Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].C1COCC1.[CH2:26]([O:28][C:29](=[O:34])[C:30](=O)[CH2:31]Br)[CH3:27].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:26]([O:28][C:29]([C:30]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:31]=1)=[O:34])[CH3:27]
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 3-(4-trifluoromethyl-phenyl)-acrylamide (5.0 g, 23.2 mmol) and NaHCO3 (7.80 g, 92.9 mmol) in THF (90 ml) 3-bromo-2-oxo-propionic acid ethyl ester (5.53 g, 25.6 mmol) is added under an argon atmosphere. The mixture is heated to reflux for 15 h when another portion of 3-bromo-2-oxo-propionic acid ethyl ester (5.53 g, 25.6 mmol) is added and stirring continued for 5 h. After cooling to r.t. the mixture is filtered, concentrated in vacuo and the resulting residue suspended in THF (20 ml). At 0° C. trifluoroacetic acid anhydride (16.3 g, 77.9 mmol) is added and the mixture stirred at room temperature for 16 h. The mixture is neutralized with sat. NaHCO3, the aqueous layer extracted with ethyl acetate (2×200 ml) and the combined organic phases dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/heptane 4:1) yielding 2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid ethyl ester as a colorless solid. Yield 5.84 g (81%)
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:25])([F:26])[F:27])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1
Reactant: OB(O)c1ccccn1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccccn4)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 2-pyridylboronic acid by the method described for Example 36 Step 3. MS (ES+) 521 ([MH]+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Cl.C(O[C:14]([SH:16])=[S:15])C.[K]>CN(C=O)C>[SH:16][C:14]1[S:15][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: CCOC(=S)S
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(S)sc2c1
Yield: 97 %

Procedure:
The title compound was prepared using the method of example 239, starting with 4-amino-3-chloro-benzonitrile (Lancaster, 5.0 g, 32.7 mmol), O-ethylxanthic acid, potassium salt (Lancaster, 11.8 g, 73.7 mmol) in DMF (40 mL). The mercaptobenzothiazole (241) (6.1 g, 97%) was obtained as a pale brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH:13]2[CH2:15][CH2:14]2)O)=[CH:5][CH:4]=1)#[N:2].[Br-].[Li+].N1C(C)=CC(C)=CC=1C.P(Br)(Br)[Br:28]>CCOCC.O>[Br:28][CH2:15][CH2:14][CH:13]=[CH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: BrP(Br)Br
Reactant: N#Cc1ccc(CCC(O)C2CC2)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1cc(C)nc(C)c1
Product: N#Cc1ccc(CCC=CCCBr)cc1
Temperature: -60 °C
Reaction time: 2 h
Yield: 130.7 %

Procedure:
To a solution of 9.8 g of 4-cyanophenylethyl cyclopropyl carbinol in 140 ml of ether was added 4.24 g of lithium bromide and 3 ml of 2,4,6-collidine. The mixture was cooled to -60° C. and 9.8 g of phosphorus tribromide was added over a five minute period. The reaction mixture was allowed to warm to 0° C., kept at that temperature for two hours and then allowed to warm to 18° C. Collidine (18 ml) was added, and after 15 minutes of stirring, the mixture was poured into 200 ml of water and 100 ml of ether. The ether extracts were washed with dilute aqueous sulfuric acid and water, dried over anhydrous magnesium sulfate and concentrated to a volume of 150 ml. Zinc bromide (11.6 g) was then added with cooling, and the mixture was stirred at room temperature for 29 hours. The ether solution was washed with water, dried and concentrated to give 12.5 g of 4 -(6-bromohex-3-enyl)benzonitrile as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12](SC)=[CH:11][CH:10]=2)[O:4]1)[CH3:2].O[O:20][S:21]([O-:23])=O.[K+].[CH3:25]O>O>[CH2:17]([C:3]1([CH2:1][CH3:2])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:21]([CH3:25])(=[O:23])=[O:20])=[CH:11][CH:10]=2)[O:4]1)[CH3:18]
Reactant: CCC1(CC)OC(c2ccc(SC)cc2)=CC1=O
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CCC1(CC)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of the crude 2,2-diethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone (5.6 g) obtained in the previous step in 50 ml TBF and 50 ml methanol, was added dropwise 20 g of OXONE dissolved in 50 ml water at 0° C. Then the mixture was then stirred at room temperature for 14 hours. The insoluble materials were filtered off and the filtrate was concentrated in vacuo. The resulting residue was extracted with water and ethylacetate (150 ml×2). The ethylacetate layer was concentrated and the resulting crude product was purified by column chromatography (hexane/ethylacetate=2:1) to give 4.5 g of 2,2-diethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 109-110° C. NMR: 0.86 (t, J=7.5 Hz, 6H), 1.91 (q, J=7.5 Hz, 4H), 3.10 (s, 3H), 6.14 (s, 1H), 8.04 (d, J=9.0 Hz, 2H), 8.09 (d, J=9.0 Hz, 2H). IR (cm−1): 2973, 1695, 1588, 1561, 1408, 1315, 1152.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[OH:16])[C:9]([O:11][CH3:12])=[O:10])(=O)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl.[NH2:24][OH:25]>C(O)C>[OH:16][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1/[C:1](=[N:24]/[OH:25])/[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc(C(=O)OC)ccc1O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCC/C(=N\O)c1cc(C(=O)OC)ccc1O

