Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([CH:6]=[C:7]([CH3:12])[C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[H][H]>C(OCC)(=O)C>[NH2:5][C:4]1[CH:6]=[C:7]([CH3:12])[C:8]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[C:3]=1[NH2:13]
Reactant: Cc1cc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: Cc1cc(N)c(N)c(C)c1[N+](=O)[O-]
Yield: 98.6 %

Procedure:
A solution of 3,5-dimethyl-2,4-dinitroaniline (1.5 g, 7 mmol) in ethyl acetate (100 mL) is treated with hydrogen at atmospheric pressure for 2 hours. The mixture is filtered on Celite and the filtrate is rotary evaporated to afford 1,2-diamino-3,5-dimethyl4-nitrobenzene (1.25 g) as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]([OH:22])=O)[C:14]=3[CH:13]=[CH:12][N:11]=2)=[N:7][CH:8]=1.NC1C2C=CC=C(C([NH:36][C:37]3[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=4)=[O:45])[CH:40]=[CH:39][C:38]=3[CH3:57])=O)C=2C=CN=1.NC1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]([NH:36][C:37]4[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]5[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:55])[F:56])[CH:48]=5)=[O:45])[CH:40]=[CH:39][C:38]=4[CH3:57])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[N:7][CH:8]=1
Reactant: COc1ccc(Nc2nccc3c(C(=O)O)cccc23)nc1
Reactant: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(N)nccc12
Solvent: Nc1ccccc1
Product: COc1ccc(Nc2nccc3c(C(=O)Nc4cc(NC(=O)Nc5cccc(C(F)(F)F)c5)ccc4C)cccc23)nc1
Yield: 65 %

Procedure:
The procedures of Example 18 were repeated, except for using 1-((5-methoxypyridin-2-yl)amino)isoquinoline-5-carboxylic acid obtained in Step (3) of Example 19 and 1-(3-amino-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea obtained in Example 14 instead of carboxylic acid and aniline in Step (3) of Example 1 to obtain the title compound (48 mg, 65%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[C:29]([O:33][C:34]([N:36]1[C:40]([CH:41]2[CH2:43][CH2:42]2)=[CH:39][C:38]([NH2:44])=[N:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>ClCCl>[CH:41]1([C:40]2[N:36]([C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:35])[N:37]=[C:38]([NH:44][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:39]=2)[CH2:42][CH2:43]1
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(NC(=O)C(c2ccccc2)c2ccccc2)cc1C1CC1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
To a solution of 45.6 mg (0.215 mmol) of diphenylacetic acid in 3 ml of dichloromethane at 0° C. 41.2 mg (0.215 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added. After 1 hour at the same temperature under stirring 40 mg (0.179 mmol) of tert-butyl-3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate were added. The mixture was maintained at room temperature for 16 hours, then was diluted with dichloromethane and washed with a saturated solution of sodium hydrogenocarbonate. The organic layer was dried over anhydrous sodium sulfate evaporated to dryness, to give, after column chromatography (hexane-ethylacetate) 60 mg (80% yield) of N-(5-cyclopropyl-1-terbutoxycarbonyl-pyrazol-3-yl)-2,2-diphenyl acetamide. This intermediate was submitted to hydrolysis with 15 ml of trifluoroacetic acid 10% v/v in dichloromethane for an hour. The solvent was then evaporated under vacuum, the residue redissolved with dichloromethane and washed with a saturated solution sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 42 mg (92% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-].[OH-].[K+]>O1CCCC1.CCOCC>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1c2c(nc3ccccc13)CCCC2O
Temperature: -5 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
In 100 ml of dry tetrahydrofuran was added 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one. The mechanically stirred suspension was cooled to -5° C. and 21.4 ml (1.0 eq) of 1.1M LiAlH4 solution in ether was added dropwise. After completion of the addition, the reaction mixture was stirred further for 2 hours, whereupon the reaction appeared complete based on thin layer chromatography analysis. The LiAlH4 was neutralized with 2 ml of saturated NH4Cl and the salts were dissolved with 30% potassium hydroxide. The insoluble product was filtered off and rinsed with water. The precipitate was then dissolved in 3N HCl and the residual insoluble salts filtered off. The acid solution was washed with EtOAc and made basic (pH 9) with 10% NaOH. The precipitated product was filtered and washed with water. After drying at 80° C. under vacuum overnight, 4.15 g (82%) of a powder was obtained, melting point 245° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.Cl[CH2:30][C:31]1[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[O:33][N:32]=1>C(O)(CC)(C)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:30][C:31]4[CH2:35][CH:34]([C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][CH:37]=5)[O:33][N:32]=4)[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: FC(F)(F)c1ccc(C2CC(CCl)=NO2)cc1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Solvent: CCN(CC)CC
Solvent: CCC(C)(C)O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CC4=NOC(c5ccc(C(F)(F)F)cc5)C4)CC3)ccc2s1
Temperature: 95 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
