Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3B3OC(C)(C)C(C)(C)O3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:43]1[S:44][CH:45]=[C:46]([Br:48])[N:47]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:43]3[S:44][CH:45]=[C:46]([Br:48])[N:47]=3)[C@H:14]2[CH3:39])[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(Br)cs1
Temperature: 100 °C

Procedure:
In a tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (59 mg, 0.099 mmol), 2,4-dibromothiazole (60 mg, 0.247 mmol), DME (420 μL), EtOH (140 μL), and 1M Na2CO3 (296 μL, 0.296 mmol). The mixture was degassed with N2 and then Pd(PPh3)4 (5.7 mg, 4.94×10−3 mmol) was added. The mixture was degassed with N2 again, and then the tube was sealed, and the reaction was heated at 100° C. for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with water and brine (10 mL) each, dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-bromo-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.33 (25% EtOAc/hexanes). LCMS=635.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (bs, 2H), 7.78 (s, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.68 (dd, J=8.1, 1.0 Hz, 1H), 7.41 (s, 1H), 5.66 (d, J=8.0 Hz, 1H), 5.02 (d, J=15.8 Hz, 1H), 4.84 (d, J=15.8 Hz, 1H), 4.20 (m, 1H), 0.78 (d, J=6.7 Hz, 3H).
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC=C(I)C=1C(O)=O.N1C=CN=N1>>[F:16][C:10]1[CH:2]=[CH:3][CH:4]=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: O=C(O)c1c(F)cccc1I
Agent: c1c[nH]nn1
Product: O=C(O)c1c(F)cccc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 2-fluoro-6-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 208 [M+1]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=[N:13][N:12]=1.[Cl:35][C:36]1[CH:37]=[C:38]([OH:57])[CH:39]=[CH:40][C:41]=1[CH:42]([CH3:56])[C:43]([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([Cl:55])[CH:50]=1)([OH:48])[C:44]([F:47])([F:46])[F:45].O>CN1CCCC1=O>[Cl:55][C:51]1[CH:50]=[C:49]([C:43]([OH:48])([CH:42]([C:41]2[CH:40]=[CH:39][C:38]([O:57][CH2:8][CH2:9][CH2:10][C:11]3[N:15]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:14]=[N:13][N:12]=3)=[CH:37][C:36]=2[Cl:35])[CH3:56])[C:44]([F:47])([F:46])[F:45])[CH:54]=[CH:53][N:52]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: ClCCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(c1ccc(OCCCc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 60 °C
Yield: 51.5 %

Procedure:
To a suspension of K2CO3 (93 mg), KI (90 mg) in N-methyl-2-pyrrolidone (0.5 mL) were added 5-(3-chloropropyl)-1-(triphenylmethyl)-1H-tetrazole (137 mg, CAS 823797-34-8, preparation see Bosmans et al., WO2005003124 A1, page 23) and 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (99 mg, Example 133). The mixture was heated to 60° C. for 20 hours and TLC confirmed almost complete conversion. The mixture was allowed to cool and poured into water. The aqueous layer was extracted with ethyl acetate and the organic extracts were washed with brine, dried and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (100 mg). MS (neg. ion, m/e)=716.2 ((M−H)−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([N:8]2[CH2:19][CH2:18][C:11]3[N:12]=[C:13]([NH:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH2:9]2)[CH:7]=1.[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[C:22]=[O:23].CCCCCC>C1COCC1.O>[CH3:20][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22]([NH:21][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[O:23])=[CH:7][C:6]=1[N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([NH:16][CH3:17])[N:14]=[CH:15][C:10]=2[CH2:9]1
Reactant: CNc1ncc2c(n1)CCN(c1cc(N)ccc1C)C2
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CNc1ncc2c(n1)CCN(c1cc(NC(=O)Nc3cccc(C(F)(F)F)c3)ccc1C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.7 %