Procedure:
A stirred solution of methyl 3-butyryl-4-hydroxybenzoate, pyridine (3.7 mL, 46 mmol), and hydroxylamine hydrochloride (3.55 g, 51 mmol) in ethanol (30 mL) was heated reflux for 2 h. The mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 10:1 hexanes/ethyl acetate) provided methyl 4-hydroxy-3-[(1E)-N-hydroxybutanimidoyl]benzoate (170 mg): 1H NMR (500 MHz, CD3OD): δ 8.30-8.28 (m, 1H), 7.85-7.82 (m, 1H), 6.92-6.89 (m, 1H), 3.88 (s, 3H), 2.87-2.84 (m, 2H), 1.67-1.60 (m, 2H), 1.05-1.00 (m, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O-:18])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].Cl>C1COCC1.O.CCOC(C)=O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C([O-])Cc1ccc(OCCn2ccnc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetate (240 mg) in THF/water (3.3 mL, 10:1) was added fine powder KOH (77 mg). The reaction mixture was stirred at rt overnight. The crude product mixture was acidified with 1.0 N HCl and diluted with EtOAc. A normal aqueous workup with EtOAc was followed. The organic layers were dried over MgSO4, filtered, and concentrated under reduce pressure. The crude acid was taken directly to the next reaction without further purification. Method[1], MS (ESI) 247.1, Retention time=0.323 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=O>CCOCC>[ClH:1].[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH2:10])=[CH:14][CH:15]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCOCC
Product: C=C(c1ccccc1)c1ccc(N)cc1
Product: Cl

Procedure:
A mixture of 400 ml of ethyl ether containing 0.5 mole of 4-chlorophenylmagnesium bromide was added over 1 hour to a mixture of 13.5 g of 4-aminoacetophenone in 500 ml of ether under nitrogen. After heating at reflux for 3 hours, the cooled mixture was quenched with 250 ml of saturated ammonium chloride solution. The dried ethereal layer was evaporated. The residual oil was mixed with 250 ml of 3N hydrochloric acid. After heating on the steam bath for 3 hours, the cooled mixture was separated from a soft solid. The product was taken up in 100 ml of ethanol. Ether (600 ml) was added to give a solid, 14.3 g of 1-(4-aminophenyl)-1-phenylethylene hydrochloride, m.p. 181°-183°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10](Cl)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[N:17]1[CH:22]=[C:21]([S:23]([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)(=[O:25])=[O:24])[CH:20]=[N:19][CH:18]=1.ClC(Cl)C.C([SiH](CC)CC)C.[F:45]C(F)(F)C(O)=O>C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:45])=[CH:11][CH:12]=2)[C:7]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[S:23]([C:21]2[CH:22]=[N:17][CH:18]=[N:19][CH:20]=2)(=[O:25])=[O:24])=[C:6]1[CH3:15]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)Cn1c(C)cc2cc(Cl)ccc21
Reactant: O=Cc1ccccc1S(=O)(=O)c1cncnc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2cncnc2)c2cc(F)ccc21
Temperature: -70 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
A mixture of (5-chloro-2-methylindol-1-yl)acetic acid methyl ester (0.50 g), 2-(pyrimidine-5-sulfonyl)benzaldehyde (0.35 g) and dichloroethane (50 mL) at −70° C. was treated sequentially with triethylsilane (2.5 g) and trifluoroacetic acid (0.81 g), and the resulting mixture was stirred at −70° C. for 1 hour. The mixture was slowly warmed to room temperature and stirred at this temperature for 18 hours. The mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and the phases were separated. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4:1 to 2:3 by volume) to afford the title compound as a brown oil (0.12 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:18](=O)[CH3:19])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].S(O)(O)(=O)=O.[CH3:31][O:32][C:33](=[NH:35])[NH2:34]>CN(C)C=O.O>[CH3:31][O:32][C:33]1[NH:35][C:18]([CH3:19])=[C:11]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:34]=1
Reactant: COC(=N)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Temperature: 60 °C
Yield: 67 %

