Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (50.0 mg, 0.0894 mmol) and 4-methylmorpholine-N-oxide (15.7 mg, 0.134 mmol) in dichloromethane (1 ml) was stirred with powdered molecular sieve 4A at room temperature for 10 minutes. This was combined with tetra-n-butylammonium perruthenate (1.6 mg, 0.00447 mmol) and stirred at room temperature for 30 minutes. The reaction solution was filtered and then diluted with dichloromethane, and the organic layer was washed with saturated aqueous sodium bicarbonate solution, brine and saturated aqueous copper sulfate solution successively and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by preparative thin layer chromatography (0.5 mm×1, hexane:ethyl acetate=5:1, developed once) to give the title compound as a colorless solid (37.1 mg, 74%).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=4[F:37])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:45][CH3:46].O>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH2:45][CH3:46])[CH:33]=[CH:32][C:31]=4[F:37])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(O)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OCC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((6-(2-fluoro-5-hydroxyphenyl)-5-neopentylpyridin-3-yl)oxy)methyl)phenyl)propanoate (50 mg) in DMF (989 μL) were added cesium carbonate (97 mg) and iodoethane (12.0 μL) at 0° C., and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (49.8 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)OCc2ccccc2)s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCc1ccccc1)c1ccc(CBr)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a mixture of 5.27 g of benzyl 5-methylthiophene-2-carboxylate and 100 mL of carbon tetrachloride were added 4.18 g of N-bromosuccinimide (NBS) and 142 mg of azobisisobutyronitrile (AIBN), followed by stirring overnight at 80° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3), thereby obtaining 4.44 g of benzyl 5-(bromomethyl)thiophene-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[N:3][CH:4]=1
Reactant: O=C1CCOCC1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: OC1(c2ccc(Br)cn2)CCOCC1
Temperature: 25 °C
Yield: 33.3 %

Procedure:
A solution of 2,5-dibromopyridine (1 g, 4.22 mmol) in anhydrous toluene (15 mL) was cooled to −78° C. with stirring under nitrogen. n-Butyllithium (2.5M solution in hexanes, 1.7 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 1 h, then tetrahydro-4H-pyran-4-one (0.43 mL, 4.66 mmol) was added slowly. The reaction mixture was allowed to warm to ambient temperature, then stirred for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The resulting pale brown oil (983 mg) was purified by chromatography on silica (Biotage, 25 g cartridge), eluting with 0-60% ethyl acetate in heptanes. The resulting yellow solid (578 mg) was re-purified by chromatography on silica (Biotage, 10 g cartridge), eluting with 0-50% ethyl acetate in heptanes, to afford the title compound (363 mg, 32.3%) as a yellow solid. δH (500 MHz, DMSO-d6) 8.60 (d, J 2.2 Hz, 1H), 7.86 (dd, J 8.4, 2.3 Hz, 1H), 7.31 (d, J 8.4 Hz, 1H), 4.67 (s, 1H), 3.98 (td, J 11.7, 1.8 Hz, 2H), 3.94-3.89 (m, 2H), 2.11 (td, J 12.7, 5.5 Hz, 2H), 1.56 (d, J 12.2 Hz, 2H). Method B HPLC-MS: MH+ m/z 258/260, RT 1.44 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[CH2:36][C@H:35]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[CH2:36][C@H:35]([NH:40][C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.38 g, 1.2 mmol), HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL) and DIPEA (0.65 mL, 3.7 mmol) was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.435 g, 51%). LCMS calc. for C34H38BrN6O5[M+H]+: m/z=689.2. found: 689.3.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](F)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[OH-].[Na+].Cl>CN1CCCC1=O>[F:24][C:22]1[CH:21]=[CH:20][C:19]([C:25]2[C:26]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:32])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5F)ccc(F)c43)ccc21
Reactant: C1COCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5N5CCOCC5)ccc(F)c43)ccc21
Temperature: 180 °C
Reaction time: 48 h

