Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(Br)c2n1C
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(-c3ccc(C#N)cc3)c2n1C
Temperature: 140 °C
Yield: 33.8 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (100 mg, 0.27 mmol), 4-cyanobenzeneboronic acid (51 mg, 0.35 mmol), Pd(PPh3)4 (31 mg, 0.03 mmol) and Cs2CO3 (175 mg, 0.54 mmol) in dioxane (3 mL) and H2O (1.5 mL) was heated for 30 min by microwave irradiation at 140° C. The reaction solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3 in MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was dissolved in DCM and the fine precipitate filtered and washed with DCM. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford 423 as a white solid (36 mg, 34%). LCMS (Method K): RT 2.30 min [M+H]+ 395. 1H NMR (DMSO-d6, 400 MHz): δ 8.04 (1H, s), 7.96-7.94 (2H, m), 7.72-7.67 (4H, m), 7.32 (2H, bs), 7.27, (1H, dd, J=8.0, 7.5 Hz), 7.07 (1H, dd, J=7.5, 1.0 Hz), 5.66 (1H, dq, J=7.0, 7.0 Hz), 3.28 (3H, s), 1.60 (3H, d, J=7.0 Hz)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[C:9]([O:12][CH:13]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:14][NH:15][C:16]([C:18]1[C:23]([I:24])=[C:22]([NH2:25])[C:21]([I:26])=[C:20]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:19]=1[I:41])=[O:17])(=[O:11])[CH3:10]>>[C:9]([O:12][CH:13]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:14][NH:15][C:16]([C:18]1[C:23]([I:24])=[C:22]([NH:25][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:21]([I:26])=[C:20]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:19]=1[I:41])=[O:17])(=[O:11])[CH3:10]
Reactant: O=C(Cl)CCCCCl
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)CCCCCl)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 1 h
Yield: 97 %

Procedure:
5-Chloropentanoyl chloride (5.1 g, 33 mmol) was added dropwise to a stirred solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (20.5 g, 23 mmol) in N,N'-dimethylacetamide (75 ml) at 0°-5°. The reaction mixture was stirred at 5° for 1 hour, and then at room temperature for 30 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (250 ml). The solution was washed with water (2×50 ml), followed by saturated aqueous NaCl (50 ml), and then dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[(5-chloro-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off-white fluffy solid (22.1 g, yield 97%, purity 98.5%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19].[N:22]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:21][O:20][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]3[CH2:24][CH2:23][N:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]3)[CH:10]=1)[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19]
Reactant: CCOC(=O)N1CCNCC1
Reactant: COc1cc(NCCCCCCCl)c2nccc(C)c2c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(CCCCCCNc2cc(OC)cc3c(C)ccnc23)CC1
Yield: 21 %

