Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1.C([Li])CCC.[Cl:20][CH2:21][C:22](N(OC)C)=[O:23].Cl>CC(OC)(C)C.O>[Cl:20][CH2:21][C:22]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[CH:4][CH:3]=1)=[O:23]
Reactant: Cc1ccc(C)n1-c1ccc(Br)cn1
Reactant: CON(C)C(=O)CCl
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
A solution of 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine (1.00 Kg 3.98 mol) in TBME (7.5 L) was cooled to −70° C. n-Butyl lithium (2.5N in hexane; 1.73 L, 4.32 mol) was added drop-wise over 1 hour maintaining the temperature between −74° C. and −69° C. The mixture was then stirred at a temperature between −74° C. and −69° C. for a further 15 minutes. A solution of 2-chloro-N-methoxy-N-methylacetamide (0.65 Kg, 4.72 mol) in TBME (3.0 L) was then added drop-wise over 100 minutes maintaining the temperature between −73° C. and −67° C. The resulting mixture was then stirred at temperature between −73 and −67° C. for a further 100 minutes. 2N HCl (5.0 L) was then added drop-wise over 45 minutes, allowing the temperature to rise from −70° C. to 17° C. during the addition. TBME (4.0 L) and water (2.0 L) was added to the resulting suspension and the mixture was stirred before allowing the phases to separate. The organic layer was washed with water (2.0 L), and aqueous NaHCO3 (0.13 Kg in 2.0 L of water) and water (2.0 L) before concentrating in vacuo. IPA (1.50 L) was added to the residue and the mixture was heated to reflux. The mixture was then allowed to cool to room temperature and stirred overnight, before cooling to 8-12° C. for 1 hour. The product was collected by filtration, washed with IPA (2×0.1 L) and dried at 45° C. under vacuum overnight. Yield 78.8% (0.78 Kg), δH (CDCl3, 300 MHz) 2.20 (6H, s), 4.70 (2H, s), 5.95 (2H, s), 7.35 (1H, d), 8.40 (1H, dd), 9.15 (1H, d) ppm. MS m/z 249 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1[OH:24])=[O:5])C.C(OC(C)C)(=O)CC(OC(C)C)=O>>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([OH:5])=[O:3])=[C:7]([OH:24])[C:8]2[S:23][CH:22]=[CH:21][C:9]1=2
Reactant: CCOC(=O)c1c(O)c2sccc2n(Cc2cccc(F)c2)c1=O
Agent: CC(C)OC(=O)CC(=O)OC(C)C
Product: O=C(O)c1c(O)c2sccc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared by using the same procedure as described for 4-(3-fluoro-benzyl)-7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (15) by using diisopropyl malonate. 1H-NMR (DMSO-d6) δ 1.30 (d, J=6.4 Hz, 6H), 5.17 (m, 1H), 5.36 (s, 2H), 7.08 (m, 3H), 7.31 (m, 2H), 8.15 (dd, J=2.4, 5.2 Hz, 1H), 13.41 (b, 1H) ppm; EIMS m/z 362 (M+1).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8]([C:10]1[NH:11][C:12](=[S:16])[NH:13][C:14]=1[CH3:15])=[O:9])[CH3:6].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CCO>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[C:12]([S:16][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])[NH:13][C:14]=1[CH3:15])=[O:9])[CH3:6]
Reactant: CCOC(=O)c1[nH]c(=S)[nH]c1C
Reactant: CCOC(CBr)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc(SCC(OCC)OCC)[nH]c1C
Temperature: 25 °C

Procedure:
A solution of sodium ethoxide (5.37 mmol) in EtOH (3.3 mL) is added to a solution of 5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (5.37 mmol) in EtOH (7.0 mL). Bromoacetaldehyde diethyl acetal (5.37 mmol) is added and the mixture is stirred at reflux for 12 h. After cooling to RT the mixture is filtered and concentrated in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.70 min; [M+H]+=303.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](F)[CH:24]=1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([N:14]2[C:13]([C:12]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][O:10][C:11]=3[CH3:18])=[CH:17][N:16]=[CH:15]2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1c[nH]cn1
Reactant: CCOC(=O)c1cccc(F)c1
Product: CCOC(=O)c1ccc(-n2cncc2-c2c(-c3cccc(F)c3)noc2C)cc1
Yield: 53 %

Procedure:
As described for Example 1, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (3.89 g, 16.0 mmol) was converted, using 3-fluorobenzoic acid ethyl ester instead of 4-fluoroacetophenone, to the title compound (3.34 g, 53%) which was obtained as a yellow solid. MS: m/e=391.9[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([Br:16])[N:6]=1)=[O:4].[C:17]1(C)[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.C(CC(=O)C)C(C)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:22]2[CH3:21])=[CH:9][C:8]([C:12]([F:15])([F:13])[F:14])=[C:7]([Br:16])[N:6]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(Br)c(C(F)(F)F)cc1-n1c(C)ccc1C
Temperature: 25 °C