Procedure:
A mixture of {(S)-6-[(R)-7-fluoro-4-(2-fluoro-pyridin-3-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.10 g), morpholine (0.10 g) and N-methyl-pyrrolidone (2 mL) is stirred at 180° C. for 48 h. After cooling to room temperature, 2 N aqueous NaOH solution (0.5 mL) is added, and the resulting mixture is stirred at 40° C. for 2 h. The mixture is neutralized with 1 N aqueous HCl solution and concentrated. The residue is chromatographed on reversed phase (HPLC; acetonitrile/water) to give the title compound. LC (method 7): tR=0.89 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[Si:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
to a stirred solution of 4-hydroxybenzaldehyde (25.0 g, 205 mmol) in dry DMF (200 mL) was added imidazole (28.0 g, 410 mmol) and TBDMS-Cl (32.4 g, 215 mmol) under an argon atmosphere. The resulting mixture was stirred for 4 h at room temperature (rt) then water was added and the mixture was extracted with ether (2×300 mL) and dichloromethane (2×300 mL). The combined organics were dried (MgSO4), filtered and concentrated under vacuum. The crude oil was purified by filtration through silica gel (eluting with hexane-EtOAc, 95:5) to give the product as a colourless oil (48.0 g, 99%).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:35]1[C@H:39]2[CH2:40][CH2:41][C@H:42]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C@H:38]2[CH2:37][NH:36]1>ClCCl>[CH3:13][CH:2]([CH3:1])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([N:36]1[CH2:37][C@@H:38]2[C@@H:42]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:41][CH2:40][C@@H:39]2[CH2:35]1)=[O:6]
Reactant: CC(C)C(C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C(C(=O)N1C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)[C@H]2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Methyl-2-phenylbutanoic acid (63 mg, 0.353 mmol), 1-hydroxybenzotriazole (54.1 mg, 0.353 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.063 mL, 0.353 mmol) were combined in dichloromethane (5 mL). The reaction was stirred at room temperature for 20 minutes, and then tert-butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate (80 mg, 0.353 mmol) from Step B was added. After 30 minutes, the reaction was quenched with water and extracted with dichloromethane. The combined extracts were concentrated, and the crude material purified using 10-100% ethyl acetate/hexanes to give tert-butyl(3aR,4S,6aS)-2-(3-methyl-2-phenylbutanoyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate: MS (ESI+) m/z 387 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C=O)C>[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:28][CH2:27]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: COC(=O)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1N1CCN(c2ncccn2)CC1

Procedure:
3.4 g of methyl chloronicotinate, 11.1 g of potassium carbonate and 4.7 g of N-(2-pyrimidyl)piperazine dihydrochloride were reacted in 75 ml of DMF analogously to Example 1a, 4.6 g (78%) of the product being obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][C@H:27]([OH:30])[CH2:28][OH:29]>>[OH:30][C@H:27]([CH2:28][OH:29])[CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NC[C@H](O)CO
Product: COc1ccc(C(=O)NC[C@H](O)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (S)-3-amino-1,2-propanediol (produced by Wako Pure Chemical Industries) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.S(=O)(=O)(O)O.[CH3:19]O>>[C:1]1([C:11]([O:13][CH3:19])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CO
Reactant: O=C(O)c1nccc2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1nccc2ccccc12
Temperature: 65 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of isoquinoline-1-carboxylic acid (10 g, 57.74 mmol) in MeOH (150 mL) was added concentrated sulfuric acid (15 mL) at 0° C. The mixture was warmed to 65° C. and stirred at 65° C. for 24 hours. After cooling to RT, the reaction mixture was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (11.2 g, 100%). ESI-MS m/z [M+H]+ 188.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)[CH:7]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1>CC(O)C.C(OCC)(=O)C>[N:13]1([CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: Brc1cncc(OCC2CO2)c1
Reactant: c1ccc2[nH]cnc2c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: OC(COc1cncc(Br)c1)Cn1cnc2ccccc21
Yield: 49.8 %

Procedure:
A solution of Example 436A (500 mg, 2.17 mmol) and 1H-Benzoimidazole (28 mg, 2.39 mmol) in 2-propanol (10 mL) was refluxed under N2 for 2 hrs. The reaction mixture was cooled, diluted with ethyl acetate(50 mL) and washed with brine (2×25 mL). The residue was concentrated and purified by flash column chromatography on silica gel eluting with 100% ethyl acetate to 5% methanol/ethyl acetate to provide the desire product (1.08 mmol, 50%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>ClCCCl.B(Br)(Br)Br>[CH2:15]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Oc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Reaction time: 3 h
Yield: 17.8 %