Procedure:
A mixture of 6.0 g (0.0195 mole) of N-(6-chlorohexyl)-6-methoxy-4-methyl-8-quinolinamine and 6 ml of 1-piperazinecarboxylic acid, ethyl ester in 2 ml of toluene was heated in an oil bath at 135° for 3 hr, allowed to cool, diluted with ethyl acetate and toluene, washed with water, dried, and concentrated to dryness in vacuo. The residue was chromatographed over 700 g of silica gel first with 2 l of ethyl acetate and then with 2 l each of the following solutions of methanol in ethyl acetate: 2%, 5%, 10%, and 20%. The eluant containing product, Rf (silica--ethyl acetate)=0.16, was concentrated to dryness. The residue was taken up in ether, filtered to remove dark flocculent material, and then treated with 1.2 ml of 85% phosphoric acid in 30 ml of ethanol. The gum which settled was washed with ether and acetone and then dissolved in 2-propanol and water. The pH of the solution was adjusted to 8 with ammonium hydroxide. The solution was then heated on the steambath, diluted with water to the cloud point and chilled to afford 1.7 g (21%) of the title compound, mp. 59°-60°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[S:23][CH:24]=[C:25]([C:27](OCC)=[O:28])[N:26]=2)=[C:9]1[C:32]([O:34][CH2:35][CH3:36])=[O:33].[OH-].[NH4+:38]>O1CCOCC1>[C:27]([C:25]1[N:26]=[C:22]([CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[S:23][CH:24]=1)(=[O:28])[NH2:38]
Reactant: [NH4+]
Reactant: CCOC(=O)C1=C(COCc2nc(C(=O)OCC)cs2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCc2nc(C(N)=O)cs2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A mixture of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-ethoxycarbonylthiazole (0.54 g), dioxane (20 ml) and 0.880 aqueous ammonium hydroxide solution (20 ml) was stirred at room temperature for 43 hours and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on silica (t.l.c. grade, 10 g) using dichloromethane plus 0-3% v/v methanol as eluant. Appropriate fractions were combined and evaporated and the residual oil triturated with diethyl ether. The resulting solid was collected, washed with diethyl ether and dried to give the title compound (0.30 g) as a monohydrate, m.p. 160°-164° C. decomp.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:40][CH2:39][CH2:38][N:37]([CH3:41])[CH2:36][CH2:35]2)=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15].C(O)(=O)C>C(O)C>[CH:26]1([NH:25][C:23](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][CH:32]=[C:31]([N:34]5[CH2:40][CH2:39][CH2:38][N:37]([CH3:41])[CH2:36][CH2:35]5)[CH:30]=4)[N:11]=[CH:1]3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCCN(C)CC2)ccc1N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.549 ml) was added to a stirred mixture of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methyl-1,4-diazepan-1-yl)benzamide (0.270 g) and glacial acetic acid (0.047 ml) in ethanol (5 ml). The mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was evaporated, dissolved in methylene chloride and washed with a saturated NaHCO3 solution. The organic phase was evaporated and the residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give the title compound (0.102 g); NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.67 (m, 2H), 1.91 (m, 2H), 2.11 (s, 3H), 2.24 (s, 3H), 2.44 (m, 2H), 2.64 (t, 2H), 2.84 (m, 1H), 3.52 (t, 2H), 3.60 (t, 2H), 7.22 (d, 1H), 7.36 (m, 1H), 7.50 (d, 1H), 7.58 (d, 1H), 7.78 (d, 1H), 7.87 (m, 1H), 7.96 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: C(C[CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])(OCC)=O.CNC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2C)[C@H](O)[C@@H]1O.ClC[C:52]([O:54][CH2:55][CH3:56])=[O:53].CCN(C(C)C)C(C)C>CN(C=O)C>[C:52]([CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])([O:54][CH2:55][CH3:56])=[O:53]
Reactant: CCOC(=O)CCl
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 13c was prepared by the same procedure as described for the preparation of 13a using 4a (415 mg, 1.41 mmol), ethyl chloroacetate (207 mg, 0.18 mL, 1.68 mmol), DIEA (91 mg, 0.12 mL, 0.70 mmol), and DMF (5 mL): yield 204 mg (38%), MS: m/z 381 (M+H)+; 1HNMR (DMSO-d6) δ 8.06 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.73 (d, 1H, H-1′, J1′,2′=5.4 Hz), 5.33 (bd, 1H, OH-2′, J2′-2′OH=4.7 Hz), 5.19 (bd, 1H, OH-3′, J3′-3′OH=4.9 Hz), 5.03 (ddd, 1H, H-2′, J1′,2′=5.4 Hz, J2′,3′=5.7 Hz, J2′-2′OH=4.7 Hz), 4.17 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.4 Hz, J3′-3′OH=4.9 Hz), 4.02 (q, 2H, OCH2CH3), 3.92-3.99 (m, 1H, H-4′), 3.27 (bs, 2H, N(CH3)—CH2), 2.83-2.90 (m, 1H, 5′-CH2), 2.70-2.79 (m, 1H, 5′-CH2), 2.53 (s, 3H, 8-CH3), 2.31 (s, 3H, N—CH3), 1.13 (t, 3H, OCH2CH3); UV λmax, nm, pH 1, 258.9 (∈ 16,100), pH 7, 260 (∈ 15,900), pH 13, 260.1 (∈ 16,200). Anal. (C16H24N6O5.0.5CHCl3.0.3CH3OH) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([C:20]([F:23])([F:22])[F:21])[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33](O)=[O:34])[CH:26]=[CH:25]1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33]([N:17]2[CH2:18][CH:19]([C:20]([F:21])([F:23])[F:22])[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:34])[CH:26]=[CH:25]1
Reactant: Fc1ccc(C2CCN(CC3CNCC3C(F)(F)F)CC2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1cccc2cc[nH]c12)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C(F)(F)F)C1

