Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C(CC)C.CCCCCC.C1CCCCC1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1.[Si:30](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1.O>[CH3:18][O:19][C:20]1[C:29]([Si:30]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:28][C:27]2[C:22]([CH:21]=1)=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: COc1ccc2ccccc2c1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]C(C)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: O
Product: COc1cc2ccccc2cc1[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of 15.3 mL of sec-BuLi 1.3 M in hexane/cyclohexane (19.91 mmol) was added dropwise to a stirred solution of 3.0 g of 2-methoxynaphthalene (18.96 mmol) in 70 mL of tetrahydrofuran (THF) at a temperature of −30° C. and for a period of time of 15 min. After stirring overnight at room temperature, to the resultant tinted solution was added a solution of 5.87 g of Ph3SiCl (19.91 mmol) and 3.46 mL of hexamethylphosphoramide (HMPA) (19.88 mmol) in 50 mL of THF. The reaction mixture was heated at reflux for a period of time of 20 h, cooled and diluted with 500 mL of water. The organic part was extracted with 3 times 50 mL of Et2O. The combined organic extracts were dried over MgSO4, and evaporated. The crude residue was recrystallised from heptane and dried under vacuum to give 7.11 g of (3-methoxy-2-naphthyl)(triphenyl)silane (17.07 mmol) with a yield of 90%.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5]Br.[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][N:11]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(OCC)C.C1COCC1.O>[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([CH2:5][CH2:4][CH2:3][Si:2]([CH3:8])([CH3:7])[CH3:1])[N:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[Si](C)(C)CCCBr
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCCc1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
At −20° C. to a solution of Li (3 gram) in diethyl ether (150 ml) was slowly added 3-trimethylsilyl-propyl bromide (33.8 gram). Stirred for 30 min at −20° C. and 1 hour at 0° C. This solution was slowly added to a solution of 2,4 dichloro pyrimidine (19.3 gram) in diethyl ether (388 ml) at −30° C. stirred for 30 min at −30° C. and 30 mm at 0° C. to this solution was added glacial acid (11.1 ml), H2O (1.15 ml) in THF (34.7 ml) and DDQ (29.7 gram) in THF (127 ml). Reaction mixture was stirred for 30 min. At 0° C. NaOH (3 m, 50 ml) and Na2S2O3 (saturated solution, 200 ml) was added. The reaction mixture was stirred for 30 min and extracted two times with diethyl ether. The diethyl ether layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (heptane/ethyl acetate 4/1) provided 23.6 g of 2,4-dichloro-6-[3-(trimethylsilyl) propyl]pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:5]=[C:6](Br)[CH:7]=1.[Br-].[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:5]=[C:6]([C:15]#[N:16])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc(-n2ccnc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [C-]#N
Product: N#Cc1cc(F)cc(-n2ccnc2)c1
Temperature: 80 °C

Procedure:
A solution of 3-fluoro-5-bromo-(1H-imidazol-1-yl)-benzene in DMF (36 mL) was treated with zinc cyanide and tetrakis(triphenylphosphine)palladium(0). The reaction mixture was heated under an argon atmosphere for 18 h at 80° C. when GC-MS indicated complete disappearance of starting bromide and presence of product molecular ion (M+ 187). The reaction mixture was partitioned between ethyl acetate and water, filtered to remove insoluble material, and the layers obtained in the filtrate were separated. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. 3-Fluoro-5-cyano-(1H-imidazol-1-yl)-benzene was obtained as a colourless solid and used without further purification.
