield: 98.4 %

Procedure:
6,7-Dimethoxy-1-methyl-3,4-dihydroxyisoquinoline (Table 6-2a) (1.03 g, 5 mmol) and a ruthenium catalyst (Table 7) (R, R)-1a (16 mg, 0.025 mmol) were dissolved in acetonitrile (10 ml), followed by addition of a mixture of formic acid-triethylamine (5:2), for agitation at 28° C. for 3 hours. To the reaction mixture was added an aqueous sodium carbonate solution to extract the product in ethyl acetate. After evaporation of the solvent, 1H-NMR(CDCl3) of the resulting product was measured to calculate the conversion. Then, the product was purified by silica gel chromatography, to determine the optical purity and absolute configuration of the resulting optically active amine by HPLC or GLC. As collectively shown in Table 8, (S)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (1.02 g, yield of 99%, 96% ee) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[C@H:13]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1.O>C1COCC1.CCOC(C)=O>[CH2:17]([O:16][CH2:15][CH2:14][C@H:13]([C:9]1[N:10]([S:44]([C:41]2[CH:42]=[CH:43][C:38]([CH3:48])=[CH:39][CH:40]=2)(=[O:46])=[O:45])[CH:11]=[CH:12][C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCOCc1ccccc1)c1[nH]ccc1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2[C@@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h

Procedure:
(R)-tert-Butyl 2-(3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)propyl)-1H-pyrrole-3-carboxylate (724b, 4.31 g, 10.01 mmol) was dissolved in THF (40 mL) under nitrogen and cooled in an ice bath. Sodium tert-butoxide (1M in THF, 10.01 mL, 10.01 mmol) was added and the mixture stirred for 5 min. Toluene-4-sulfonyl chloride (1.91 g, 10.01 mmol) was added to the solution and the mixture was stirred at 0° C. for 30 min. Water (50 mL) and EtOAc (50 mL) were added to the reaction mixture and the organic layer was washed with brine and dried over MgSO4, filtered and concentrated affording crude (R)-tert-butyl-2-(1-amino-3-(benzyloxy)propyl)-1-tosyl-1H-pyrrole-3-carboxylate (724c) as an orange viscous oil. m/z (ESI, +ve) 607.2 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][N:14]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:6][C:5]2[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:18])=[CH:15][N:14]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1cc(NC(=O)c2ccc(Cl)nc2)cc(OC)c1

Procedure:
6-Chloro-N-(3,5-dimethoxy-phenyl)-nicotinamide was prepared from 3,5-dimethoxy aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H13N2O3Cl [M+H]+: 293.0688. Found: 293.0687.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH3:13].O.C(=O)([O-])[O-].[Na+].[Na+]>CO.[Fe]>[CH3:13][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=1[S:3][CH3:2]
Reactant: CSc1cc([N+](=O)[O-])ccc1C
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: CSc1cc(N)ccc1C
Yield: 41.8 %

Procedure:
Concentrated hydrochloric acid (128 ml) was added slowly to a suspension of 2-methylsulphenyl-4-nitrotoluene (36.6 g) in methanol. Iron powder (36 g) was added with stirring whilst maintaining the temperature below 50° C. The mixture was stirred at room temperature for 4 hours. The mixture was poured into water, neutralized (by the addition of sodium carbonate), filtered and the residue was extracted with dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with aqueous sodium chloride solution, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography on silica eluted with a mixture of ethyl acetate and n-hexane to give 4-methyl-3-methylsulphenylaniline (12.8 g) as an orange solid, NMR (CDCl3) 2.2(s,3H), 2.35 (s,3H), 3.45 (s,2H), 6.1-6.9 (m,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.FC(F)(F)S(O[CH2:42][C:43]([F:46])([F:45])[F:44])(=O)=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:42][C:43]([F:46])([F:45])[F:44])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCN(CC(F)(F)F)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and 2,2,2-trifluoroethyl trifluoromethanesulfonate following General Procedure S.
Reaction SMILES: O[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([Br:12])[S:9][C:8]=1[Br:13].CS(O)(=O)=O>FC(F)(F)C(O)=O>[Br:13][C:8]1[S:9][C:10]([Br:12])=[C:11]2[CH:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:3][NH:4][CH2:5][CH2:6][C:7]=12
Reactant: OC(CNCCc1cc(Br)sc1Br)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Brc1sc(Br)c2c1CCNCC2c1ccccc1