To a stirred mixture of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol (30 mg, 0.08 mmol) in tert-amylalcohol (5 mL) was added triethylamine (40 μL, 0.30 mmol), followed by 3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole (20 mg, 0.08 mmol). The resulting mixture was stirred at 95° C. for 12 hours, concentrated under reduced pressure, and purified by preparative chromatograph (1:19 MeOH:CH2Cl2) to afford (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol (10 mg, M+1=535.1).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([OH:19])[C@H:6]([O:20]C(=O)C(C)(C)C)[C@H:5]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([OH:19])[C@H:6]([OH:20])[C@H:5]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)[C@H](O)[C@H]1c1ccccc1
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
160 g of (7R,8R,9R)-10-acetyl-7-hydroxy-2,3-dimethyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine are dissolved in 0.7 l of methanol with stirring and treated with 40 g of potassium carbonate. After approximately 10 min, the product begins to precipitate from the reaction mixture. After stirring for 1 h at room temperature, it is added to a solution of 200 g of ammonium chloride in 1.8 l of ice water. It is stirred for a further 1 h at ice-bath temperature, then the precipitated solid is filtered off with suction and washed with a little methanol (80 ml). After drying at 50° C. in a vacuum drying oven, 92.0 g (73%) of the title compound are isolated as a colorless solid of m.p. 260-261° C., which is used in the next stage without further purification. Alternatively, the tile compound can also be prepared according to examples 5 and 6.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:33]([C@:27]1([C:30]([N:12]2[CH2:11][CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[N:8]=3)[CH2:14][CH2:13]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 1-[6-(trifluoromethyl)pyridin-2-yl]piperazine (249 mg, 1.08 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (300 mg, 1.10 mmol), triethylamine (0.45 mL, 3.2 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (524 mg, 1.18 mmol). After being stirred overnight, the reaction was quenched with saturated sodium NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. Purification by column chromatography on silica gel (20% EA/hex to 40% EA/hexanes) provided 310 mg of the desired product. MS calculated for C24H36F3N4O3: (M+H) 485.3; found 485.3.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[Cl:29][C:30]1[CH:37]=[C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[C:44]([F:47])[CH:43]=[CH:42][CH:41]=3)[C:33]([CH:34]=O)=[CH:32][N:31]=1>C1COCC1.O>[Cl:29][C:30]1[CH:37]=[C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[C:44]([F:47])[CH:43]=[CH:42][CH:41]=3)[C:33]([CH:34]=[C:3]([CH3:4])[CH3:2])=[CH:32][N:31]=1
Reactant: O=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
n-BuLi (3.15 mL, 7.88 mmol, 2.5 M in hexane) was added dropwise to a mixture of isopropyltriphenylphosphonium iodide (3.55 g, 8.21 mmol) in THF (30 mL) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 1 hour. Then a solution of 6-chloro-4-(4-fluoro-1H-indol-2-yl)nicotinaldehyde (900 mg, 3.28 mmol) in THF (10 mL) was added dropwise to the mixture at −78° C. The mixture was stirred at room temperature overnight. The mixture was then diluted with water (100 mL) and extracted with EA (50 mL*3). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EA=4:1) to give the product of 2-(2-chloro-5-(2-methylprop-1-en-1-yl)pyridin-4-yl)-4-fluoro-1H-indole (500 mg, yield: 50.6%). 1H-NMR (CDCl3, 400 MHz) δ 8.66 (br s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.12 (br s, 2H), 6.96 (d, J=1.6 Hz, 1H), 6.70˜6.81 (m, 1H), 6.22 (br s, 1H), 1.97 (s, 3H), 1.68˜1.70 (m, 1H), 1.74 (s, 3H). MS (M+H)+: 301/303.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:39][C:40]([NH:42][CH3:43])=[O:41]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:21][C:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:39][C:40]([NH:42][CH3:43])=[O:41])[CH2:26][CH2:25]5)=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3]
Reactant: CNC(=O)CCl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Product: CNC(=O)CN1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Reaction time: 24 h
Yield: 14.3 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (150 mg, 0.35 mmol) was added triethylamine (107 μL, 0.77 mmol) followed by 2-chloro-N-methyl-acetamide (41 mg, 0.38 mmol). The resultant mixture was stirred overnight before the addition of tetrabutylammonium iodide (13 mg, 0.04 mmol) and the reaction stirred for 24 hours. The mixture was washed with water then extracted with 10% MeOH in DCM (×5). The combined organic layers were dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) twice to afford 275 (23 mg, 0.05 mmol, 14%). LCMS: RT=2.63 min, [M+H]+=464. 1H NMR δ (ppm) (CDCl3): 8.42 (1H, d, J=8.30 Hz), 7.59 (1H, s), 7.00 (1H, dd, J=8.35, 1.83 Hz), 6.88 (1H, d, J=1.79 Hz), 5.91-5.81 (1H, m), 4.48-4.44 (2H, m), 4.42-4.36 (2H, m), 3.13-2.91 (4H, m), 2.85 (3H, d, J=4.98 Hz), 2.56-2.48 (1H, m), 2.39 (3H, s), 2.33 (2H, s), 1.87 (2H, s), 1.78 (2H, s), 1.54 (6H, d, J=6.65 Hz). NH not observed.