Procedure:
To a clear stirred solution of [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-methyl-amine (75 mg, 0.278 mmol) in the THF (1.5 ml) was added 1-Isocyanato-3-trifluoromethylbenzene (57.3 mg, 0.306 mmol) all at once, and the reaction mixture was allowed to stirred for 3 hours at room temperature. After 3 hours, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was given a brine wash, dried over sodium sulphate and concentrated to dryness to get sticky mass which was given a hexane wash to get 83.4 mg of 1-[4-Methyl-3-(2-methylamino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea [43] [Yield 65.6%] as light brown colored solid.
Reaction SMILES: [Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]2[N:6]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:7](=[N:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:8]([CH3:9])[C:4]=2[CH:3]=1.[CH:32]1(O)[CH2:36][CH2:35][CH2:34][CH2:33]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]2[N:6]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:7](=[N:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:13][CH:12]=3)[N:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: OC1CCCC1
Reactant: COC(=O)c1ccc(Cn2c(=Nc3ccc(O)cc3)n(C)c3cc(Cl)c(Cl)cc32)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2c(=Nc3ccc(OC4CCCC4)cc3)n(C)c3cc(Cl)c(Cl)cc32)cc1
Reaction time: 16 h

Procedure:
To the title compound of Example 20, Step A (0.03 mmol, 14 mg) in CH2Cl2 (0.6 mL) was added cyclopentanol (0.08 mmol, 7 μL), DIAD (0.06 mmol, 12 μL) and Ph3P (0.06 mmol, 16 mg). The reaction mixture was allowed to stand at ambient temperature for 16 h, then purified by chromatography on silica eluting with 10% and 25% EtOAc in hexanes to afford the product as a white solid. LC-MS (ESI, Method B): 2.12 min, m/z 524.2 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14]>C(O)C.O>[C:13]([NH:17][C:18]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4])=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(C(N)CO)cc1
Reactant: CC(C)(C)N=C=S
Solvent: CCO
Solvent: O
Product: COc1ccc(C(CO)NC(=S)NC(C)(C)C)cc1

Procedure:
The process is performed under the conditions of Example 1, starting with 1.3 g of 2-amino-2-(4-methoxyphenyl)-1-ethanol and 1.46 cm3 of tert-butyl isothiocyanate in 12 cm3 of absolute ethanol for 21 hours at a temperature in the region of 20° C. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 10 cm3 of water. A crystalline precipitate forms, which is filtered off, washed with 3 times 5 cm3 of diethyl ether and dried under reduced pressure (10 Pa) at a temperature in the region of 40° C. 1.32 g of N-(tert-butyl)-N′-[1-(4-methoxyphenyl)-2-hydroxyethyl]thiourea are obtained in the form of a white solid melting at 127° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[C:17]([CH2:20]C(=O)C)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:6]([C:5]1[CH:4]=[C:3]([CH2:2][CH2:18][C:17](=[O:19])[CH3:20])[CH:16]=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1cccc(C(=O)c2ccccc2)c1
Yield: 39.7 %

Procedure:
A mixture of 3-bromomethylbenzophenone (2.75 g.), acetylacetone (1 g.), potassium carbonate (1.4 g.) and ethanol (50 ml) was refluxed for 2 hours. The solvent was then evaporated and the residue extracted with ether. Distillation of the concentrated extracts gave 4-(m-benzoylphenyl)-2-butanone (1 g.), b.p. 220° C (4 mm). [An alternative preparation of this compound appears in German Offenlegungsschrift No. 2,243,444].
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]=[N:21][OH:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[CH2:23]([OH:27])[CH2:24][C:25]#[CH:26].Cl[O-].[Na+]>C(N(CC)CC)C.ClCCl.O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:26]=[C:25]([CH2:24][CH2:23][OH:27])[O:22][N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:5]
Reactant: O=C(NCC1(O)CCCCCC1)c1cc(C=NO)ccc1Cl
Reactant: C#CCCO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCC1(O)CCCCCC1)c1cc(-c2cc(CCO)on2)ccc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 22.1 %

