Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[C:4]([CH3:18])[CH:3]=1.[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[C:4]([CH3:18])[CH:3]=1)=[O:25]
Reactant: O=C(Cl)CCCCCl
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2C)cc1
Product: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCCl)cc2C)cc1

Procedure:
Similar procedure to Description 3 from D2 and 5-chlorovaleryl chloride.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1.O>CN(C)C=O>[Si:25]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate (Tetrahedron, 28, 4395, 1972) (10.0 g) in dimethylformamide (75 ml) was added t-butyldimethylsilyl chloride (4.97 g) and imidazole (2.24 g). The mixture was heated at 50° C. for 1 hour, then left at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The extract was washed twice with water, dried over magnesium sulfate and evaporated under vacuum to give methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate as a beige solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:40]=[CH:39][CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][CH:39]=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2Cl)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2Cl)CN1C(=O)Cn1cncn1
Yield: 55 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 57, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (71 mg, 55%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.03 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.59-7.52 (m, 2H), 7.49-7.15 (m, 6H), 7.05-6.90 (m, 4H), 5.25 (q, 2H), 4.60-4.49 (m, 1H), 3.92-3.79 (m, 1H), 2.97-2.73 (m, 3H), 2.30-1.88 (m, 2H). MS (EI) for C28H25FN5O3. found 533.9 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[N-:11]=[N+:12]=[N-:13].[Na+].CCOC(C)=O.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:11]([CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)=[N+:12]=[N-:13]
Reactant: BrCCOC1CCCCO1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2-bromo-ethoxy)-tetrahydro-pyran (1.00 mL, 6.62 mmol), NaN3 (4.34 g, 66 mmol) and tetrabutylammonium iodide (245 mg, 0.66 mmol) in DMF (7.0 mL) was stirred at RT for 18 h. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 20:80 as the eluent to afford the title compound as colourless oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH3:56])([CH3:55])[C@H:16]3[C@:29]([CH3:32])([CH2:30][CH:31]=2)[C@@H:28]2[C@:19]([CH3:54])([C@@:20]4([CH3:53])[C@H:25]([CH2:26][CH2:27]2)[C@H:24]2[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]2([CH2:39][N:40]([CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:44]([CH2:43][CH2:42][C:41]([N:40]([CH2:39][C@:23]12[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:24]1[C@@H:25]1[C@@:20]([CH3:53])([CH2:21][CH2:22]2)[C@@:19]2([CH3:54])[C@@H:28]([C@:29]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:56])([CH3:55])[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:13][CH:12]=2)=[CH:31][CH2:30]3)[CH2:27][CH2:26]1)[CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])=[O:47])([OH:46])=[O:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 57.4 %

Procedure:
To a solution of 4-((((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(tert-butoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl)(2-(dimethylamino)ethyl)amino)-4-oxobutanoic acid (47 mg, 0.061 mmol) in DCM (1 ml) was added TFA (0.25 ml, 3.24 mmol). The mixture was stirred at rt. After 1.75 h, The mixture was concentrated under reduced pressure, was diluted with dioxane and MeOH and was purified by prep HPLC to afford 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-carboxy-N-(2-(dimethylamino)ethyl)propanamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid as a white solid (25 mg, 0.035 mmol, 57.4% yield. LCMS: m/e 715.4 (M+H)+, 2.16 min (method 6).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](OC)=[O:27])=[CH:20][CH:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[OH:27][CH2:26]/[CH:25]=[CH:24]/[C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(/C=C/CO)cc1)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A THF solution of LiAlH4 (6.75 mL of a 1.0 M solution, 6.75 mmol) was added to a cooled (−78° C.) solution of methyl (2E)-3-(4-{[(benzyloxy)carbonyl]amino}phenyl)acrylate (2.1 g, 6.75 mmol) in TBF (34 mL). The solution was allowed to warm slowly to −20° C. and maintained at that temperature for 2 hours. The reaction mixture was quenched by slow addition of saturated NH4Cl and then treated with dilute citric acid. The resulting solution was stirred for 15 minutes and then extracted with three portions of ethyl acetate. The combined organic phases were washed with H2O, brine and dried (MgSO4), filtered and concentrated to give an oil. The crude product was purified by column chromatography (20-50% ethyl acetate-hexane) to provide the title compound as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[CH3:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1)[CH2:27][O:26][CH3:25]
Reactant: COCCBr
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Yield: 71.1 %

