Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[Cl-].[Li+].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.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>[CH2:15]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2nonc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2nonc2c1

Procedure:
5-Bromo-2,1,3-benzoxadiazole (10 g, 50.3 mmol) was dissolved in toluene (300 ml) and added Lithium chloride (6.4 g, 150 mmol), Pd(Ph3P)4 (2.90 g, 2.50 mmol), and allyl tributyltin (19 ml, 60 mmol). The reaction mixture was degassed and refluxed under N2 for 3 hrs. It was cooled and poured into water then extracted with ethyl acetate. The organic layer was washed with brine 1×, dried and evaporated to dryness. The residue was chromatographed through 120 g ISCO Redi-Sep columns and eluted with 0-10% ethyl acetate/hexane to yield 5-allyl-2,1,3-benzoxadiazole.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:15][C:16](=O)[CH3:17].[I-].[Na+]>CO>[NH2:12][C:10]1[N:11]2[CH:15]=[C:16]([CH3:17])[N:1]=[C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]=1[Cl:13]
Reactant: CC(=O)CBr
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)n2cc(C)nc12
Reaction time: 24 h
Yield: 59 %

Procedure:
A mixture of methyl 2,6-diamino-5-chloronicotinate (EXAMPLE 26, Step 3, 15 g, 74.4 mmol), bromoacetone (10.4 mL, 112 mmol) and sodium iodide (16.7 g, 112 mmol) in methanol (700 mL) was stirred under reflux for 22 h. Another 2.5 mL (33 mmol) of bromoacetone was added and the stirring was continued for 24 h. The reaction mixture was quenched with saturated aqueous sodium carbonate and removed methanol in vacuo. The residue was extracted with ethyl acetate (250 mL×10) adding a small amount of methanol to dissolve the organic solid. The organic extracts were dried over sodium sulfate and concentrated. Purification by column chromatography on silica gel eluting with dichloromethane/methanol (20:1) gave a dark brown solid, which was washed with ethyl acetate and filtered to afford 10.5 g (43.9 mmol, 59%) of the title compound as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][N:12]=[CH:13][C:6]=12.[OH-].[K+].[I:23]I.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C.C(Cl)Cl>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:11]2[C:7]3=[N:8][CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:2]=4[F:1])=[C:6]3[C:13]([I:23])=[N:12]2)=[CH:28][CH:29]=1
Reactant: II
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ncc23)c(F)c1
Reactant: COc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a stirred solution of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (16.7 g, 60.9 mmol; obtained from Example 3, Step A) in DMF (250 mL) was added freshly ground potassium hydroxide (10.3 g, 183 mmol) followed by iodine (23.2 g, 91.4 mmol) under N2 at room temperature. The dark reaction was stirred at room temperature for 18 hours, covered by a foil to minimize light exposure. The reaction was then heated to 50° C. for 3 hours. The reaction was allowed to cool to room temperature. The crude reaction mixture was transferred via cannula into a stirred solution of 1-(chloromethyl)-4-methoxybenzene (11.1 g, 70.7 mmol) in DMF (100 mL) which was cooled in an ice bath under N2. The reaction was allowed to stir for 18 hours under N2 at room temperature. The mixture was then diluted with DCM (1 L) and washed with 5% aqueous Na2S2O3 (1 L). The aqueous phase was back-extracted with DCM (2×200 mL). The combined organic phases were washed with water (4×500 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was triturated with DCM (100 mL), and the undissolved solid removed by filtration. The filtrate was purified by Biotage Flash 65, eluting with 10% EtOAc/hexanes, 20% EtOAc/hexanes, then 30% EtOAc/hexanes to elute the desired product. The product was obtained as a pale yellow solid (16.6 g, 47%). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=6 Hz, 1H), 8.16 (m, 2H), 7.38 (d, J=9 Hz, 2H), 7.34 (m, 1H), 6.84 (d, J=9 Hz, 2H), 6.36 (d, J=6 Hz, 1H), 5.63 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [Na].C(OP([CH:10]([Cl:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=O)OCC)C.[CH3:20][C:21]([CH3:25])=[CH:22][CH:23]=O.O>C(O)C.O1CCCC1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([Cl:19])=[CH:23][CH:22]=[C:21]([CH3:25])[CH3:20])=[CH:16][CH:15]=1
Reactant: CC(C)=CC=O
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(OC)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(Cl)=CC=C(C)C)cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
4.6 g (0.2 mol) of sodium were dissolved incrementally in 100 ml of dry ethanol. When all the sodium had dissolved, 100 ml of anhydrous tetrahydrofuran were added and 58.4 g (0.2 mol) of 4-methoxy-α-chloro-benzyl-phosphonic acid diethyl ester, dissolved in 50 ml of anhydrous tetrahydrofuran, were added dropwise at 0° C., while stirring. After stirring had been continued at 0°-10° C. for a further 1 hour, 16.8 g (0.2 mol) of β,β-dimethylacrolein, dissolved in 30 ml of anhydrous tetrahydrofuran, were added dropwise, while stirring. Stirring was then continued at room temperature for a further 12 hours. 600 ml of water were then added to the reaction mixture and the mixture was extracted twice with 300 ml of methylene chloride each time. The organic phase was separated off and dried over magnesium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was distilled in vacuo. 25 g of 1-(4'-methoxyphenyl)-1-chloro-4,4-dimethyl-1,3-butadiene (isomer mixture) were obtained as a yellow oil which had a boiling point of 130°-145° C./2 mm Hg and partially crystallized after some time.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1.Cl[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C(O)(=O)C>ClCCl>[CH2:32]([NH:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1)[C:31]1[CH:34]=[CH:35][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1NCCc2ccc(NCc3ccccc3)cc21
Reaction time: 8 h
Yield: 36.9 %