Reaction SMILES: CC1(C)CO[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[N:3]1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])#[N:3]
Reactant: COC(=O)c1cccc(-c2ccccc2C2=NC(C)(C)CO2)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2ccccc2C#N)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of methyl 3-[2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl]benzoate (1.25 g) in pyridine (5 ml) at 7° C. was added dropwise phosphoryl chloride (0.75 ml) keeping the reaction temperature below 20° C. The reaction mixture was stirred at 100° C. for 4 hours. After being cooled to room temperature, the mixture was quenched by water, and the emulsion was extracted with ethyl acetate (50 ml). The organic layer was successively washed with 6N-hydrochloric acid and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (25 g) with dichloromethane as an eluent. The fractions containing the object compound were combined and evaporated in vacuo. The crystalline residue was recrystallized from methanol to afford methyl 3-(2-cyanophenyl)benzoate (0.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][N:9]3[CH2:24][CH2:23][CH2:22][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][CH2:19][C:20]#[CH:21])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)(=[O:27])C>C([O-])(=O)C.[Hg+2].C([O-])(=O)C.O>[Cl:1][C:2]1[C:7]2[C:8](=[O:27])[N:9]3[CH2:24][CH2:23][CH2:22][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:20]([CH3:21])=[CH:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCCN1Cc1c(Cl)cccc1-2
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: O
Product: Cc1cnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)o1

Procedure:
3.5 g (10 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-N-(2-propynyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide, 30 mg of mercury (II) acetate and 20 ml of glacial acetic acid are heated to reflux for 5 hours. The solution obtained is then poured into water and extracted three times with methylene chloride. The combined organic phases are dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with methylene chloride and 10% methanol and there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-(5-methyl-2-oxazolyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 228°-230°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:4]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:10]#[C:9][C:5]2[CH:4]=[C:3]([CH2:2][N:23]3[CH2:29][CH2:28][CH2:27][N:26]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[C:10][C:11]5[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=5)[CH:4]=4)[CH2:25][CH2:24]3)[CH:8]=[CH:7][N:6]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C#Cc2cc(CCl)ccn2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(C#Cc2cc(CN3CCCN(Cc4ccnc(C#Cc5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-Trimethoxyphenylethynyl)-pyridine (230 mg) and homopiperazine (32 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][NH:8][C:9](=[O:31])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][C:15]=2[F:30])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Cl.Br[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:31])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:16][C:15]=2[F:30])[O:11][CH2:12][CH3:13])=[CH:32][CH:33]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccncc2)cc1F
Temperature: 85 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a stirred solution of (RS)-N-(4-cyano-benzyl)-2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-ethoxy-acetamide (300 mg) in 1,2-dimethoxyethane (8 ml) was added 4-bromopyridine hydrochloride (387 mg). A solution of sodium carbonate (210 mg) in water (2.1 ml) and dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (II) (48 mg) were added. The mixture was stirred at 85° C. for 4 h and at rt overnight. After cooling to rt, ice water was added. The mixture was filtered and the filtrate was extracted with EtOAc. The org. phase was washed with brine, dried, filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 2:1=>EtOAc) to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-pyridin-4-yl-phenyl)-2-ethoxy-acetamide (189 mg). Off-white solid. MS 408.2 ([M+H]+)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[NH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>C(Cl)(Cl)Cl.CO>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:39]1[CH:40]=[CH:41][CH:42]=[C:37]([NH-:36])[CH:38]=1
Reactant: Nc1cccnc1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [NH-]c1cccnc1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 200 mg (0.41 mmol) of borrelidin according to Example 3 188 mg (2 mmol) of 3-aminopyridin were added. After stirring for 3 hours, the starting borrelidin (Rf=0.43) disappeared and the product (Rf=0.25) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/methanol 95:5). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 100 ml of chloroform, washed with 3×30 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of dichloromethane and ethyl acetate of increasing ethyl acetate content. The fractions containing the product eluting with a 1:9 eluting mixture were combined and evaporated to dryness. The structure of the thus-obtained solidifying oily product (144 mg) was confirmed by spectroscopic (PMR, CMR, TS) data.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][CH2:11][O:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27](Br)[CH:26]=[CH:25][C:23]=3[N:24]=2)=[C:16]([F:30])[CH:15]=1.C[CH2:32][O:33][C:34](C)=[O:35]>CN(C=O)C.C1COCC1.CO>[O:8]1[CH2:13][CH2:12][CH2:11][O:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([C:34]([O:33][CH3:32])=[O:35])[CH:26]=[CH:25][C:23]=3[N:24]=2)=[C:16]([F:30])[CH:15]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Br)cc2s1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Temperature: 95 °C