Procedure:
A reaction mixture containing 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (10.0 g, 36.0 mmol), sodium bicarbonate (8.40 g, 108 mmol), and O-methylpseudourea hydrogen sulfate (8.06 g, 46.8 mmol) in dimethylformamide (54 ml) was heated at 60° C. under argon for about 21/2 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water (six times) and saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue was passed through a short pad of silica gel and crystallized from isopropyl ether/hexanes to give the title compound as yellow crystals (8.04 g).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:27]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([CH3:43])[CH3:42])(=O)=O>CN(C=O)C>[F:20][C:14]1[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:27]3)[C:18]=2[CH:17]=[C:16]([O:19][CH2:40][C:41]([F:44])([CH3:43])[CH3:42])[CH:15]=1
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1c(F)cc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(F)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reaction time: 0.17 h

Procedure:
A 25 ml RBF was charged with (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (629 mg, 1.723 mmol), tetrakis(triphenylphosphine)palladium (199 mg, 0.172 mmol), and pyrimidin-5-ylboronic acid (320 mg, 2.58 mmol). DMF (8613 μL) and sodium carbonate (2M solution) (2584 μL, 5.17 mmol) were added and the mixture was stirred at 85° C. for 2.5 hrs. The mixture was cooled to RT, water (˜5 ml) was added and stirring was continued for 10 min. The precipitate was filtered out, washed with water (3×5 mL), 1:1 i-PrOH/water to remove color and dried in vacuo to afford (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as yellow solid. Step 2: A vial was charged with (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (61.0 mg, 0.167 mmol), cesium carbonate (82 mg, 0.251 mmol), and DMF (670 μL). The resulting mixture was stirred vigorously for 10 min, then the vial was placed in large ice-bath for 10 min and 2-fluoro-2-methylpropyl trifluoromethanesulfonate (33.3 μL, 0.201 mmol) was added dropwise. The ice bath was removed after 5 minutes and the mixture was stirred at RT for 6 hours before being diluted with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12 g Redi-Sep column, eluting with 5-60% gradient of DCM/MeOH/NH4OH (90:10:1) in DCM to give (S)-4′-fluoro-2′-(2-fluoro-2-methylpropoxy)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])=[CH:17][CH:16]=1.[OH-].[Na+].Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Br)c(-c3ccc(-c4ccccc4O)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Br)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 7.8 %

Procedure:
To a semi suspension of crude methyl 6-bromo-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylate (120 mg, 0.284 mmol) in methanol (4 ml) was added 1N NaOH (1 mL, 1 mmol) then heated to 70° C. for 16 hrs. 5N NaOH (1 mL, 5 mmol) was then added and heating continued for 24 hrs. The reaction was cooled and quenched with 4N HCl in dioxane (2 ml, 8 mmol) then concentrated to give a brown solid which was purified by reverse phase preparative HPLC to afford the title compound as a tan solid (9 mg, 8%) MS (AP−) 406.0 (M−H)−. 1H NMR (400 MHz, MeOH-d4) δ: 8.10 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.63 (d, 2H), 7.46 (d, 2H), 7.35 (dd, 1H), 7.17 (td, 1H), 6.86-6.98 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH:25]3[CH2:27][O:26]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH:9]1C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)#[N:30].[CH3:43]CO>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:27]([OH:26])[CH2:43][N:40]3[CH2:41][CH2:42][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:29]#[N:30])[CH2:38][CH2:39]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(-c2nn(C3CO3)c3c2C(C)N(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Temperature: 80 °C
Yield: 83 %

