Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:10]B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)Cl.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>[C:1]([C:3]1[C:4]([CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccnc1Cl
Reactant: CB(O)O
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: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ncccc1C#N
Temperature: 25 °C
Yield: 46.1 %

Procedure:
To a mixture of 3-cyano-2-chloro-pyridine (422 mg, 3.05 mmol), methylboronic acid (209 mg, 3.49 mmol) and K2CO3 (1.22 g, 8.83 mmol) in degassed dioxane (5 mL) under argon was added Pd(PPh3)4 (222 mg, 0.19 mmol) and the mixture stirred at reflux over the weekend. The reaction was cooled to room temperature, diluted with CH2Cl2 (20 mL) and filtered through Celite, washing the cake with CH2Cl2 and MeOH. The filtrate was concentrated in vacuo and purified by column chromatography on silica gel (Hexanes/ethyl acetate, 9:1 then 4:1) to afford the desired product (166 mg, 46%) as a white solid. 1H NMR (CDCl3): δ 2.78 (s, 3H), 7.25 (dd, 1H, J=9, 6 Hz), 7.90 (dd, 1H, J=6, 3 Hz), 8.69 (d, 1H, J=3 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[N:9][C:8]=2[CH:18]=1)([O-:3])=[O:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.N(CCCC#N)=NCCCC#N>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH2:17][Br:19])=[N:9][C:8]=2[CH:18]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccsc1-c1nc2cc([N+](=O)[O-])ccc2o1
Agent: N#CCCCN=NCCCC#N
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(-c3sccc3CBr)nc2c1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A mixture of 5-nitro-2-(3-methyl-2-thienyl)benzoxazole (11.0 g, 0.042 mole) and N-bromosuccinimide (7.55 g, 0.042 mole) are refluxed for 36 hours in 400 ml of chloroform. Approximately every 12 hours azobisbutyronitrile (0.1 g) is added as a catalyst. The reaction mixture is cooled to room temperature and the precipitated succinimide removed by filtration. The chloroform solution is washed with 150 ml of 5% sodium hydroxide and dried over anhydrous magnesium sulfate. The chloroform is removed under vacuum yielding a solid. Crystallization from ethanol yields 8.6 g of product, melting point 146°-148°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](Cl)=[O:20])=[CH:5]2.C(N(CC)CC)C.Br.Br.[NH2:31][C:32]1[CH:33]=[C:34]2[CH2:40][C:39](=[O:41])[NH:38][C:35]2=[N:36][CH:37]=1.O>ClCCl>[O:41]=[C:39]1[NH:38][C:35]2=[N:36][CH:37]=[C:32]([NH:31][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])[CH:33]=[C:34]2[CH2:40]1
Reactant: O=C(Cl)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1cnc2c(c1)CC(=O)N2
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1Cc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1.3 g (4.25 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid chloride, prepared in the preceding step, 2.1 mL (14.9 mmol) of triethylamine and 1.45 (4.68 mmol) of 5-amino-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine dihydrobromide (US 2005/256 125) in 42.5 mL of dichloromethane is stirred for 24 hours at room temperature. After this time, the mixture is poured into 200 mL of water. 100 mL of dichloromethane are added and the organic phase is then separated out, washed with twice 50 mL of water and concentrated under reduced pressure. The product obtained is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and dichloromethane. The product thus purified is taken up in 100 mL of hot methanol, and the resulting suspension is filtered. The filtrate is concentrated under reduced pressure, thus allowing 0.4 g of the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][N:26]=3)[CH3:29])[N:7]=2)[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCOc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A mixture of 6-chloro-N-(5-ethoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 26, 0.35 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.20 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.37 g of the title compound. MS (electrospray): 388 (M+1) for C17H17FN7O3.
Reaction SMILES: [Cl:1][CH:2]([Cl:4])[CH3:3].[Cl:5][CH2:6][CH2:7][C:8](Cl)([CH3:11])[CH2:9][CH3:10].[ClH:13]>[Cl-].[Al+3].[Cl-].[Cl-]>[CH2:9]([C:8]([CH3:11])([CH2:7][CH2:6][Cl:5])[CH2:3][C:2]([Cl:13])([Cl:4])[Cl:1])[CH3:10]
Reactant: CCC(C)(Cl)CCCl
Reactant: CC(Cl)Cl
Reactant: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(C)(CCCl)CC(Cl)(Cl)Cl
Temperature: -70 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
2,180 g (22.5 moles) of 1,1-dichloroethane are initially introduced into the reaction vessel at -70° C., 75 g of powdered aluminum chloride are added and 1,160 g (7.5 moles) of 1,3-dichloro-3-methylpentane are then added dropwise. The reaction mixture is stirred at -70° C. for 4 hours and is then poured onto ice and dilute hydrochloric acid. It is extracted with methylene chloride and the organic phase is dried over sodium sulphate and concentrated. The residue is distilled. 1,572 g (83% of theory) of 3-ethyl-3-methyl-1,1,1,5-tetrachloropentane of boiling point 85° C./0.1 mbar are obtained. ##STR104##
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=2)[C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2c(C)oc3cc(OC)ccc23)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(6-methoxy-2-methyl-1-benzofuran-3-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (781 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (702 mg, 95%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].[Br:13]Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([Br:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
16.52 g (100 mmol) of 2-pyridylacetic acid ethyl ester is dissolved in 50 ml of carbon tetrachloride. It is cooled to 0° C. and 15.98 g (100 mmol) of bromine, dissolved in 15 ml of carbon tetrachloride, is then instilled in it within 30 minutes. Then, it is allowed to react for one more hour at 25° C. The bromine coloring fades away. It is concentrated by evaporation in a vacuum and the hydrobromide of the title compound is obtained. The free compound is obtained by extraction of ether from the aqueous solution after adding sodium bicarbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:6]([C:8]2[NH:9][C:10]([CH3:23])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([O:19]CC)=[O:18])[NH:13][C:12]3=[O:22])[CH:7]=1.[OH-].[Li+].Cl>O1CCCC1.CO.O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:6]([C:8]2[NH:9][C:10]([CH3:23])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]3=[O:22])[CH:7]=1
Reactant: CCOC(=O)c1cc2c(-c3cc(Cl)ccc3Oc3ccc(F)cc3F)[nH]c(C)c2c(=O)[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1[nH]c(-c2cc(Cl)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c(=O)c12