Procedure:
3 g (8.66 mmol) of 1,4,7-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecane is stirred in 50 ml of dimethylformamide for 10 hours with 1.57 g (11.29 mmol) of 2-methoxyethyl bromide and 4.15 g of potassium carbonate at 90° C. It is concentrated by evaporation in a vacuum and the residue is spread between 100 ml of water and 50 ml of diethyl ether. The aqueous phase is adjusted to pH 2 with 5 N hydrochloric acid and evaporated to dryness. The residue is refluxed with 200 ml of methanol, the undissolved material is filtered out, it is evaporated to dryness in a vacuum, the residue is dissolved in 50 ml of water, adjusted to pH 2 with 5 N hydrochloric acid and the solution is put on a column with 200 ml of cation exchanger IRC 50. It is eluted first with 0.5 l of water, which is discarded. Then, it is eluted with 0.5 l of 0.5 N ammonia solution. It is evaporated almost to dryness in a vacuum, mixed with 100 ml of water and enough cation exchanger IRC 50 is added with stirring until pH 3.5 is reached. The solution is then filtered and freeze-dried. 2.49 g of the title compound with a water content of 4.30% is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:47]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:47][CH2:50][NH:51][C:52](=[O:54])[CH2:53]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cncc(Cl)c3)n2)CCN1

Procedure:
75 mg (0.16 mmol) of the compound of Example 43A is reacted analogously to the synthesis of the compound of Example 1 with 18 mg (0.18 mmol) of 2-oxopiperazine. 76 mg (86% of theory) of the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24](OCC)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Br:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35]>C(O)C>[Br:18][C:6]1[CH:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:32]=3)=[O:25])[O:21][N:20]=2)[CH:3]=[C:2]([Br:1])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(OCc3ccc(OC)cc3)c(Br)c2)no1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: COc1ccc(COc2c(Br)cc(-c3noc(C(=O)NCc4cccc(C(F)(F)F)c4)n3)cc2Br)cc1
Yield: 9.7 %

Procedure:
Ethyl 3-(3,5-dibromo-4-(4-methoxybenzyloxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (2.6 g, 50 mmol) was heated at reflux with 3-(trifluoromethyl)benzylamine (1.75 g, 100 mmol) in ethanol (30 mL) for 7 h. The mixture was cooled and filtered. The solid was washed with cold ethanol and dried to give the title compound (3.1 g) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 3.81 (3H, s), 4.62 (2H, d), 5.04 (2H, s), 6.99 (2H, d), 7.51 (2H, d), 7.61-7.73 (3H, m), 7.79 (1H, s), 8.31 (2H, s), 10.11 (1H, t).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)(=[O:19])=[O:18])[C:3]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].O.[NH2:37][NH2:38].O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH:37][NH2:38])=[NH:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)(=[O:19])=[O:18])[C:3]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: NN
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)c1ccc(C)cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C(=N)NN)c2)nc1NS(=O)(=O)c1ccc(C)cn1
Temperature: 20 °C
Reaction time: 17.5 h
Yield: 102.9 %