Procedure:
A mixture of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(hydroxyimino-methyl)-benzamide (50 mg, 0.15 mmol), but-3-yn-1-ol (27 mg, 0.38 mmol), sodium hypochlorite (1 mL, 4%) and triethylamine (2 drops) in dichloromethane (2 mL) was stirred at room temperature for 5 d. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, and brine, dried over sodium sulfate, filtered and adsorbed onto silica gel. The residue was purified by flash column chromatography (65% ethyl acetate-hexanes) to afford the title compound (13 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:32])[F:33])=[CH:26][CH:27]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CC(C)O
Solvent: CCCCO
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc3c2ncn3C2CCSC2)cc1
Reaction time: 20 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.081 ml of 4-(trifluoro-methoxy)-benzenamine in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for approximately 20 hours, left to return to ambient temperature, diluted with 3 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 203 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([CH:7]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]1=O)=O.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[CH2:14][C:10]4[S:11][CH:12]=[CH:13][C:9]=4[C:8]=3[NH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1cccc(Br)c1)C1Cc2sccc2C1=O
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Brc1cccc(-c2n[nH]c3c2Cc2sccc2-3)c1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
5-(3-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol), hydrazine monohydrate (0.6 mL, 12 mmol), glacial acetic acid (1.5 mL) and ethanol (30 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(3-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.8 g, 2.5 mmol) as white solid in 30% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5]CN.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].[CH3:29][N:30](C)C=O>>[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:30]([CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[CH3:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: NCCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
N-(3-bromobenzyl)methylamine (2.00 g; 10.0 mmol) and sodium carbonate (2.02 g; 19.0 mmol) were added to N,N-dimethylformamide (20 ml). While the mixture was stirred at room temperature, 4-tert-butylbenzyl bromide (2.16 g; 9.52 mmol) in N,N-dimethylformamide (15 ml) was added dropwise. The mixture was stirred for 30 minutes at room temperature, and the reaction was stopped by pouring the mixture into ice/water, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then 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 (n-hexane:ethyl acetate), to thereby yield 2.26 g of the target compound (yield: 68.5%).
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CN(C=O)C.S(Cl)([Cl:20])=O>>[Cl:20][C:2]1[O:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2nc(S)oc2c1
Solvent: CN(C)C=O
Product: COc1ccc2nc(Cl)oc2c1
Reaction time: 0.17 h

Procedure:
Finally, pure 2-mercapto-6-methoxybenzoxazole (4.0 g, 22.2 mmol) was dissolved in thionyl chloride (15 mL). DMF (1 mL) was added to the solution and the reaction mixture was stirred at r.t for 10 min. The solvent was removed under reduced pressure. The crude product was dissolved in ethyl acetate, washed with water, dried over Na2SO4, and concentrated to give crude 2-chloro-6-methoxybenzoxazole, which was purified by chromatography with petroleum ether/ethylacetate (3:1 v/v) to afford 2-chloro-6-methoxybenzoxazole, compound 25, (3.7 g, yield 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[C:21]#[CH:22].C(NCC)C>C(#N)C.C(#N)C.C(#N)C.[Pd](Cl)Cl.[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:22]#[C:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#Cc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(I)c(N)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCNCC
Solvent: CC#N
Product: COC(=O)c1ccc(C#Cc2c(Cl)cccc2Cl)c(N)c1
Temperature: 120 °C

Procedure:
A mixture of methyl 3-amino-4-iodobenzoate (604 mg, 2.18 mmol) (from Example 3-4), 2,6-dichlorophenylacetylene (447 mg, 2.61 mmol), palladium (II) chloride bis(acetonitrile) (23 mg, 89 μmol), diethylamine (449 μL, 318 mg, 4.35 mmol), and copper (I) iodide (21 mg, 110 μmol) in acetonitrile (10 mL) was heated for 35 min at 120° C. in a microwave apparatus. The mixture was filtered, and the filtrate concentrated, then chromatographed using a gradient of 0-30% heptane/ethyl acetate to give methyl 3-amino-4-(2,6-dichlorophenylethynyl)-benzoate.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][C:12]1[C:13]([F:38])=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][C:16]1[C:17](=[O:34])[O:18][C:19]2[CH:27]=[C:26]([O:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH:25]=[CH:24][C:20]=2[C:21]=1[CH2:22][F:23].C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[NH2:5][S:2]([NH:11][C:12]1[C:13]([F:38])=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][C:16]1[C:17](=[O:34])[O:18][C:19]2[CH:27]=[C:26]([O:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH:25]=[CH:24][C:20]=2[C:21]=1[CH2:22][F:23])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc(N)c3F)c(=O)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=CO
Product: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc(NS(N)(=O)=O)c3F)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorosulfonyl isocyanate (0.150 mL) and formic acid (0.065 mL) were mixed at 0° C., and the mixture was stirred at room temperature for 1 hour. Dichloromethane (1.2 mL) was added to this mixture and dissolved, and the mixture was further stirred at room temperature for 4 hours. 0.060 mL was taken from the solution, and added at 0° C. to a solution of dimethylcarbamic acid 3-(3-amino-2-fluorobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester (compound 1h-1-4F) (25.2 mg) in dichloromethane (1.0 mL)/pyridine (0.0065 mL), and the mixture was stirred at room temperature for 3 hours. Saturated sodium hydrogen carbonate was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The extracted liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the resultant residue was purified by thin layer silica gel chromatography (aminogel) (dichloromethane:methanol=90:10) to yield the title compound (12.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10](OC)=[O:11])=[N:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:6]1.O.[NH2:25][NH2:26]>CO>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([NH:25][NH2:26])=[O:11])=[N:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:6]1
Reactant: COC(=O)c1nc(-c2ccccn2)nn1Cc1ccccc1F
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(-c2ccccn2)nn1Cc1ccccc1F
Temperature: 70 °C