Procedure:
3-(4-Chloro-3-methyl-phenyl)-1-oxiranyl methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (5.33 g, 13.2 mmol) and 1-(2-cyanophenyl)-piperazine (2.97 g, 15.86 mmol) were partially dissolved in EtOH (50 mL) and triethylamine (2 mL). The reaction mixture was heated to 80° C. for 18 h. The mixture was concentrated and purified by column chromatography (silica, 20% acetone/CH2Cl2) to give 3-(4-chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (6.51 g, 83%) as a yellow solid. TLC (silica, 20% acetone/CH2Cl2): Rf=0.35. MS (electrospray): m/z 591.3 (591.3, calculated for C32H39ClN6O3, [M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:44])=[O:43])=[CH:38][CH:37]=1>CN(C=O)C>[CH3:44][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]2[CH3:14])=[CH:37][CH:38]=1)=[O:43]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)c1ccc(CBr)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.512 g, 2.51 mmol) in dry DMF (5.6 ml) at room temperature is treated with BEMP (1.17 ml, 4.01 mmol) dropwise. The reaction mixture is stirred at room temperature for 80 minutes and then treated with 1-bromomethyl-4-methanesulfinyl-benzene (0.934 g, 4.01 mmol). After stirring at room temperature for a further 2 hours, the reaction mixture is partitioned between ethyl acetate/ether (300 ml of a 1:1 mixture) and water (30 ml). The organic portion is separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with DCM/methanol (10:1) to yield the titled product. (MH+ 357)
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][C:23]([CH3:28])([CH3:27])[O:22]4)[C:7]1=[O:29])C.C(OC(=O)CN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O)C>>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]1([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]1=3)[CH2:24][C:23]([CH3:28])([CH3:27])[O:22]4)[C:7](=[O:29])[N:6]2[CH2:5][C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CC(C)(C)O4)c2c(Br)cccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: CC1(C)Cc2cc3c(cc2O1)OCC31C(=O)N(CC(=O)O)c2cccc(Br)c21

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl(4′-bromo-6,6-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained. The product was used directly in the next step.
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13])([CH3:6])[CH3:5].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13])([CH3:6])[CH3:5])=[N+:18]=[N-:19]
Reactant: CC(C)(C(=O)CBr)c1ccc(F)c(C#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C(=O)CN=[N+]=[N-])c1ccc(F)c(C#N)c1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a stirred solution of 5-(4-bromo-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile (10 g, 35.2 mmol) in DMF (100 mL) at 0° C. was added NaN3 (2.52 g, 38.7 mmol, 1.1 eq) portionwise. After stirring 2 h, the residue was diluted with water and extracted with EtOAc. The combined extracts were washed with brine (100 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (silica, Hex/EtOAc=4:1) to give 5-(4-azido-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile (6.6 g, 2 step overall yield 78%). 1H NMR (400 MHz, CDCl3) δ 7.57-7.55 (m, 1H), 7.50-7.46 (m, 1H), 7.25 (t, J=7.2 Hz, 1H), 3.8 (s, 2H), 1.55 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([C:8](=[CH2:12])C(O)=O)=O)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(=O)(O)O.[C:31](=[O:34])(O)[O-].[Na+].[NH2:36][NH2:37]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:8]=[CH:12][C:31](=[O:34])[NH:37][N:36]=2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: O=C([O-])O
Reactant: C=C(C(=O)O)C(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=c1ccc(-c2ccc(F)cc2)n[nH]1

Procedure:
(4'-Fluorobenzoyl)-acrylic acid (582 g, 2.998 mol of m.p.=134°-137° C.) was dissolved in ethanol (3300 ml), p-toluenesulfonic acid (23 g) and sulfuric acid (conc., 4 ml) was added, and the mixture was then refluxed for 18 hours. The mineral acid was then neutralized by adding anhydrous sodium bicarbonate. The inorganic salts were then filtered off, a hydrazine solution (6 mol hydrazine, 700 ml of water) was added to the mechanically stirred solution of the esterification product, and the mixture was refluxed for three hours. A solid product precipitated, and this product was isolated, washed with water, mixed with dilute hydrochloric acid (700 ml of concentrated HCl, 1600 ml of water) while still moist from filtration with suction, and the mixture was refluxed for 2 hours. The mixture was cooled, and the resulting solid product was isolated, washed with water and dried to constant weight. 3-(4'-Fluorophenyl)-6-pyridazinone was obtained in the form of a yellowish solid product (390 g, 2.0508 mol, 68.4% of theory) of m.p.=266°-269° C. Recrystallization from dioxane gave a virtually colorless product which sublimes from about 170° C. in the form of broad crystals and which melts at 269°-270.5° C.