Procedure:
A solution of 0.12 g (0.36 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(trifluoromethyl)pyrrolidine, 0.069 g (0.43 mmol) of indole-7-carboxylic acid, 0.088 g (0.72 mmol) of DMAP and 0.097 g (0.5 mmol) of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (Aldrich) in 10 mL of CH2Cl2 was stirred at rt for 4 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:5) to give the title compound. 1H NMR (key peaks) (CDCl3) δ9.96 (s, 1H), 7.82 (d, 1H, J=8.0 Hz), 7.44 (d, 1H, J=7.5 Hz), 7.32 (t, 1H, J=3.0 Hz), 7.17-7.21 (m, 3H), 7.03 (t, t, 2H, J=8.5 Hz), 6.62-6.63 (m, 1H); Mass Spectrum (ESI) m/e=474 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH:1]1([CH2:7][C@@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(CC2CCCCC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1CC1CCCCC1
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
A solution of methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.5 g, 4.2 mmol) in MeOH (4 mL) was added to a solution of NaOH (221 mg, 5.5 mmol) in MeOH/H2O (4 mL/0.25 mL) at −30° C. After 10 minutes was added hydroxylamine-HCl (0.59 g, 8.5 mmol) and NaOH (0.339 g, 8.5 mmol) in MeOH (5 mL) and H2O (5 mL). Stirring was continued at −30° C. for 30 minutes. The reaction solution was poured into 6M HCl (6 mL) at 80° C. and heated for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through Celite® and the solvent was evaporated. Crude 1.7 g. Purification using reversed phase chromatography, which gave 0.3 g, yield 22%. Chiral separation using Chiralcel OJ, mobile phase heptane/ethanol 80/20 at 40° C. gave of (2R,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.11 g). 1H NMR (600 MHz, cdcl3) δ 0.91 (d, 2H), 1.06-1.39 (m, 5H), 1.68 (dt, 7H), 1.85 (s, 2H), 1.94 (s, 1H), 2.99 (t, 2H), 3.68 (s, 3H), 4.11 (d, 1H), 4.50 (d, 1H), 5.60 (s, 1H). [α]20D +3.2 (MeCN, c=1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C@H:5]([CH3:16])[CH2:4][N:3]1[C@H:17]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1.[CH3:38]I>>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C@H:5]([CH3:16])[CH2:4][N:3]1[C@H:17]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:38])[CH:19]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccccc3F)C[C@@H]2C)cc1
Reactant: CI
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccccc3F)C[C@@H]2C)cc1

Procedure:
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide was alkylated with methyl iodide by a procedure essentially identical to that of Example 29 to give 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide. Calc. for C32H40FN3O2.0.1 H2O: C, 73.99; H, 7.80; N, 8.09; F, 3.66. Found: C, 73.98; H, 7.86; N, 8.00; F, 3.77.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].Cl.[S:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)(=[O:13])(=[O:12])[NH2:11]>>[S:10]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][N:21]=[C:1]([C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)[CH3:2])=[CH:18][CH:19]=1)(=[O:13])(=[O:12])[NH2:11]
Reactant: CC(=O)c1cccs1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CC(=NNc1ccc(S(N)(=O)=O)cc1)c1cccs1

