Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25](OC)=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[C:31]2[CH:38]=[N:37][N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[C:32]=2[N:33]=[CH:34][N:35]=1)[C:25]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:26])([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
A solution of trimethylaluminium (2M in hexane) (0.491 mL, 0.98 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (92 mg, 0.85 mmol) in toluene (5 mL) cooled to 0° C., over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 5-(tert-butyldimethylsilyloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pentanoate (Intermediate O2) (420 mg, 0.85 mmol) in toluene (5 mL) was added dropwise over a period of 2 minutes. The resulting solution was stirred at 0° C. for 10 minutes allowed to warm to ambient temperature and then heated at 60° C. for 20 hours. The mixture was cooled and 1M citric acid (10 mL) added with vigorous stirring. The mixture was diluted with ethyl acetate (35 mL), washed with water (10 mL) and brine (10 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to give the product (180 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 0.04 (3H, s), 0.05 (3H, s), 0.89 (9H, s), 1.78-1.81 (2H, m), 2.20-2.30 (2H, m), 2.29 (3H, s), 3.71 (2H, t), 5.90-5.93 (1H, m), 7.45 (1H, dd), 7.51 (1H, dd), 7.99 (1H, dd), 8.07-8.08 (1H, m), 8.14 (1H, d), 8.42 (1H, s), 8.53 (1H, s), 8.60 (1H, dd), 8.62 (1H, s); m/z (ESI+) (M+H)+=568; HPLC tR=3.33 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH3:11][NH:12][CH2:13][CH:14]=[O:15]>C1C=CC=CC=1>[CH3:11][N:12]([CH2:13][CH:14]=[O:15])[C:9]([NH:8][C:6]1[S:7][C:3]([CH2:2][Cl:1])=[N:4][N:5]=1)=[O:10]
Reactant: O=C=Nc1nnc(CCl)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(CCl)s1

Procedure:
A mixture of 5-chloromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer (9.5 grams), the dimethyl acetal of 2-methylaminoacetaldehyde (5.8 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This product is recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-chloromethyl-1,3,4-thiadiazol-2-yl)ureido]-acetaldehyde.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:13]([N:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: OCCNc1ccccc1
Product: C=CCN(CCO)c1ccccc1

Procedure:
2-anilinoethanol (13.7 g, 0. 10 mol) is treated with allyl bromide (18.15 g, 0.15 mol), in the manner as set forth in Example 3, to provide N-allyl-N-(2-hydroxyethyl)benzenamine.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][CH3:20])=[C:10]([C:14](OC)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:24]([NH:31]C=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:21]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][CH3:20])=[C:10]([C:14]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:22][CH3:23]
Reactant: O=CNCc1ccccc1
Reactant: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)OC)cc2C1
Product: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)NCc3ccccc3)cc2C1

Procedure:
Using procedure 41, methyl 2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxylate (77, 0.32 g, 1 mmol) was treated with N-benzylformamide (1.35 g, 10 mmol). Chromatographic purification yielded pure product 84 as a oil which was converted into the HCl salt and crystallized from EtOAc to give a white solid (m.p. 219-221° C.).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[C:13]([O:17][C@H:18]([CH3:31])[C@H:19]([NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([Cl:30])[N:24]=1)CO)([CH3:16])([CH3:15])[CH3:14].N1C(C)=CC=CC=1C>C(Cl)Cl.[Cl-].[Na+]>[C:13]([O:17][C@@H:18]([C@H:19]1[CH2:7][O:6][C:5](=[O:11])[N:22]1[C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([Cl:30])[N:24]=1)[CH3:31])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)nc(Cl)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)nc(Cl)n1
Temperature: 25 °C
Yield: 151.4 %

Procedure:
Triphosgene (35 mg, 0.12 mmol, 0.4 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, 0.30 mmol) in DCM (3 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.14 mL, 1.2 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 5 hours. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one (0.057 g, white solid) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 4.73 (ddd, J=8.6, 4.1, 3.0 Hz, 1H), 4.65 (dd, J=9.4, 2.9 Hz, 1H), 4.48 (m, 1H), 4.41 (m, 1H), 2.52 (s, 3H), 1.26 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z 314.1 (M+H)+; Rt-1.02 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:21]3[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1>>[F:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[CH:13]([NH:12][C:7]1[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)[CH:3]=3)[N:8]=1)[CH2:14][CH2:15]2
Reactant: Fc1ccc2c(c1)CCC2Nc1ccc2cc(Br)ccc2n1
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(Nc2ccc3nc(NC4CCc5cc(F)ccc54)ccc3c2)n1