Procedure:
Sodium triacetoxyborohydride (1.29 g, 6.16 mmol) was added to a stirred solution of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (500 mg, 3.08 mmol), 4-chlorobenzaldehyde (431 mg, 3.08 mmol) and acetic acid (183 μl, 3.08 mmol) in anhydrous dichloromethane (25 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (50% ethyl acetate in dichloromethane) to yield the title compound as a pale yellow solid (287 mg, 16%). HPLC retention time 4.09 min. Mass spectrum (ES+) m/z 287 (M+H).
Reaction SMILES: [F:1][CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].N1CCCCC1>CCO>[NH2:10][CH2:9][C:11]1[C:12](=[O:13])[NH:14][C:3]([CH3:4])=[C:2]([F:1])[C:6]=1[CH3:7]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(F)C(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(CN)c(C)c1F
Temperature: 85 °C

Procedure:
A mixture of 3-fluoro-2,4-pentanedione (247 mg, 2.10 mmol), cyanoacetamide (176 mg, 2.1 mmol, 1 equiv) and piperidine (0.21 mL, 2.1 mmol, 1 equiv) in 3 mL of EtOH was heated at 85° C. for 16 h, resulting in a clear but dark brown solution. The mixture was concentrated in vacuo. The residue was taken up in 2 mL of 1N HCl to give a suspension, which was filtered. The tan solids collected were dried under vacuum to give the desired product as 80 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11](=[C:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:4][CH:3]=1.[CH3:20]OC(OC)N(C)C.[NH4+].[Cl-]>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:20]=[CH:19][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)C(C(=O)Nc1ccc(F)cc1)=C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)ccn(-c2ccc(F)cc2)c1=O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
A mixture of ethyl 2-(4-fluorophenylcarbamoyl)-3-methylbut-2-enoate (1.85 g, 6.97 mmol) and N,N-dimethylformamide dimethyl acetal (5 mL, 37.45 mmol) is stirred at 90° C. for 90 min. After the reaction is cooled, EtOAc (30 mL) and saturated NH4Cl solution (20 mL) are added. The organic phase is separated, dried and concentrated. The residue is purified by silica gel column chromatography eluting with DCM:MeOH (10:1). The fractions containing product are concentrated, and the residue is mixed with ether to give 1.2 g of yellow solid which is filtered and discarded. The filtrate is concentrated and purified again by silica gel column chromatography eluting with DCM:MeOH (20:1) to give the product (500 mg, 26% yield). MS (m/z): 276.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].N1C=CC=CC=1.Cl>C(#N)C>[CH2:28]([O:27][C:25](=[O:26])[O:13][C:12]1[C:11]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:10][C:9](=[O:21])[C:8]=1[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:23])[C:5]=1[CH3:22])[CH3:29]
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(Br)cc(F)c1C)=C2O
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)OC1=C(c2cc(Br)cc(F)c2C)C(=O)NC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-bromo-3-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (350 mg) and ethyl chloroformate (77 μl) in acetonitrile (2 ml) was added pyridine (80 μA) and the reaction mixture stirred at room temperature for one hour. The mixture was poured on diluted HCl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 3:1). Yield: 310 mg of carbonic acid 3-(5-bromo-3-fluoro-2-methyl-phenyl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester (title compound E4) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.3 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (1.92 g, 4.53 mmol) was added to a solution of 1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine (1.00 g, 4.01 mmol) in methylene chloride (20 mL) and the mixture was stirred at rt for 45 min. Ether (75 mL) and 1.3 N aq. NaOH (25 mL) were added and stirring was continued for 15 min. The mixture was transferred to a separatory funnel with additional ether (30 mL) and 1.3 N aq. NaOH (20 mL). The organic layer was separated, washed with saturated aq. brine (20 mL), dried (sodium sulfate), decanted, and evaporated to give 846 mg of 1-(benzyloxycarbonyl)4-piperidine carboxaldehyde as a colorless syrup.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)=[N:2]1.[OH-].[Li+].Cl>O1CCCC1.O>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([C@H:12]3[CH2:13][CH2:14][C@H:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:17]3)=[CH:10][CH:11]=2)=[N:2]1
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1