Procedure:
To a solution of 1-(4-methoxyphenyl)-4-phenethylpiperazine (165 mg) in 1,2-dichloroethane (1.5 mL), boron tribromide (132 μL) was added under cooling with ice. The temperature was raised to the ambient level, followed by 3 hours' stirring. The reaction mixture was poured in saturated saline solution, rendered weakly alkaline with saturated aqueous sodium hydrogencarbonate solution, and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. Distilling the solvent off, the crude product recovered was purified on TLC (developer, chloroform: methanol=15:1) to provide 4-(4-phenethylpiperazin-1-yl)phenol (28 mg).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([NH2:8])[CH:3]([CH2:4]2)[CH2:2]1.[OH-].[Na+].Cl[CH2:12][CH:13]([OH:19])[CH2:14][S:15]([OH:18])(=[O:17])=[O:16].[Na]>O1CCOCC1.O>[CH:3]12[CH2:4][CH:5]([CH2:1][CH2:2]1)[CH2:6][CH:7]2[NH:8][CH2:12][CH:13]([OH:19])[CH2:14][S:15]([OH:18])(=[O:17])=[O:16]
Reactant: O=S(=O)(O)CC(O)CCl
Reactant: NC1CC2CCC1C2
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(O)CC(O)CNC1CC2CCC1C2
Temperature: 80 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
To an 80° C. solution of exo-2-aminonorbornane (910 mg, 8.2 mmol) and sodium hydroxide (242 mg, 6.1 mmol) in 1,4-dioxane (4 mL) and water (4 mL) was added via syringe pump (1 hour addition) a solution of 3-chloro-2-hydroxy-propane sulfonic acid, sodium salt (1.09 g, 5.5 mmol) in 1,4-dioxane (0.5 mL) and water (5.5 mL). The solution was stirred at 80° C. for an additional 5 hours. The reaction was cooled to room temperature. The solvent was evaporated under reduced pressure. The solid was suspended in EtOH (25 mL). The mixture was heated to reflux for 1 minute. The solid was recovered by filtration and it was passed through an ion exchange column (Dowex 50×8, 100 g, solvent: water). The product was recrystallized in EtOH/water (99/1). Yield: 17%. 1H NMR (D2O, 500 MHz) δ ppm 4.25 (m, 1H), 3.25 (m, 2H), 3.01 (m, 4H), 2.39 (m, 1H), 2.27 (m, 1H), 1.69 (m, 1H), 1.51 (m, 1H), 1.38 (m, 3H), 1.19 (m, 1H), 1.07 (m, 2H). 13C (D2O, 125 MHz) δ ppm 63.66, 63.50, 62.21, 61.98, 54.94, 50.11, 50.04, 39.26, 39.21, 36.02, 35.97, 35.91, 35.80, 34.70, 34.61, 27.11, 27.08, 26.50, 26.45. ES-MS 250 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14](Cl)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CN(C=O)C>[Cl:1][C:2]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([NH:26][CH:23]2[CH2:25][CH2:24]2)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1
Reactant: Fc1ccc2nn3c(Cl)c(-c4ccccc4)c(Cl)nc3c2c1
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: Fc1ccc2nn3c(NC4CC4)c(-c4ccccc4)c(Cl)nc3c2c1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
1 g (7.5 mmol) 2,4-Dichloro-9-fluoro-3-phenylpyrimido[1,2-b]indazole (intermediate example Int-1-0, step 2) and 430 mg (8.4 mmol) cyclopropylamine were dissolved in 8.4 mL DMF and heated in the microwave for 20′ at 100° C. The solvent was evaporated and the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) to yield 560 mg (52.7%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].N#N>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a solution of 5.0 g (1.0 eq, 28.6 mmol) 5,7-dimethyl-2ethylimidazo[4,5-b]pyridine in 30 mL DMF under N2 at rt was added 1.37 g (1.2 eq, 34.3 mmol) of a 60% oil dispersion of NaH. After stirring for 5 minutes, 8.64 g (1.4 eq, 40.0 mmol) of p-nitrobenzyl bromide was added. The dark brown mixture was stirred for 2 hours under a blanket of N2 at rt. The mixture was diluted with 1 L CH2Cl2 and washed with 500 mL H2O and 500 mL saturated aqueous NaCl. The organic phase was dried is over MgSO4 and concentrated to a yellow oil. The oil was flash chromatographed with 50% ethyl acetate/hexane. The product-containing fractions were combined and concentrated to a yellow oil which crystallized on standing, yielding 6.81 g (76.8%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C([O:16][C:17](=O)[NH:18][C:19]1[S:23][C:22]2[C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:21]=2[CH:20]=1)C1C=CC=CC=1>>[CH3:29][O:28][C:27]1[C:21]2[CH:20]=[C:19]([NH:18][C:17]([N:6]3[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]3)=[O:16])[S:23][C:22]=2[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Reactant: COC1CCNCC1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCC(OC)CC3)cc12

Procedure:
The title compound MS: m/e 395.3 (M−H) was obtained as a light brown solid (54% yield) by the reaction of 4-methoxy-piperidine with (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester according to the method described above for example 1.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][C:55]([O:58][Si](C(C)(C)C)(C)C)=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:53]=[CH:54][C:55]([OH:58])=[CH:56][CH:57]=3)[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc(O)cc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Yield: 68.4 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4"'-tert-butyldimethylsilyloxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (42.5 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 3H at 0° C. and then 3H at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) affording 25.7 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4"'-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis were consistent with the desired structure).