Procedure:
The title compound, yellow foam, MS: m/e=385.3 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(5-fluoro-indan-1-yl)-amine (see example 102, step A) and commercially available 2-amino-6-methyl-pyridine.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:4]1)=[O:2].[CH3:41][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:4]1)[CH3:41]
Reactant: C[Mg]Br
Reactant: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Reaction time: 3 h

Procedure:
tert-Butyl(3R,5S)-3-formyl-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (360 mg) was dissolved in THF (4 ml), a solution (1M, 1.95 ml) of methyl magnesium bromide in THF was added under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (325 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][S:17](=[NH:20])[CH2:16][CH2:15]3)=[C:10]([F:21])[CH:9]=2)[CH:7]=1.[C:22](=O)(O)[O-:23].[Na+].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:22][O:23][C:27](=[S:28])[NH:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:15][CH2:16][S:17](=[NH:20])[CH2:18][CH2:19]3)=[C:10]([F:21])[CH:9]=2)[CH:7]=1
Reactant: O=C([O-])O
Reactant: S=C(Cl)Cl
Reactant: N=S1CCN(c2ccc(-n3cc(CN)nn3)cc2F)CC1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=S)NCc1cn(-c2ccc(N3CCS(=N)CC3)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To an ice-cooled solution of the 4-[4-(4-aminomethyl-[1,2,3]triazol-1-yl)-2-fluoro-phenyl]-1-imino-1lambda*4*-thiomorpholine (100 mg, 0.3 mmol), obtained in Example 32 in CHCl3 (10 ml) was added sat. sodium bicarbonate solution followed by thiophosgene (36 μl, 0.33 mmol). The reaction mixture was stirred at room temperature for 0.5 h and then diluted with ethyl acetate (30 ml). The organic portion was washed with water followed by brine and dried over sodium sulfate. Evaporation of volatiles left a residue, which was refluxed with methanol (20 ml) for 20 h. Removal of volatiles and purification of the resulting residue by silica gel column chromatography (CHCl3/MeOH, 1:4) yielded the title compound as white solid (70 mg, 71%). Mp. 198° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH2:42]([N:44](CC)[CH2:45][CH2:46]N)[CH3:43].NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:42]([N:44]([CH2:45][CH3:46])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:29]=[N:30]1)[CH3:43]
Reactant: CCN(CC)CCN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCO
Product: CCN(CC)CCNCCn1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Yield: 42 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting N,N-diethyl-1,2-ethanediamine (50 mg, 0.43 mmol) for the 2-aminoethanol to afford 12 mg of the title compound (42%).
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O.I[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1>CCOC(C)=O.[Cu]I>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=2)[N:3]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: Brc1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Temperature: 100 °C
Yield: 72.6 %

Procedure:
To a 250 mL reaction flask was added 3-bromo-1H-1,2,4-triazole (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol) and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with nitrogen gas, and then DMSO (33.8 ml) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 20 hours (h). The reaction wascooled to room temperature (RT), diluted with EtOAc and filtered through a plug of Celite®. The Celite® was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash column chromatography using EtOAc/hexanes as eluent provided the title compound as an off-white solid (3.78 g, 73%): mp 69-70° C.; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ-58.04; EIMS m/z 307 ([M]+).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:15](#[N:17])[CH3:16].O>CO.C(OCC)C>[O:9]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][C:15]#[N:17]
Reactant: CCOC(=O)c1ccccc1
Reactant: CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: N#CCC(=O)c1ccccc1
Temperature: 80 °C