Procedure:
Triethylamine (0.32 mL, 2.28 mmol), 1,3-(bis[diphenylphosphino]propane) dichloropalladium(II) (0.051 g, 0.076 mmol), and 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-bromobenzo[d]thiazole (0.75 g, 1.90 mmol) were mixed in DMF:THF:MeOH (2:7:2, 11 mL total volume) in a heavy-walled pressure tube. The tube was placed under CO atmosphere (20 psi) and then heated to 95° C. for 16 h. The mixture was cooled to RT and EtOAc (5 mL) was added. The suspension was filtered and the collected solid was washed with EtOAc. The solid obtained was then partitioned between DCM and water, the layers were separated, and the organic layer was dried (MgSO4) and concentrated under vacuum to give methyl 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)benzo[d]thiazole-6-carboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([OH:10])[N:3]=1.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH:16]=O>C(O)(=O)C.CCO>[F:11][C:12]([F:25])([F:26])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[CH:16]=[N:9][NH:8][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([OH:10])[N:5]=1
Reactant: NNc1nc(O)nc(Cl)n1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1nc(Cl)nc(NN=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a solution of 4-chloro-6-hydrazino-[1,3,5]triazin-2-ol (0.13 g, 0.0008 mol) and 3,5-bis(trifluoromethyl)benz aldehyde (0.39 g, 0.0016 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give red solid 0.21 g, in 72% yield, mp: 258.3° C. 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 8.97 (s, 1H), 8.54 (s, 1H), 7.59 (s, 1H), 7.30 (s, 2H). 13C NMR (DMSO-d6) δ 179.0, 160.2, 149.8, 148.8, 128.3, 127.6, 125.4, 124.7.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1.O.C(Cl)Cl.[NH4+].[OH-]>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH:14]=[CH:13]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3ccccc3Cl)c2O1
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC[C@H]1C=Cc2cc(F)cc(-c3ccccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-2-azidomethyl-8-(2-chloro-phenyl)-6-fluoro-chroman (210 mg, 0.67 mmol) in tetrahydrofuran (10 mL) and water (0.5 mL) was added triphenylphosphine (0.26 g, 10 mmol) and the reaction mixture stirred at room temperature for 24 hours. The solvent was removed under vacuum to form a colorless oil. Chromatography with 0–5% methanol in methylene chloride plus 1% NH4OH afforded {[(R)-8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl}amine as a colorless oil. The colorless oil was dissolved in ethyl acetate and made into its hydrochloride salt (56 mg, 25%) as a beige solid using excess ethereal hydrochloric acid, mp 145–147° C.; [α]D25=+256.01° (c=5.3 mg/0.7 mL MeOH).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O[C@@H:11]1[C@H:17]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH2:15][CH3:16])[C:13](=[O:31])[CH2:12]1)[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)(=O)C.O>CO>[CH3:16][CH2:15][C@:14]12[CH2:29][CH2:28][C@H:27]3[C@@H:18]([CH2:19][CH2:20][C:21]4[C@@H:26]3[CH2:25][CH2:24][C:23](=[O:30])[CH:22]=4)[C@@H:17]1[CH:11]=[CH:12][C:13]2=[O:31]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 40 °C
Yield: 68.7 %

Procedure:
Potassium carbonate (0.6 g, 4.4 mmol) was added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (3 g, 8.7 mmol) in methanol (27 ml) and the mixture was heated at 40° C. for 1 h. The mixture was allowed to cool to room temperature and water (100 ml) was then added. The precipitate was filtered, washed with water and dried under vacuum, to afford 18-methyl-estra-4,15-dien-3,17-dione (1.7 g, yield: 70%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[NH:21][N:20]=[C:19]([C:22](OCC)=[O:23])[N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[NH:21][N:20]=[C:19]([CH2:22][OH:23])[N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1n[nH]c(NCCCCOc2cccc(CN3CCCCC3)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1n[nH]c(NCCCCOc2cccc(CN3CCCCC3)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A mixture of ethyl 5-[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino-1H-1,2,4-triazole-3-carboxylate (0.3 g) and lithium aluminium hydride (0.1 g) in tetrahydrofuran (50 ml) was stirred at room temperature for 0.5 h, then quenched with water. The solid was filtered off and washed with methanol. The filtrate and washings were evaporated to leave a residue which was extracted with hot ethyl acetate. Evaporation of the extract gave an oil that solidified. It was crystallised from ethyl acetate to give the title compound as an off-white solid (0.094 g) m.p. 127°-8° dec. tlc System B, Rf 0.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)CCl.C(OCC)(=O)C>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)=[O:18]
Reactant: COc1cc(N)c2ncccc2c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2c(Cl)cccc2Cl)c2ncccc2c1
Yield: 68.2 %

Procedure:
A mixture of 8-amino-6-methoxyquinoline (121 mg), 2,6-dichlorobenzoyl chloride (175 mg) and triethylamine (91.4 mg) in ethylene chloride (3 ml) was refluxed for 3 hours. After cooling, the mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane, 1:2, v/v) to give 8-(2,6-dichlorobenzoylamino)-6-methoxyquinoline (164.5 mg).