Procedure:
A mixture of Example 24b (0.14 g, 0.305 mmol) and lithium hydroxide (0.073 g, 3.05 mmol) in tetrahydrofuran/methanol/water (2 mL each) was stirred at 80° C. for 2 hours. The mixture was cooled, diluted with water and brought to pH 4 with 1M HCl producing a yellow solid that was collected by filtration, washed with water and dried to constant mass (0.10 g, 76%).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Br.Br[CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O.C(N(CC)CC)C>C(#N)C>[CH3:1][NH:2][C:3]1[S:4][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:5]=1
Reactant: CNC(N)=S
Reactant: O=C(c1cccnc1)C(Br)c1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1nc(-c2cccnc2)c(-c2ccccc2)s1
Yield: 83.6 %

Procedure:
To a solution of N-methylthiourea (484 mg) in acetonitrile (40 mL), was added 2-bromo-2-phenyl-1-(3-pyridyl)ethanone hydrobromide (2.0 g), and then triethylamine (0.8 mL) was added dropwise to the mixture with stirring. After addition, the resulting mixture was stirred at reflux for 3 h and the solvent was evaporated. An aqueous saturated solution of sodium hydrogen carbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried and the solvent was evaporated. The crystalline residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (1.2 g, yield 80%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:15]([O:14][C:12]([NH:19][CH:20]1[CH2:21][CH2:22][N:23]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)[CH2:24][CH2:25]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Yield: 84.9 %