Procedure:
Ethyl benzoate (20 g, 133 mmol) and NaOMe (133 mmol, from 3 g Na) in methanol was mixed and heated with stirring to 80° C. until a homogeneous gelatinous mass had formed. Acetonitrile (6.8 g, 165 mmol) was then added slowly under the surface of this mass over a period of 30 min. The temperature was raised to 120° C. and heated at reflux for 24 h, and the reaction mixture was then cooled on an ice bath and treated with water and diethyl ether until the solid material had dissolved. The aqueous layer was separated and acidified with 5% H2SO4, washed with NaHCO3 (aq; sat.), dried over sodium sulfate and concentrated. The crude product was used in the next reaction without any further purification. Yield: 7.3 g, 37.8%.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.C(O[CH:16]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)(=O)C>C1C=CC=CC=1>[CH:18]1[C:17]2[CH:16]([N:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH3:11])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:23][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CN(C)CCC1CCCCN1
Solvent: c1ccccc1
Product: CN(C)CCC1CCCCN1C1c2ccccc2Oc2ccccc21

Procedure:
A solution of 3.12 g. (0.02 mole) of 2-(2-dimethylaminoethyl)piperidine and 4.8 g. (0.02 mole) of 9-acetoxyxanthene in 75 ml. of anhydrous benzene was refluxed for 20 hours. The cooled solution was washed with 100 ml. of a 5 percent aqueous sodium bicarbonate solution, dried over anhydrous potassium carbonate, filtered, and evaporated in vacuo. The residue was taken up in low boiling petroleum ether and filtered to remove dixanthenyl ether. The filtrate was chromatographed on 125 g. of alumina, eluting successively with petroleum ether, petroleum etherbenzene mixtures, benzene, and finally ether. Evaporation of the ether fractions gave 1-(9-xanthenyl)-2-(2-dimethylaminoethyl)piperidine, m.p. 64°-67°C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([OH:11])[CH:5]=1.[C:13]1([CH:19]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:20][N:21]([CH2:34][CH2:35][CH2:36]O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=2[Cl:33])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[ClH:33].[Cl:33][C:24]1[C:25]([C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:21]([CH2:20][CH:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH2:36][O:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([OH:2])=[O:12]
Reactant: COC(=O)c1ccc(C)c(O)c1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)O)cc1OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Product: Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.2 %

Procedure:
To a stirring solution of 3-hydroxy-4-methyl-benzoic acid methyl ester (102 mg, 0.61 mmol) in anhydrous toluene (5 mL) was added N-(2,2-diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (211 mg, 0.47 mmol). Polymer bound triphenylphosphine (250 mg, 0.75 mmol, 3 mmol/g, Fluka Chemie) was then added, and the mixture stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (115 ul, 0.58 mmol) was added in a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered and the resulting solid was washed with toluene. The filtrate was concentrated and the crude product was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile: H2O, UV detection at 254 nm) to give 150 mg (54% yield) of the title compound as a viscous oil. MS(ESI) 596.0(M+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]O.[CH3:6][C@@:7]12[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C@@H:11]1[CH2:17][CH2:18][C:19]3[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=3[C@H:10]1[CH2:9][CH2:8]2.[OH-:26].[Na+].[I-].[K+]>CO.O.C(Cl)Cl>[OH:26][CH:3]([CH3:4])[CH2:2][O:25][C:23]1[CH:22]=[CH:21][C:20]2[C@@H:10]3[C@H:11]([C@H:12]4[C@@:7]([CH2:8][CH2:9]3)([CH3:6])[C:15](=[O:16])[CH2:14][CH2:13]4)[CH2:17][CH2:18][C:19]=2[CH:24]=1
Reactant: OCCCBr
Reactant: [OH-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(O)COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 65.8 %