Procedure:
To a solution of methyl 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate I-35 (115 mg, 0.368 mmol) in methanol (2 mL) was added hydrazine hydrate (72 μL, 1.5 mmol). The solution was heated to 70° C. for 3.5 h, at which point the solvent was removed in vacuo to give 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbohydrazide C as a white solid. To the crude solid (17 mg, 0.054 mmol) suspended in ethyl acetate (600 μL) was added acetic formic anhydride (0.03 mL, taken from a 2:1 (molar ratio) of formic acid to acetic anhydride, allowed to age 2 h prior to addition). After stirring for 1.25 h, the solution was diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were dried over MgSO4, filtered, and the solvent was removed in vacuo to give the crude intermediate D that was carried on without further purification. To the crude solid was added phosphoryl chloride (237 μl, 2.54 mmol) and the solution was heated to 60° C. for 6.5 h. The solution was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate (75 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (20-95% ethyl acetate in hexanes) gave 2-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,3,4-oxadiazole I-42 (7.5 mg, 0.023 mmol, 42% yield for three steps) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([Cl:13])[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:18]=1[O:19][CH:20]([CH3:31])[CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C>O1CCOCC1>[ClH:13].[NH2:23][CH2:22][CH2:21][CH:20]([O:19][C:18]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:17]=1[NH:16][C:12]1[C:7]2[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=2[N:9]=[CH:10][N:11]=1)[CH3:31]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(CCNC(=O)OC(C)(C)C)Oc1cc(F)ccc1N
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)CCN)c2c1C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (1.25 g), tert-butyl 3-(2-amino-5-fluorophenoxy)butylcarbamate (1.7 g) and p-toloulsulfonic acid (175 mg) was dissolved in dioxane (30 ml) and the solution was heated under reflux overnight. Then the reaction mixture was concentrated in vacuo. The residue was treated with trifluoracetic acid 25% in dichloromethane and stirred at room temperature for 1 h. The solution was concentrated in vacuo and the residue was dissolved in dichloromethane and washed with sodium bicarbonate. The organic phase was separated, dried and concentrated in vacuo. The residue was triturated with Et2O and the precipitate was filtered.
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[CH:12]([OH:27])[CH2:11][CH2:10]1.[CH3:28][NH:29][CH2:30][CH2:31][CH2:32][C:33]([F:51])([F:50])[C:34]([F:49])([F:48])[C:35]([F:47])([F:46])[C:36]([F:45])([F:44])[C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39].[Cl-].[Na+].[CH3:54]N1CCCC1=O>>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:28][N:29]([CH3:54])[CH2:30][CH2:31][CH2:32][C:33]([F:50])([F:51])[C:34]([F:49])([F:48])[C:35]([F:46])([F:47])[C:36]([F:44])([F:45])[C:37]([F:42])([F:43])[C:38]([F:40])([F:39])[F:41]
Reactant: CNCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CN1CCCC1=O
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2O
Agent: [Cl-]
Agent: [Na+]
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A solution of 466 mg of 7α-(5-bromopentyl)-11β-fluor-estra-1,3,5(10)-triene-3,17-diol in 10 ml of 1-methyl-2-pyrrolidinone is stirred with 1.17 g of methyl-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)-amine for 3 hours at a bath temperature of 80° C. For working-up, the batch is added to saturated sodium chloride solution, extracted with ethyl acetate, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 625 mg of 11β-fluor-7α-{5-[methyl-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-nonyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam, [α]D=+35° (c=0.5 in CHCl3).