Procedure:
A scintillation vial was charged with the product from Example 37B (31.3 mg, 0.100 mmol), lithium hydroxide (21 mg, 0.50 mmol) and 10 mL of 4:1 tetrahydrofuran/water and placed in a shaker overnight at room temperature. The reaction was neutralized by the addition of 4 M HCl, and the resultant mixture was concentrated and purified by RP-HPLC to provide the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.07-1.17 (m, 2H), 1.42-1.53 (m, 2H), 1.70-1.88 (m, 5H), 2.14 (d, J=6.75 Hz, 2H), 2.44-2.48 (m, 1H), 6.63 (d, J=2.15 Hz, 1H), 7.26 (d, J=7.97 Hz, 2H), 7.65 (d, J=2.15 Hz, 1H), 7.68 (d, J=7.97 Hz, 2H), 12.46 (br, s, 2H): MS (ESI) m/z 285.0 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:7]1[O:11][CH:10]=[N:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:12]([OH:14])C>O>[C:3]([C:7]1[O:11][C:10]([C:12]([OH:14])=[O:1])=[N:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)(C)c1cnco1
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cnc(C(=O)O)o1
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of sodium hydroxide (0.96 g, 24 mmol) in water (25 ml) is added to a stirred solution of 5-tert-butyl-oxazole .2-carboxylic acid ethyl ester (3.94 g, 20 mmol) In ethanol (35 ml), and the mixture is warmed to 60° C. and stirred for 1 h. The ethanol is then removed by distillation and the aqueous residue is washed with diethyl ether and acidified with 5 N hydrochloric acid. The resulting precipitate is collected by filtration and dried to give 5-tert-butyl-oxazole-2-carboxylic acid (2.30 g, 68%) as beige crystals. This material is used immediately without further purification since, on prolonged storage, it undergoes spontaneous decarboxylation to 5-tert-butyl-oxazole.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[Cl-:21].[NH4+].N>C(OCC)(=O)C.O>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[ClH:21]
Reactant: [Cl-]
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: N
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cl

Procedure:
In a solution of sertraline base (50 g) in ethyl acetate/water 10/1 (400 ml), ammonium chloride (8,7 g) was added. The resulting mixture was heated at reflux temperature and stirred for 15 hours during which ammonia evolution was observed and a white crystalline solid precipitated. When the evolution of ammonia ended the solid product was filtered, washed with ethyl acetate and dried under vacuum. 50,5 g of sertraline hydrochloride form I (yield 90%) were obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>COCCOC.C(OCC)(=O)C.O>[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]3)=[CH:32][CH:31]=1
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of methyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthoate (271 g, 0.81 mol) (from multiple batches), tetrakis(triphenylphospine)palladium (0) (37.4 g, 0.032 mol), 2 M sodium carbonate solution (1.3 L) and 4-hydroxyphenyl boronic acid (134 g, 0.97 mol) in ethylene glycol dimethyl ether (1.5 L) was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (2 L) and water (2 L). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to a dark semisolid residue. The crude material was purified by crystallization from dichloromethane-heptane to give 199 g of the product as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13]C)=[O:12])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.O([Si](C)(C)C)[K:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O-:13])=[O:12])[CH2:9][CH2:10]2)[CH:5]=[N:6][CH:7]=1.[K+:16]
Reactant: C[Si](C)(C)O[K]
Reactant: COC(=O)C1(c2cncc(Br)c2)CC1
Solvent: C1CCOC1
Product: O=C([O-])C1(c2cncc(Br)c2)CC1
Product: [K+]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(5-bromopyridin-3-yl)cyclopropanecarboxylate (1 g, 3.9 mmol) in THF (40 mL) was added 90% KOTMS (0.557 g, 3.9 mmol), and the mixture was stirred at room temperature overnight. The mixture was filtered and washed with THF to give potassium 1-(5-bromopyridin-3-yl)cyclopropanecarboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.63-0.69 (m, 2H), 1.09-1.15 (m, 2H), 7.79-7.80 (m, 1H), 8.34-8.37 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][C:18](C)([O-])[CH3:19].[K+].BrC(C)C>CS(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:19]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Product: COC(=O)c1sc(-c2ccccc2)cc1OC(C)C
Temperature: 80 °C
Yield: 94.1 %