Procedure:
Methyl 6-chloropyridine-3-carboxylate (1.00 g, 5.83 mmol) and 4-(N-Boc-amino)piperidine (2.33 g, 11.7 mmol) were dissolved in DMF (10 mL) and the reaction mixture was heated using a microwave reactor at 100° C. for 50 min. DIPEA (1.22 mL, 6.99 mmol) was added and the reaction mixture was heated using a microwave reactor at 100° C. for 30 min. The reaction mixture was diluted with DCM (50 mL), washed with sat aq NaHCO3 (2×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.66 g, 84.9%) as an off-white solid. LCMS (ES+): 336.1 [MH]+. HPLC: Rt 4.73 min, 98.2% purity.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[N:28]=[CH:27][C:26]([N+:34]([O-:36])=[O:35])=[C:25]2Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1.CN(C)C=O.O>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[N:28]=[CH:27][C:26]([N+:34]([O-:36])=[O:35])=[C:25]2[CH:9]([C:10]#[N:11])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccc(C#N)cc1
Reactant: COc1cc2ncc([N+](=O)[O-])c(Cl)c2cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc([N+](=O)[O-])c(C(C#N)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Under a nitrogen atmosphere, 4-cyanophenylacetonitrile (3.86 g, 27.12 mmol) is dissolved in dry tetrahydrofuran (185 ml). Sodium hydride (60% dispersion in paraffin oil, 2.17 g, 54.25 mmol) is subsequently added in portions with ice-bath cooling, and the mixture is stirred for a further 30 min. A suspension of 6-benzyloxy-4-chloro-7-methoxy-3-nitro-quinoline (9.35 g, 27.12 mmol) in N,N-dimethylformamide (50 ml) is then added at room temperature, and the mixture is subsequently stirred for a further 2 h. When the reaction is complete, the mixture is added to 2.5 l of water and neutralised using 1.0 M hydrochloric acid with vigorous stirring. After stirring for 30 min, the suspension is acidified to about pH 2, and, after a further 30 min, the precipitate obtained is filtered off with suction, rinsed with water and dried overnight in a high vacuum. The crude product is subsequently purified over flash silica gel (solvent gradient cyclohexane/0-50% by vol. of ethyl acetate), giving 4-[(6-benzyloxy-7-methoxy-3-nitroquinolin-4-yl)cyanomethyl]benzonitrile (11.31 g, 25.11 mmol) as a solid having a melting point of 147.9° C. MS: 451.1 (M+H+), TLC (HPTLC) (HPTLC): Rf=0.68 (cyclohexane/ethyl acetate 1:1 parts by volume).
Reaction SMILES: I[C:2]1[C:3](=[O:15])[O:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[As](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>C1C=CC=CC=1.[OH-].[Na+]>[C:16]1([C:2]2[C:3](=[O:15])[O:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ccc(C2=C(I)C(=O)OC2)cc1
Reactant: OB(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)OC2)cc1

Procedure:
A mixture of 4 g of the product of Step 3, 3.7 g of PhB(OH)2, 0.4 g of Ph3As, 0.4 g of PdCl2 (PhCN)2 in 100 mL of benzene and 15 mL of 2N NaOH is refluxed for 6 hr. Et2O (200 mL) is then added and the mixture is washed with 100 mL of saturated NaHCO3. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the title compound.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1)=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][Mg]Br>C1COCC1.C(OCC)C>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1)([OH:22])[CH3:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)c1cc2ccccc2s1
Temperature: -30 °C

Procedure:
To a stirring solution consisting of (3aR,4R,5R,6aS)-4-((E)-3-(benzo[b]thiophen-2-yl)-3-oxoprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (intermediate 4a prepared in Example 2, Step A) in THF (0.2 M) at −30° C. under a nitrogen atmosphere is slowly added a solution consisting of methylmagnesium bromide in diethyl ether (3 M, 1.5 molar equivalents). The reaction mixture is stirred at −30° C. until the reaction is complete as judged by TLC. Upon completion, the reaction mixture is warmed to 0° C. and is quenched with water and extracted into ethyl acetate. The layers are separated and the aqueous phase is extracted with a fresh portion of ethyl acetate. The organic layers are combined and dried over magnesium sulfate. The solvents are evaporated and the crude material is purified on regular silica gel eluted with an ethyl acetate-hexanes solvent system to afford the title intermediate.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH3:26][O:27][CH2:28]Cl>O.O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:26][O:27][CH3:28])[CH2:23][CH2:24][CH3:25]
Reactant: COCCl
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.9 %