Procedure:
A solution of N-(2-hydroxy-2-phenylethyl) 2,5-dibromothiophene-3-ethylamine (7.0 g) and methane sulphonic acid (1.57 ml) in trifluoroacetic acid (35 ml) was heated under reflux for 5 hours. The brown reaction mixture was evaporated and the residue suspended in iced water (70 ml), basified with 0.880 ammonia solution (7 ml) and extracted with dichloromethane (2×100 ml). The extracts were dried, filtered and evaporated to a dark brown oil. Chromatography on silica eluting with 2% methanol in dichloromethane gave 1,3-dibromo-4-phenyl-5,6,7,8-tetrahydro-4H-thieno[3,4-d]azepine. The crystal salt was prepared by addition of ethanolic hydrogen chloride (I equivalent) to an ethanol (15 ml) solution of the amine. The solution was cooled and filtered to give 1,3-dibromo-4-phenyl-5,6,7,8-tetrahydro-4H-thieno[3,4-d]azepine hydrochloride (m.p. 248°) as a tan solid. A second crop of product was obtained by diluting the mother liquors with diethyl ether.
Reaction SMILES: [OH:1][C@H:2]([CH2:48][OH:49])[CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]2[CH2:36][CH2:37][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:39][CH:40]=2)([CH3:34])[CH3:33])[NH:9]1)=[O:7]>C(OCC)(=O)C.O=[Pt]=O>[OH:1][C@H:2]([CH2:48][OH:49])[CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH:35]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:37][CH2:36]2)([CH3:34])[CH3:33])[NH:9]1)=[O:7]
Reactant: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1=CCN(Cc2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1CCN(Cc2ccccc2)CC1

Procedure:
In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide prepared in Example 127e (60 mg, 0.08 mmol) was treated with PtO2 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-piperidin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (15 mg, 25%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]34[CH2:23][CH:18]5[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]5)[CH2:15]3)[CH2:21]4)[O:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:26]=1[NH2:27]>>[CH3:33][O:32][C:30]1[C:29]([O:34][CH3:35])=[CH:28][C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([C:14]45[CH2:23][CH:18]6[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]6)[CH2:15]4)[CH2:21]5)[O:11][N:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:25]([CH3:24])[CH:31]=1
Reactant: COc1cc(C)c(N)cc1OC
Reactant: Clc1nccc(Nc2cc(C34CC5CC(CC(C5)C3)C4)on2)n1
Product: COc1cc(C)c(Nc2nccc(Nc3cc(C45CC6CC(CC(C6)C4)C5)on3)n2)cc1OC

Procedure:
The title compound was prepared by the method described in Example 1 using 2-chloro-N4-(5-adamantylisoxazol-3-yl)-4-pyrimidineamine and 2-methyl-4,5-dimethoxyaniline. MS (MH+)=462.2; Calc'd for C26H31N5O3— 461.57.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([N+:23]([O-])=O)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([NH2:23])=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc([N+](=O)[O-])sc2-c2ccc(F)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2cc(N)sc2-c2ccc(F)cc2)cc1
Yield: 81.5 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-nitrothiophene (3.6 g), iron powder (3.6 g) and ammonium chloride (0.36 g) in ethanol (58 ml) and water (22 ml) was stirred and refluxed for 1 hour. The insoluble was filtered and washed with N,N-dimethylformamide (40 ml). The filtrate was concentrated. The residue was triturated with water, filtered, and washed with water and ethanol to give a pale yellow powder of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thiophenamine (2.7 g).
Reaction SMILES: ClC(OCC)=O.Br.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:21]3[C:26]([N:27]=[C:28]4[C:33]=2[CH:32]=[CH:31][CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=1)([OH:10])=[O:9].C(N(CC)CC)C.Br.COC1C=CC(N(S(C2C=CC(CCCCC(O)=O)=CC=2)(=O)=O)C(C2C3C(N=C4C=2C=CC=C4)=CC=CC=3)=O)=CC=1.O[N:94]1[C:98](=[O:99])[CH2:97][CH2:96][C:95]1=[O:100]>O1CCCC1>[C:95]1(=[O:100])[N:94]([O:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])[C:18]([C:20]3[C:33]4[C:28]([N:27]=[C:26]5[C:21]=3[CH:22]=[CH:23][CH:24]=[CH:25]5)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:19])=[CH:15][CH:16]=2)=[O:10])[C:98](=[O:99])[CH2:97][CH2:96]1
Reactant: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)O)cc2)cc1
Reactant: O=C1CCC(=O)N1O
Agent: Br
Agent: CCOC(=O)Cl
Agent: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCCCC(=O)O)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Reaction time: 1 h

Procedure:
0.11 g (1 mmol) of ethyl chloroformate is added, while stirring at -15° C., to a solution of 0.57 g (1 mmol) of N-(4-carboxyphenyl)-N-(4-toluenesulfonyl)acridine-9-carboxamide hydrobromide and 0.21 g (2 mmol) of triethylamine in 25 ml of anhydrous tetrahydrofuran. The mixture is stirred at the same temperature for 1 hour and then 0.12 9 (1 mmol) of N-hydroxysuccinimide is added. After a further hour, the mixture is left to stand at room temperature for 15 hours. It is evaporated in vacuo, the residue is taken up in ethyl acetate, and the solution is washed with water, sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation yields 0.42 g (70.8% of theory) of the desired product.
Reaction SMILES: C([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12]([CH3:22])([C:18]([O:20][CH3:21])=[O:19])[CH2:13]2)C1C=CC=CC=1>[Pd].CO>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12]([CH3:22])([C:18]([O:20][CH3:21])=[O:19])[CH2:13]2
Reactant: COC(=O)C1(C)Cc2cccc(NCc3ccccc3)c2C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(C)Cc2cccc(N)c2C1