Procedure:
A solution of 3-bromo-1-propanol (0.400 ml, 4.42 mmol), (+)-estrone (1.00 g, 3.70 mmol), sodium hydroxide (150 mg, 3.75 mmol) and potassium iodide (100 mg, 0.602 mmol) in 10 ml methanol and 10 ml water was refluxed overnight. The reaction mixture was shaken with 100 ml methylene chloride and 100 ml water. The organic layer was washed with a 10% NaHCO3 solution (100 ml×2) and water (100 ml×2) before drying over anhydrous Na2SO4. Further purification was performed by silica gel column chromatography with methylene chloride: acetone (50:1) as the eluent to yield 3-(2-hydroxy-propoxy)-estra-1,3,5(10)-trien-17-one (800 mg, 66%). 1H NMR spectral data, 6(CDCl3): 0.93–2.94 (m, 23H on estrone), 3.88 (2H, —CH2OH), 4.13 (t, 2H, estrone-OCH2—), 6.68–7.23 (m, 3H, aromatics).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][N:20]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:16]=[C:15]([CH2:33][N:34]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:14]=2)C(=O)C2=CC=CC=C12.[OH-].[Na+].Cl.S(Cl)(Cl)=O>O1CCOCC1.C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH2:33][N:34]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:16]=[C:17]([CH2:19][N:20]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=1
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1cc(CCCCCCCN2C(=O)c3ccccc3C2=O)cc(CN(CC(=O)OCC)CC(=O)OCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN(CC(=O)OCC)Cc1cc(CCCCCCCN)cc(CN(CC(=O)OCC)CC(=O)OCC)n1

Procedure:
Compound (23) (400 mg, 0.55 mmol) was dissolved in dioxane (5 ml) and sodium hydroxide (2 M, 5 ml) was added. A mixture was stirred neutralized with conc. hydrochloric acid and evaporated almost to dryness. The residue was treated with hydrazine hydrate (2.0 ml) dissolved in ethanol (10 ml) and refluxed for 6 h. Volatile matter was evaporated and coevaporated with dry acetonitrile. The residue obtained was suspended in dry ethanol (50 ml) previously treated with thionyl chloride (4 ml). The mixture was refluxed for 2 h, filtered, evaporated and partitioned between saturated sodium hydrogen carbonate and chloroform. Combined chloroform extracts were dried over sodium sulphate, concentrated and finally purified using short column chromatography.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:2]1.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:16]=1.C(N(CC)CC)C>O1CCCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:3]2[O:4][CH2:5][CH2:6][N:1]([C:15]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[N:16]=3)[CH2:2]2)=[CH:8][CH:9]=1
Reactant: Nc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2)cc1=O
Yield: 54.3 %

Procedure:
A solution of 4-((2S)-morpholin-2-yl)phenylamine (0.17 g, 0.95 mmol), 2-chloro-3-methyl-4-oxo-6-(pyridin-4-yl)-3,4-dihydropyrimidine (0.17 g, 0.76 mmol), and triethylamine (0.25 g, 2.85 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for one hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to afford 2-[(2S)-2-(4-aminophenyl)morpholin-4-yl]-3-methyl-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (0.15 g, 54%) as pale yellow crystals.
Reaction SMILES: [C:1]([Si:5]([CH3:44])([CH3:43])[O:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([N+:16]([O-])=O)=[C:14]([NH:19][C:20]([C:22]2[N:23]([CH3:32])[N:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=2[Cl:27])=O)[CH:13]=[C:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[N:11]=1)([CH3:4])([CH3:3])[CH3:2].CC(O)=O.CCO>[Fe].CCOC(C)=O>[C:28]([C:25]1[C:26]([Cl:27])=[C:22]([C:20]2[NH:16][C:15]3[C:10]([O:9][CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:44])[CH3:43])=[N:11][C:12]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:40])([F:42])[F:41])=[CH:13][C:14]=3[N:19]=2)[N:23]([CH3:32])[N:24]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1cc(-c2ccccc2C(F)(F)F)nc(OCCO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCCO[Si](C)(C)C(C)(C)C)c2[nH]1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide (428 mg, 0.650 mmol, prepared as described in the previous step) and iron powder (291 mg, 5.22 mmol) in 1:1 AcOH/EtOH (7 mL) was stirred at 100° C. under Ar for 1 h. After cooling to room temperature, the mixture was treated with EtOAc (20 mL) and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (0:100-10:90 EtOAc/hexanes) to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 7.81 (d, 1H), 7.65-7.71 (m, 1H), 7.55-7.62 (m, 2H), 7.31 (s, 1H), 4.64 (t, J=4.9 Hz, 2H), 4.02-4.10 (m, 5H), 1.44 (s, 9H), 0.86 (s, 9H), 0.06 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calculated For C29H37ClF3N5O2Si: 608.2 (M+H), Measured: 608.3.