Procedure:
A solution of 2-acetylthiophene (5 mmol) and 4-sulfamylphenylhydrazine hydrochloride is subjected to the General Procedure. The title compound is isolated as described in the general procedure.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Cl:6].[O:7]=[C:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH:10]3[OH:18])[CH2:14]2.C(N(CC)CC)C>C1COCC1>[O:7]=[C:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH:10]3[O:18][CH2:2][O:3][CH2:4][CH2:5][Cl:6])[CH2:14]2
Reactant: O=C1C2CC3CC(C2)C(O)C1C3
Reactant: ClCCOCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C2CC3CC(C2)C(OCOCCCl)C1C3
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A two neck Kjeldahl flask of 50 ml into which a stirrer was put was charged with 1.55 g (12 mmol) of 2-chloroethyl chloromethyl ether obtained in Example 1 (1), 1.66 g (10 mmol) of 4-oxo-2-adamantanol, 1.52 g (15 mmol) of triethylamine and dried THF, and it was equipped with a coiled condenser to reflux and stir the solution for 8 hours. Triethylamine hydrochloride was filtered, and gas chromatographic analysis was carried out to find that 4-oxo-2-adamantanol was converted by 98.3 and that 2.56 g (9.8 mmol, isolation yield: 97.6%) of a colorless liquid which was the intended product was obtained at a selectivity of 99.3%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][NH:10][C:9](=S)[C:8]=2[CH:15]=1)([O-:3])=[O:2].CO[CH:18](OC)[CH2:19][NH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.[Hg](OC(C)=O)OC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][N:10]3[C:9](=[N:20][CH:19]=[CH:18]3)[C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: COC(CN)OC
Reactant: O=[N+]([O-])c1ccc2c(c1)C(=S)NCCC2
Agent: CC(=O)O[Hg]OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)-c1nccn1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
A solution of 8-nitro-2,3,4,5-tetrahydro-benzo[c]azepine-1-thione (2 g, 9 mmol) and 2,2-dimethoxy-ethylamine (4.7 g, 45 mmol, 5.0 eq.) in THF (100 mL) was treated with Hg(OAc)2 (4.3 g, 13.5 mmol, 1.5 eq.) at 5° C. The mixture was warmed to 25° C. and stirred for 2 hours, then concentrated. The residue was dissolved in toluene/water (11:1, 150 mL) and treated with p-toluenesulfonic acid (0.76 g, 4 mmol). This mixture was then heated at 65° C. for 24 h and subsequently concentrated under vacuum. The resulting residue was dissolved in methanol/HCl solution (2:1, 100 mL) and heated at 90° C. for 12 hours. Solvent evaporation and purification with silica gel chromatography (DCM/MeOH (9:1)) gave 9-nitro-5,6-dihydro-4H-1,3a-diaza-benzo[e]azulene (300 mg, 1.3 mmol, 15%). 1H NMR (300 MHz, CD3OD) δ 8.50 (d, 1H), 8.23 (dd, 1H), 7.61 (d, 1H), 7.32 (d, 1H), 7.12 (d, 1H), 4.05 (t, 2H), 2.85 (t, 2H), 2.42 (pent, 2H); MS (m/e) 230 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[O:6][C@@H:5]2[C:7]([CH2:13][O:14][C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:8][C@@H:9]([C@H:10]3[CH2:12][O:11]3)[C@@H:4]2[O:3]1.[NH3:35]>CO>[NH2:35][CH2:12][C@H:10]([C@H:9]1[C@H:4]2[C@H:5]([O:6][C:2]([CH3:34])([CH3:1])[O:3]2)[C:7]([CH2:13][O:14][C:15]([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)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8]1)[OH:11]
Reactant: CC1(C)O[C@H]2[C@H]([C@H]3CO3)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Reactant: N
Solvent: CO
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CN)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Temperature: 100 °C