Reaction SMILES: [C:1]([OH:6])(=O)[C@H:2]([CH3:4])[OH:3].[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@H:34]([CH3:38])[CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@H:34]([CH3:38])[CH2:35][N:36]([CH3:37])[C:1](=[O:6])[C@@H:2]([OH:3])[CH3:4])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[C@H](O)C(=O)O
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@H](CN(C)C(=O)[C@H](C)O)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 35 %

Procedure:
The procedure described in Example 1 was repeated using L-(+)-lactic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the title compound as a white solid in 35% yield; NMR spectrum (DMSO-d6 373K) 1.07 (d, 3H), 1.45 (d, 3H), 2.98 (s, 3H), 3.22 (m, 1H), 4.19 (m, 1H), 4.43 (m, 1H), 5.15 (m, 1H), 5.27 (s, 2H), 7.22 (m, 2H), 7.35 (m, 2H), 7.59 (m, 2H), 7.69 (t, 1H), 7.84 (dt, 1H), 8.08 (d, 1H), 8.47 (s, 1H), 8.58 (d, 1H), 9.93 (s, 1H); Mass spectrum MH+ 522.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:17])[CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])=[CH:5][C:4]=1[Br:18].[BH4-].[Na+]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:17])[CH2:12][NH:13][CH:14]([CH3:15])[CH3:16])=[CH:5][C:4]=1[Br:18]
Reactant: CC(C)NCC(=O)c1cc(Br)c(N)c(C#N)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)NCC(O)c1cc(Br)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 186°-189° C., was prepared from 4'-amino-3'-bromo-5'-cyano-2-isopropylamino-acetophenone and sodium borohydride analogous to Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[F:35])[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]([CH3:57])[CH3:56])(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[C:34]([F:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:40])[CH3:41]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2cc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3cc2F)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C(C)C)ccc1[C@@H](C)CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C(C)C)c(c1)CN(C)C(=O)[C@@H]2Nc1cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
A solution of 34A (170 mg, 0.206 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution, was added phosgene (20% in toluene, 0.112 mL, 0.226 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via syringe pump into a solution of TEA (0.287 mL, 2.058 mmol) in CH2Cl2 (260 mL). The solution was stirred for 16 h, and then concentrated and purified by flash chromatography to give a mixture of diastereoisomers (98 mg, 0.115 mmol, 55.9% yield). The diastereomers were separated by a prep chiral HPLC equipped with a OD column to give 34B (38 mg, 0.045 mmol, 38.8% yield). MS (ESI) m/z: 852.3 [M+1]+. 1H NMR (500 MHz, methanol-d4) δ ppm 8.10 (1H, d, J=5.8 Hz), 7.78 (1H, dd, J=7.8, 1.5 Hz), 7.55 (1H, d, J=5.8 Hz), 7.51 (1H, d, J=8.0 Hz), 7.41 (1H, d, J=12.1 Hz), 7.06 (1H, d, J=8.3 Hz), 7.04 (1H, d, J=1.7 Hz), 6.61 (1H, dd, J=12.0, 2.1 Hz), 6.27 (1H, d, J=1.1 Hz), 5.67-5.78 (2H, m), 4.63 (1H, t, J=11.0 Hz), 4.24 (1H, d, J=17.9 Hz), 3.98 (1H, dd, J=10.7, 4.4 Hz), 3.45-3.57 (2H, m), 3.34-3.41 (3H, m), 2.28 (3H, s), 1.38 (3H, d, J=6.9 Hz), 1.35 (3H, d, J=6.9 Hz), 1.33 (3H, d, J=6.9 Hz), 1.28 (18H, s).