Reaction SMILES: COC1C=CC(O)=C(C2OC3C=CC=C(CNCC4C=CC=CN=4)C=3N=2)C=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][N:35]([CH2:43][C:44]1[C:49]2[N:50]=[C:51]([C:53]3[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:54]=3[O:61]COC)[O:52][C:48]=2[CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][N:35]([CH2:43][C:44]1[C:49]2[N:50]=[C:51]([C:53]3[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:54]=3[OH:61])[O:52][C:48]=2[CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CN(Cc3ccccn3)Cc3ccccn3)cccc2o1
Agent: COc1ccc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)c1
Product: COc1ccc(O)c(-c2nc3c(CN(Cc4ccccn4)Cc4ccccn4)cccc3o2)c1

Procedure:
4-bis(2-pyridylmethyl)aminomethyl-2-(2-hydroxy-5-methoxyphenyl)benzoxazole (F25) was prepared in a similar manner for the preparation of 2-(5-methoxy-2-hydroxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F23) using 4-bis(2-pyridylmethyl)aminomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F17) (136 mg, 0.275 mmol) instead of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F16) in 98% (122 mg); 1H-NMR (500 MHz, CDCl3) δ3.87 (s, 3H), 3.89 (s, 4H), 4.12 (s, 2H), 7.06 (br s, 2H), 7.14 (dd, 1H, J=7.5, 4.0 Hz), 7.35 (t, 1H, J=8.0 Hz), 7.49-7.53 (m, 3H), 7.64-7.70 (m, 4H), 8.52 (d, 2H, J=4.0 Hz), 11.06 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:5]([C:14]([O:16]C)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(=O)O)sc(N3CCOCC3)c2C#N)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 4 methyl 4-cyano-3-(4-methylphenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.060 g, 0.18 mmol) in THF/MeOH/water (2/1/1) (3 mL) was added sodium hydroxide (0.072 g, 1.8 mmol). The reaction mixture was allowed to stir at 50° C. for 3 h and was concentrated. The residue was acidified with 2N HCl and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with diethyl ether and hexanes to give 4-cyano-3-(4-methylphenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (4) (0.055 g, 93%). LCMS: (FA) ES+ 329.0. 1H NMR (400 MHz, d6-DMSO) δ: 7.20-7.23 (m, 4H), 3.76-3.79 (m, 4H), 3.56-3.59 (m, 4H) and 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[N:15][CH:14]=1)(=[O:10])=[O:9].I[CH2:29][CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=2)=[N:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: CC(C)CI
Reactant: CS(=O)(=O)c1cccc(-c2ncc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1cnc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 10, step 3, 2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide (example 10, step 2) was reacted with 1-iodo-2-methylpropane and cesium carbonate in N,N-dimethylacetamide to give 2-chloro-N-isobutyl-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 499.0 ([M+H]+)
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH:11]([NH:13]C(=O)OC(C)(C)C)[CH3:12])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:22])([CH3:21])[O:3]1.[ClH:23].O>CO>[ClH:23].[NH2:13][CH:11]([C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:21])([CH3:22])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)[CH3:12]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc2c(c1)B(O)OC2(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(N)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethyl-carbamate (0.93 mmol) in MeOH (10 mL) was added 6N HCl (10 mL). The mixture was stirred at rt overnight. The mixture was poured into water and washed with EA (50 mL×2). The water layer was lyophilized to give crude 6-(1-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride. It was used in the next step without further purification.