Procedure:
20 g (39 mmol) of 5-methyl-pyridine-2-sulfonic acid [6-chloro-2-(2-cyano-pyridine-4-yl)-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide were suspended in 100 ml of N,N-dimethyl formamide and 7.6 ml (156 mmol) of hydrazine hydrate were added within 15 min. The reaction mixture was allowed to warm up slowly to 20° C. After 17.5 hr, at a temperature of 15° C., 250 ml of de-ionized water were added followed by slow addition of 10.5 ml acetic acid (until pH=5.4). The resulting suspension was stirred for 2 hr at 20° C. and then for additional 2 hr 0° C. The solid was filtered off under suction, firstly washed with 200 ml of de-ionized water and thereafter with 100 ml of t-butylmethylether. The residue was dried at 40° C., 2000 Pa for 18 hr. There were obtained 21.7 g (102% of theory) of 5-methyl-pyridine-2-sulfonic acid [6-chloro-2-[2-(hydrazino-imino-methyl)-pyridine-4-yl]-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide with a HPLC purity of 81.4% (w/w).
Reaction SMILES: [N:1]([CH:4]([CH3:21])[CH2:5][N:6]1[C:14]2[C:13]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:12]2[CH2:11][CH2:10][C:9]3[CH:8]=[N:7][N:6]([CH2:5][CH:4]([NH2:1])[CH3:21])[C:14]=3[C:13]=2[CH:15]=1
Reactant: COc1ccc2c(c1)-c1c(cnn1CC(C)N=[N+]=[N-])CC2
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: COc1ccc2c(c1)-c1c(cnn1CC(C)N)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
1 g (3.5 mmol) of (RS)-1-(2-azido-propyl)-4,5-dihydro-8-methoxy-1H-benz[g]indazole dissolved in 50 ml of anhydrous ethanol was hydrogenated over 100 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 70 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 406 mg (3.5 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 0.98 g (75%) of (RS)-2-(4,5-dihydro-8-methoxy-1H-benz[g]indazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 174°-176° was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:8]2[CH:9]3[CH2:12][CH2:13][CH:7]2[C:6]([CH3:14])([C:10]3=[CH2:11])[CH2:5][CH2:4][CH2:3]1.C(O)(=[O:18])C>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:11])[CH:12]2[C:3]3([CH2:14][CH:6]1[CH2:5][CH2:4]3)[C:2]([CH3:15])([CH3:1])[CH2:8][CH2:7][C:13]2=[O:18]
Reactant: CC(=O)O
Reactant: C=C1C2CCC3C2C(C)(C)CCCC13C
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC3(C2)C1C(=O)CCC3(C)C

Procedure:
In a 2 L four-necked flask, 500 g of longifolene (manufactured by Yasuhara Chemical Co., Ltd.) and 250 mL of acetic acid were placed, to which 250 mL of boron trifluoride-diethyl etherate was added dropwise at 20° C. over 4 hours with stirring to carry out the isomerization. The reaction mixture was washed with ice water, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and then refined by distillation. Thereafter, the refined product was mixed to 1,800 mL of methylene chloride and 900 mL of 0.5 N aqueous sodium hydrogen carbonate solution, to which 400 g of 3-chloroperbenzoic acid was slowly added at a temperature of 10° C. or less. After completion of the reaction, the reaction mixture was washed with 1 N aqueous sodium hydroxide solution and with water and concentrated in vacuo. The thus obtained crude product was dissolved in 3 L of toluene, to which 260 mL of boron trifluoride-diethyl etherate was slowly added dropwise at 5° C. or less. After completion of the reaction, the reaction mixture was washed with water and then refined by distillation to obtain 270 g of 1,1,5,5-tetramethyl-hexahydro-2,4a-methano-naphthalene-8-one. This was added dropwise at 5° C. or less to 640 mL of 2.1 N diethyl ether solution of methyllithium to carry out the alkylation. After completion of the reaction, the reaction mixture was washed with saturated aqueous ammonium chloride solution and with water and, then, charged in a 1 L autoclave together with 30 g of a nickel/diatomaceous earth hydrogenation catalyst (N-113, manufactured by Nikki Chemical Co., Ltd.) and was hydrogenated (hydrogen pressure: 6 MPa, reaction temperature: 250° C., reaction time: 6 hours).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH:37]=[C:36]1[C:44](O)=[O:45].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH:37]=[C:36]1[C:44]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:45]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)c2cc3ccccc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A mixture of 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (100 mg, 0.22 mmol), 2-benzofurancarboxylic acid (36 mg, 0.22 mmol) and triethylamine (66 mg, 0.66 mmol) in dimethylformamide (0.75 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and the resulting precipitate was collected, washed with water and dried. The precipitate was purified by chromatography on silica gel eluting with 1:20 methanol:dichloromethane to give 1-((1R,5S)-8-{2-[1-(1-benzofuran-2-ylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a clear oil (0.075 g, 60%). 1H NMR (400 MHz, CDCl3) δ 7.66 (m, 2H), 7.52 (m, 1H), 7.26-7.44 (m, 9H), 7.16 (m, 2H), 4.61 (m, 1H), 4.16 (m, 2H), 3.40-3.57 (m, 2H), 3.26 (m, 1H), 2.57 (m, 3H), 2.34 (m, 4H), 1.94 (m, 9H), 1.62 (m, 4H). HRMS C37H40N4O2 m/z 573.3229 (M+H)Cal., 573.3238 (M+H)Obs..
Reaction SMILES: [NH2:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[N:15][C:16]=3[NH2:18])[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[N:10]=2)=[CH:5][CH:4]=1.[C:38]([O:41][C:42](=[O:44])[CH3:43])(=[O:40])[CH3:39]>N1C=CC=CC=1>[C:38]([OH:41])(=[O:40])[CH3:39].[C:38]([OH:41])(=[O:40])[CH3:39].[NH2:18][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:1][C:42](=[O:44])[CH3:43])=[CH:4][CH:5]=3)[C:17]=12
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: c1ccncc1
Product: CC(=O)NC(c1ccccc1)c1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1
Product: CC(=O)O
Temperature: 25 °C