Procedure:
n-Butyl lithium (2.4 M, n-hexane solution, 25 mL, 61 mmol) was dropped into a mixture of diisopropylamine (9.4 mL, 67 mmol) and tetrahydrofuran (150 mL) at −78° C. followed by stirring for 30 minutes at the same temperature. Tributyl tin hydride (16 mL, 61 mmol) was dropped in at the same temperature followed by stirring for 30 minutes while cooling with ice. The reaction mixture was brought to a temperature of −78° C. followed by dropping in chloromethyl methyl ether (4.6 mL, 61 mmol) and gradually warming to room temperature. Water (100 mL) was added to the reaction mixture followed by extraction with diethyl ether (300 mL). After washing the organic layer with sat. NaCl, the organic layer was distilled under a reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane/ethyl acetate=30/1) to obtain the title compound (18 g, 0.52 mmol, 86%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:35]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:35]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: CCN1CCCC(N)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCCC(NC(=O)Cn2c(-c3ccc(Br)cc3)nc3cccnc32)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (3.1 g, 0.019 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and a solution of 3-amino-N-ethylpiperidine (2.6 g, 0.020 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (100 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol to give 4.9 g (62%) of a white solid, mp 190°-192° C.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]([Mg]Br)#[CH:6].[F:9][C@H:10]1[CH2:27][C@@:25]2([CH3:26])[C@@H:21]([CH2:22][CH2:23][C:24]2=[O:28])[C@H:20]2[C@H:11]1[C@@H:12]1[C:17](=[CH:18][C@H:19]2[CH3:29])[CH:16]=[C:15]([O:30]C)[CH2:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1.O>[C:5]([C@:24]1([OH:28])[CH2:23][CH2:22][C@H:21]2[C@H:20]3[C@H:11]([C@@H:10]([F:9])[CH2:27][C@:25]12[CH3:26])[C@@H:12]1[C:17](=[CH:16][C:15](=[O:30])[CH2:14][CH2:13]1)[CH2:18][C@H:19]3[CH3:29])#[CH:6]
Reactant: C#C[Mg]Br
Reactant: COC1=CC2=C[C@@H](C)[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@]1(O)CC[C@H]2[C@H]3[C@H]([C@@H](F)C[C@@]21C)[C@H]1CCC(=O)C=C1C[C@H]3C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 9.17 g of cerium(III) chloride in 60 ml of tetrahydrofuran was mixed drop by drop at 0° C. with 74.2 ml of an ethinylmagnesium bromide solution (0.5 M in tetrahydrofuran) and stirred for 1 hour at 0° C. Then, a solution of 2 g of crude 11β-fluoro-3-methoxy-7α-methylestra-3,5-dien-17-one in 40 ml of tetrahydrofuran was added drop by drop and stirred for another 3.5 hours at 0° C. For working-up, a saturated ammonium chloride solution was added, added to water, extracted three times with ethyl acetate, washed with semiconcentrated hydrochloric acid, sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 1.15 g of pure 17α-ethinyl-11β-fluoro-17β-hydroxy-7α-methylestr-4-en-3-one with a melting point of 218-220° C. was obtained. [α]D=+19.2° (CHCl3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH:14]1([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=3)[CH:20]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C>[CH:14]1([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22](=[CH2:25])[CH:21]([NH:26][C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([O:9][CH2:8][C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:32][CH:33]=3)[CH:20]=2)[CH2:15][CH2:16]1
Reactant: Cc1cccnc1CO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: C=C1C=CC(C(=O)NC2CC2)=CC1NC(=O)c1ccc(OCc2ncccc2C)cc1
Temperature: 80 °C
Yield: 102.2 %

Procedure:
To (3-methylpyridine-2-yl)methanol (157 mg, 1.272 mmol) in DCM (5 mL) was added thionyl chloride (200 μl) and the mixture stirred and heated at reflux for 4 h. The mixture was evaporated to dryness. To the residue was added N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197 mg, 0.636 mmol) and potassium carbonate (176 mg, 1.27 mmol) in acetonitrile (5 mL) and the resulting mixture heated at 80° C. for 16 h. The reaction mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was concentrated under reduced pressure. Precipitation with DCM in diethyl ether gave the title compound as a solid (270 mg); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.40 (s, 3H), 2.86 (m, 1H), 5.30 (s, 2H), 7.17 (d, 2H), 7.33 (m, 2H), 7.65 (m, 2H), 7.82 (s, 1H), 7.97 (d, 2H), 8.39 (m, 2H), 9.81 (s, 1H); Mass Spectrum: M+H+ 416.