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:13][Mg]Cl.Cl>CCOCC>[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:13][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Reactant: BrC1=Cc2ccccc2C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(CC1=Cc2ccccc2C1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-bromoindene (2.0 g, 10.2 mmol) and 460 mg of Pd(AcO)2 in 60 mL of ether was treated with 21 mL of 2-methyl-2-phenyl-propanyl magnesium chloride (0.5 M in ether; 10.2 mmol). The mixture was refluxed for one hour, cooled to room temperature and treated with 30 mL of aqueous hydrochloric acid (5 percent). The reaction was worked-up and the product purified (hexanes/silica) as for 2-benzyl-indene. Yield: 1.6 g (63 percent).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.[C:28]1(C)[CH:33]=CC=C[CH:29]=1.C([Sn](CCCC)(CCCC)CCCC)C=C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:33]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2)[CH:28]=[CH2:29]
Reactant: Cc1ccccc1
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: C=CCc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.00 g), toluene (10 ml), Pd(PPh3)4 (26.7 mg) and allyltributyltin (2.46 g) was boiled at reflux for 5 hours. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product was thus obtained with the molecular weight of 391.51 (C25H29NO3); MS (ESI): 392 (M+H+).
Reaction SMILES: C1C2C3C(C=C4C=2C=CC=C4)=CC=CC=3C=C1.[N+:18]([C:21]1[CH:22]=[CH:23][C:24]2C=CCC3=C4C(=C[C:34]=1[C:25]=23)C=CC=C4)([O-:20])=[O:19].C[C:39]1[CH:51]=[CH:50][C:42]2[S:43]C3C=CC=CC=3[C:41]=2[CH:40]=1>>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]2[S:43][C:42]3[CH:50]=[CH:51][CH:39]=[CH:40][C:41]=3[C:25]=2[CH:34]=1)([O-:20])=[O:19]
Reactant: Cc1ccc2sc3ccccc3c2c1
Reactant: O=[N+]([O-])c1ccc2c3c(c4ccccc4cc13)CC=C2
Agent: C1=Cc2cccc3cc4ccccc4c(c23)C1
Product: O=[N+]([O-])c1ccc2sc3ccccc3c2c1

Procedure:
For example, as a result of the nitration, the reaction between the 1H-benzo[de]anthracene of the asphaltene polycyclic core forms 6-nitro-1H-benzo[de]anthracene (19) and the nitration reaction with 2-methyldibenzo[b,d]thiophene yields 2-nitrodibenzo[b,d]thiophene (20).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1COCC1.C(#N)C>C(N(CC)CC)C>[C:20]([O:12][CH2:11][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:13])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC[C@@H](O)COCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O[C@@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
5 grams (27.44 mmol) of (R)-(+)-3-benzyloxy-1,2-propanediol and 10 grams (35.87 mmol) of triphenylchloromethane were added to 100 ml dry THF and 25 ml dry acetonitrile. 8 ml of dry triethylamine were added and the reaction mixture was refluxed for 17 hours. The reaction mixture was cooled to room temperature, poured on ice (100 grams), transferred to a separatory funnel and extracted thrice with 100 ml diethyl ether. The organic phase was washed consecutively with 100 ml water, twice with 100 ml dilute (1.5%) sulfuric acid, 100 ml water, 100 ml concentrated sodium bicarbonate solution, and again with 100 ml water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure, yielding 11 grams of 1-trityl-3-benzyl-sn-glycerol as a yellow oil. The yield was 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>CS(C)=O>[CH2:20]([NH:22][C:23]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[N:7]=1)=[O:24])[CH3:21]
Reactant: CCN=C=O
Reactant: COc1ccc2nc(N)sc2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2ccc(OC)cc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Methoxy-1,3-benzothiazol-2-amine (5.00 g, 27.74 mmol) was dissolved in anhydrous DMSO (20 mL) and triethylamine (15.50 mL, 110.97 mmol) followed by ethyl isocyanate (4.39 mL, 55.49 mmol). The mixture was stirred at rt under N2 for 4 h then quenched with water (˜200 mL) and stirred for 1 h. A white solid formed, was collected by filtration, rinsed with water then washed with acetone (100 mL) and the filtrate collected separately to the aqueous filtrate. The solid was partially soluble in acetone so the filtrate was concentrated to dryness under reduced pressure and combined with the solid collected by filtration to obtain the desired compound as a white solid, 6.27 g (90%). m/z: 251.96 [M+H]+.