Procedure:
Cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.0001 mol) was dissolved in anhydrous pyridine (1 mL), acetic anhydride (0.010 g, 0.0001 mol) was added and the resulting solution was stirred at ambient temperature for twenty hours. The solvent was removed under reduced pressure and the resulting residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile—0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-N1-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]acetamide diacetate (0.015 g, 0.000021 mol) as a white solid.
Reaction SMILES: C(OC([N:8]=[C:9]([N:16](C(OC(C)(C)C)=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=O)(C)(C)C.Cl>CCO>[NH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]([NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(NCCCCN)N(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: N=C(NCCCCN)NCc1ccc(F)cc1
Reaction time: 4 h
Yield: 74.2 %

Procedure:
The product was prepared starting from 4-[N2,N3-bis(ter-butoxycarbonyl)-N3-(4-fluorobenzyl)-guanidino]-1-aminobutane (116 mg, 0.26 mmol) solubilised in EtOH (1.5 ml). Every 2 hours 1 ml of HCl 12 N was added; after 4 hours, the solution was left for 15 min at room temperature, and then brought to T=55° C. and kept at that temperature for 6 hours. The solution was concentrated at reduced pressure and the residual aqueous phase was washed with CH2Cl2 and AcOEt. The aqueous phase was concentrated to dryness in vacuo, giving 46 mg of product as a yellow oil (yield: 57%). 1H-NMR (CD3OD) δ 7.31-7.24 (2H, m), 7.03-7.12 (2H, m), 4.34 (2H, s), 3.26 (2H, t), 3.17 (2H, t), 1.58-1.53 (2H, m).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH:16]1([NH:19][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[CH2:18][CH2:17]1
Reactant: Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1nc2cc(C(F)(F)F)cc(NC3CC3)n2n1
Yield: 51.1 %

Procedure:
A suspension of 5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7), 3.60 g; 15.22 mmol; 1.0 eq.), cyclopropylamine (5.27 mL; 76.1 mmol; 5.0 eq.), and N-ethyldiisopropylamine (26.22 mL; 152.2 mmol; 10.0 eq.) was heated at 80° C. in 1-butanol (36.0 mL) for 23 h., then 15 h. at 100° C. The reaction mixture was then concentrated under vacuum till dryness. Diethyl ether was added and the solid was filtered, washed with water and dried. The product was then purified by chromatography on silicagel (from 5% to 95% EtOAc in c-Hex), to give the title compound as a white solid (2.0 g; 51.1%). HPLC, Rt: 2.54 min. (purity 100%). LC/MS, M+(ESI): 258.0, M−(ESI): 256.0.