Procedure:
Methyl 3-hydroxy-5-phenyl-2-thiophenecarboxylate (20.0 g, 85 mmoles) is dissolved in dimethylsulfoxide (80 mL) under argon and cooled in an ice bath. Potassium t-butoxide (10.1 g, 90 mmoles) is added, followed after 25 minutes by 2-bromopropane (22.1 g, 180 mmoles), and the ice bath is removed. After 24 hours the mixture is heated to 80° C. for 1 hour, then poured into ice water (500 mL), stirred, and acidified with concentrated HCl. The mixture is extracted with dichloromethane (3×200 mL) and the combined extracts are washed with brine, dried over MgSO4 and stripped of solvent under reduced pressure to leave the product as a syrupy residue (22.1 g) sufficiently pure for further use.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6](O)[C:7]([C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)=O)[O:3][CH:2]=1.[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:33](#[N:37])[CH2:34][C:35]#[N:36]>C1(C)C=CC=CC=1.O>[NH2:37][C:33]1[N:21]([CH2:15][C:16]2[O:20][CH:19]=[CH:18][CH:17]=2)[C:7]([C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([C:4]2[O:3][CH:2]=[CH:1][CH:5]=2)[C:34]=1[C:35]#[N:36]
Reactant: O=C(c1ccco1)C(O)c1ccco1
Reactant: N#CCC#N
Reactant: NCc1ccco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c(-c2ccco2)c(-c2ccco2)n(Cc2ccco2)c1N

Procedure:
2-amino-1-(2-furanylmethyl)-4,5-difuryl-3-pyrrolecarbonitrile was prepared as follows: 300 g (1.56 mol) of Furoin (ex Aldrich) was reacted with 151.6 g (1.56 mol) of furfurylamine in the presence of 1.5 g of p-toluenesulphonic acid in toluene under stirring and reflux. The water produced was removed via a Dean Stark trap. When formation of water had ceased (31 ml removed), 103.1 g (1.56 mol) of malononitrile was added as a dispersion in 100 ml toluene, reflux was continued. When again formation of water had ceased (26 ml removed via the Dean Stark trap), the reaction mixture was cooled and the toluene was removed by evaporation. In this way 498 g of a black solid product was obtained. Subsequently, 100 g of this product was purified by flash chromatography (silica, hexane/ethyl acetate as eluant) and 24 g of the product was recovered.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH2:17])=[O:16])=[CH:10][CH:9]=2)=[C:6]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=2[F:28])[CH:5]=[CH:4][N:3]=1.CN(C=O)C.CCO.[NH4+].[Cl-]>[Fe].O>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH2:17])=[O:16])=[CH:10][CH:9]=2)=[C:6]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=2[F:28])[CH:5]=[CH:4][N:3]=1
Reactant: NC(=O)Cc1ccc(-c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2N)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Cc1ccc(-c2c(Oc3ccc(N)cc3F)ccnc2N)cc1
Temperature: 100 °C
Yield: 66 %

Procedure:
A mixture of 2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetamide (32 mg, 0.086 mmol), DMF (1 mL), EtOH (1 mL) and H2O (1 mL) was treated with Fe powder (67 mg, 1.2 mmol), and NH4Cl (128 mg, 2.4 mmol) and the mixture heated at 100° C. for 20 min. The mixture was filtered through Celite®, the pH of the filtrate adjusted to pH 7 using phosphate buffer and then the mixture was extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated to give the desired product (20 mg, 67%) as a yellow-brown solid. MS (ESI+): m/z 353.32 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.CCCCCC.C([Li])CCC.[C:41]1([C:47]2[CH:48]=[CH:49][C:50](=[C:52]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.O>[C:41]1([C:47]2[CH:48]=[CH:49][CH:50]([C:52]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:20]3[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]4[CH:10]=[C:9]5[C:14](=[CH:13][C:12]=4[C:19]3([CH3:26])[CH3:25])[CH2:15][C:16]3[CH:17]=[C:18]4[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]4=[CH:7][C:8]5=3)[CH:51]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1c1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC(c3ccccc3)=C1)C2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a solution of 1.0 g (2.59 mmol) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene in 30 ml of THF, 1.75 ml (2.85 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 4 hours. Then, a solution of 0.92 g (3.11 mmol) of 3,6,6-triphenylfulvene in 10 ml of THF was slowly added at room temperature, followed by stirring for 15 hours. To the reaction solution, 20 ml of water was added to terminate the reaction. The resulting solution was subjected to extraction with diethyl ether, then dried over anhydrous magnesium sulfate and vacuum evaporated to dryness to obtain a yellow solid. The solid was washed twice with a small amount of methanol and dried under reduced pressure to obtain 1.24 g of an opaque white solid (yield: 69.1%).