Procedure:
At room temperature, 50 mg of palladium on carbon (10%) were added to a solution of 860 mg (2.91 mmol) of methyl 4-(benzylamino)-2-methyl-2,3-dihydro-1H-indene-2-carboxylate in 84 ml of methanol, and the mixture was hydrogenated under atmospheric pressure overnight. After the reaction had gone to completion, the reaction solution was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→1:1). This gave 483 mg (2.35 mol, 81% of theory) of a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:8][CH2:7][C:6]([CH3:11])([CH:9]=O)[CH2:5][CH2:4]1.Cl.[NH2:21][OH:22]>C(O)C>[CH3:1][N:2]([CH3:19])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:8][CH2:7][C:6]([CH3:11])([CH:9]=[N:21][OH:22])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C)(C=O)CC1
Agent: Cl
Solvent: CCO
Product: CN(C)C1(c2cccc(F)c2)CCC(C)(C=NO)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the title compound of step 2 (1.38 g, 5.53 mmol) and hydroxylamine hydrochloride (576 mg, 8.3 mmol) in abs. ethanol (20 mL) were mixed with Amberlyst A 21 (3.9 g) and stirred for 16 h at RT. The ion exchanger was filtered off, the solution concentrated to low volume and the residue made alkaline with 1N NaOH. The aqueous phase was extracted with ethyl acetate, dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17]([NH2:19])=[NH:18].CN(C)[CH:22]=[CH:23][C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=O>>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17]1[N:19]=[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][N:18]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=N)N
Solvent: O=[N+]([O-])O
Product: COc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Yield: 63 %

Procedure:
2-Methoxy-5-nitrophenyl-guanidine nitrate (31 g, 0.113 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (20 g, 0.113 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(2-methoxy-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (23 g).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23](Br)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1cccc2ccccc12
Product: c1ccc2c(-c3ccc(Cn4ccnc4)cn3)cccc2c1

Procedure:
Synthesized using 1-naphthylboronic acid (217 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 130 mg, 0.46 mmol, 72%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.25 (s, 2H), 7.00 (t, J=1.3 Hz, 1H), 7.16 (t, J=1.3 Hz, 1H), 7.46-7.52 (m, 2H), 7.54-7.60 (m, 4H), 7.65 (br, s, 1H), 7.90-7.93 (m, 2H), 8.03-8.05 (m, 1H), 8.70 (dd, J=2.5, 0.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.19, 119.1, 125.2, 125.2, 125.3, 126.0, 126.6, 127.6, 128.4, 129.2, 130.1, 130.3, 131.0, 135.3, 137.3, 137.6, 148.3, 159.5; MS (ESI): m/z=286.05 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:27]([F:30])([F:29])[F:28])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]=[N:16][C:17]=2[C:27]([F:30])([F:28])[F:29])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)cc3)c(C(F)(F)F)nn2)CC1
Solvent: CO
Product: Fc1ccc(-c2cc(N3CCNCC3)nnc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of 4-[5-(4-fluorophenyl)-6-trifluoromethyl-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (D8) (1.25 g, 2.93 mmol) in methanol (50 ml) was added Amberlyst® 15 ion exchange resin, acidic form (4.1 mmol/g) (3.6 g, 14.64 mmol) and the reaction mixture was shaken at room temperature for 18 h. After this period, the mixture was filtered and then a saturated solution of ammonia in methanol was added. The mixture was shaken for 1 h, filtered and the filtrate evaporated in vacuo. The crude product was purified by HPLC. The desired fractions were collected and evaporated in vacuo to yield E6 (0.507 g, 53%). C15H14F4N4 requires 326; Found 327 (MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.FC(F)(F)S(O[CH2:14][C:15]([CH3:37])([O:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[CH2:23][CH2:22][CH2:21][C:20]=2[C:19]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:16])(=O)=O>C(#N)C>[N:3]1([CH2:14][C:15]([CH3:37])([CH3:16])[O:17][C:18]2[C:19]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22][CH2:21]3)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CC(C)(COS(=O)(=O)C(F)(F)F)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(Cn1ccnc1)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Yield: 92 %

Procedure:
A mixture of sodium hydride (60% dispersion in oil, 32 mg, 0.81 mmol), acetonitrile (0.4 mL), and imidazole (275 mg, 4.0 mmol) was stirred at room temperature for 10 min, whereupon a solution of 2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propyl trifluoromethane-sulfonate (190 mg, 0.40 mmol) in acetonitrile (0.8 mL) was added. The resulting mixture was stirred at reflux for 20 min and was then concentrated. The residue was purified by dry-flash column chromatography (SiO2, 1-10% 2-propanol-dichloromethane) to give 6-[2-(1H-imidazol-1-yl)-1,1-dimethylethoxy]-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone as a colorless oil, 126 mg, 92% yield. NMR spectrum was consistent with structure. MS EI: M+• 388.2149 (M+• 388.2151).