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-4-((S)-oxiran-2-yl)-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (1-4) (2 g, 4.0 mmol, 1.0 equiv) was dissolved in a solution of ammonia in methanol (100 mL, 7 N). The mixture was heated in the microwave at 100° C. for 30 min. The reaction was concentrated to afford (S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (1-5) as an amber solid that was carried to the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.21-7.45 (m, 15H), 5.81 (2 s, 1H), 5.00 (t, 1H, J=5 Hz), 4.57-4.70 (2 d, 1H, J=5.5 Hz), 3.77 (d, 1H, J=14 Hz), 3.66 (d, 1H, J=14 Hz), 3.31 (m, 1H), 2.57-2.88 (m, 2H), 1.30 (s, 3H), 1.29 (s, 3H). LRMS m/z (M+H) 472.1 found, 472.2 required.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]1[O:14][CH2:13]1>CS(C)=O>[OH:14][CH:12]([CH2:11][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: NCCc1ccc(O)cc1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CS(C)=O
Product: Oc1ccc(CCNCC(O)COc2ccccc2)cc1
Yield: 50.1 %

Procedure:
A mixture of 4.0 g of tyramine and 5.25 g of phenyl glycidyl ether in 100 ml of dimethylsulfoxide was heated to 100° for 17 hours. The solvent was evaporated in vacuo and the residue was chromatographed on 400 g of silica gel. 4.3 g of p-[2-[bis[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenol was firstly eluted with chloroform/npropanol/concentrated ammonia (1000:10:1) as an amorphous substance, ε218 =20710. The further fractions yielded 4.2 g of pure (RS)-p-[2-[(2-hydroxy-3-phenoxypropyl) amino]ethyl]phenol of m.p. 122°-124°, ε221 =15310.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[N:13]=[C:12]2[C:23](=[O:37])[N:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[N:25]=[C:11]2[CH:10]=1.[F:38][C:39]([F:50])([F:49])[CH2:40]OS(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:40][C:39]([F:50])([F:49])[F:38])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[N:13]=[C:12]2[C:23](=[O:37])[N:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)[N:25]=[C:11]2[CH:10]=1
Reactant: CSc1ccc(-n2nc3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc-3cc2-c2ccc(O)cc2Cl)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(-n2nc3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc-3cc2-c2ccc(OCC(F)(F)F)cc2Cl)cc1
Yield: 28 %

Procedure:
A mixture of 0.45 g of the compound obtained in stage A of Example 18, 0.38 g of 2,2,2-trifluoroethyltrifluoromethanesulfonate and 0.28 g of NaHCO3 in 14 ml of EtOH is refluxed for 2 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, elution being carried out with a mixture of DCM/EtOAc (100/30; V/V). 0.145 g of the expected compound is obtained after crystallization from iso ether.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C2C3C(C=C4C=2C=CC=C4)=CC=CC=3C=C1.C1(C2C3C4=C(C=CCC4=C4C=2C=CC=C4)C=CC=3)C=CC=CC=1.C[C:49]1[CH:61]=[CH:60][C:52]2[S:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=3[C:51]=2[CH:50]=1>>[C:2]1([C:57]2[CH:58]=[CH:59][C:54]3[S:53][C:52]4[CH:60]=[CH:61][CH:49]=[CH:50][C:51]=4[C:55]=3[CH:56]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2sc3ccccc3c2c1
Reactant: Nc1ccccc1
Agent: C1=Cc2cccc3c(-c4ccccc4)c4ccccc4c(c23)C1
Agent: C1=Cc2cccc3cc4ccccc4c(c23)C1
Product: c1ccc(-c2ccc3sc4ccccc4c3c2)cc1

Procedure:
For example, the reaction of aniline with 1H-benzo[de]anthracene of the asphaltene polycyclic core forms the 7-phenyl-1H-benzo[de]anthracene compound as shown (15), and the reaction of aniline with 2-methyldibenzo[b,d]thiophene yields 2-phenyldibenzo[b,d]thiophene (16).