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (2 g, 6.69 mmol) was suspended in toluene (8 ml), and treated with p-toluenesulfonic acid (TsOH) (0.115 g, 0.669 mmol) and acetonylacetone (0.941 ml, 8.03 mmol). The reaction mixture was heated at reflux for 2 hours (using Dean-Stark apparatus) and allowed to cool to RT overnight. The resulting dark red/black solution was concentrated in vacuo to remove toluene and the crude residue diluted with EtOAc (200 ml), washed with NaHCO3 (50 ml), dried (MgSO4) and concentrated in vacuo to give a brown solid. Purification of the solid by chromatography on silica eluting with EtOAc/iso-hexane afforded the title compound; LC-MS Rt=5.58 min [M+H]+377/379 (Method 10minLC_v002).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([CH:8]1[CH2:13][CH:12]([N:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=3[C:17]3=[N:25][O:26][C:27]([CH3:28])=[C:16]3[C:15]2=[O:29])[CH2:11][N:10]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:9]1)=[O:7])C>O.O1CCOCC1>[C:33]([O:32][C:30]([N:10]1[CH2:11][CH:12]([N:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=3[C:17]3=[N:25][O:26][C:27]([CH3:28])=[C:16]3[C:15]2=[O:29])[CH2:13][CH:8]([C:6]([OH:7])=[O:5])[CH2:9]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)C1CC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)CN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc2c1c(=O)n(C1CC(C(=O)O)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
Add a solution of LiOH (370 mg, 15.5 mmol) in water (50 mL) to a solution of 5-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolinyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.5 g, 3.1 mmol) in dioxane (50 mL). Stir 4 H at room temperature and concentrate to dryness. Partition between 20% iPrOH/CHCl3 and water. Acidify to pH 1 with 5N HCl. Extract 2× with 20% iPrO/CHCl3. Wash combined organics with brine, dry over Na2SO4, filter, and concentrate to dryness to afford the title compound (1.43 g, 100%) as a yellow foam as a mixture of cis isomers. MS(IS) 460.4 (M−1); TLC (10% MeOH/CHCl3) Rf=0.31.
Reaction SMILES: O=[C:2]([CH:8]1[C:17](=O)[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29]>C(O)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]1[C:17]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][CH2:9][C:8]=2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:29]1
Reactant: CCOC(=O)C(=O)C1CCCc2ccsc2C1=O
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1ccsc1-2
Yield: 35 %

Procedure:
560 mg of ethyl 2-oxo-2-(8-oxo-5,6,7,8-tetrahydro-4H-cyclo hepta[b]thiophen-7-yl)acetate prepared in example 9d are solubilized in absolute ethanol (11 mL). 580 mg of 2,4-dichlorophenyl-hydrazine hydrochloride are added. The reaction mixture is heated under reflux conditions for 14 hours. The solvent is removed under vacuum and the obtained residue is purified by chromatography on silica gel by using as eluent a mixture of ligroin/ethyl acetate 9:1 volume/volume. 300 mg of ethyl 1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-thieno[3′,2′:6,7]-cyclo-hepta[1,2-c]pyrazol-3-carboxylate are obtained (orange solid; yield 35%). Rf=0.20 (ligroin/ethyl acetate 9/1 volume/volume); 1H NMR (CDCl3) δ (ppm): 7.55 (d, 1H, ArH), 7.48 (d, 1H, ArH), 7.42 (dd, 1H, ArH), 7.03 (d, 1H, ArH), 6.79 (d, 1H, ArH), 4.44 (q, 2H, OCH2), 3.29 (m, 2H, CH2), 2.99 (m, 2H, CH2), 2.06 (m, 2H, CH2), 1.42 (t, 3H, CH3); 13C NMR (CDCl3) δ (ppm): 162.8, 143.2, 142.4, 137.2, 136.4, 135.3, 131.9, 130.3, 130.0, 128.1, 124.8, 124.2, 122.4, 61.0, 30.9, 26.1, 24.4, 14.5; FT-IR (film) νmax: 3092.7, 2928.9, 1712.5, 1486.6, 1446.9, 1245.6, 1190.9, 1100.3, 947.0, 713.9, 641.6, 610.6 cm−1.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:11][C:9]1[C:10]2[C:2]([S:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)=[CH:3][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Reactant: COc1cccc(S)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(Cl)c23)c1
Temperature: 70 °C
Yield: 41 %

Procedure:
5-Bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.74 mmol) was dissolved in 3 mL dimethylformamide. 3-Methoxybenzenethiol (140 mg, 1.10 mmol), copper(I) iodide (205 mg, 1.1 mmol) and potassium carbonate (152 mg, 1.1 mmol) were added. The reaction vessel was sealed and submitted to three vacuum-nitrogen cycles. The reaction was heated at 70° C. for 5 h. The mixture was poured into water-ice and extracted twice with ethyl acetate. The organics were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified using SP1® Purification System (0% to 20%, hexane-ethyl acetate) to obtain 128 mg (70% yield) of the title compound as a solid. Purity 83%.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]CN=C=NCCCN(C)C.Cl>CO.CN(C1C=CN=CC=1)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([O:12][CH3:23])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 12 h

Procedure:
After 1.80 g of Z-Phe was dissolved in 20 mL of MeOH, 73 mg of DMAP, 1.38 g of WSCD HCl were added at 0° C., followed by stirring at 4° C. for 12 hours. The solvent was concentrated and the concentrate was dissolved in AcOEt, followed by washing with 1N HCl aq., satd. NaHCO3 aq., and satd. NaCl aq. After drying over Na2SO4, the solvent was concentrated to give Z-Phe-OMe as oil. After dissolving in 20 mL of dry THF, 196 mg of LiBH4 was added thereto and the mixture was stirred at room temperature for 15 hours. The solvent was concentrated and the concentrate was dissolved in AcOEt and the residue was washed with 1N HCl aq., satd. NaHCO3 aq., and satd. NaCl aq. After drying over Na2SO4, the solvent was concentrated and ether-petroleum ether was added to give 1.45 g (yield 85%) of Z-Phe-ol as precipitates. After 60 mg of 60% NaH was suspended in 10 mL of dry THF, 285 mg of Z-Phe-ol, 264 mg of 18-crown-6 and 1.48 mL of tert-butyl bromoacetate were added at 0° C. While returning to room temperature, the mixture was stirred for 15 hours.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C.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:3]1([C:1]#[C:2][C:10]2[CH:4]=[CH:3][CH:1]=[CH:2][C:11]=2[CH2:12][C:13]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:1]=[CH:2][N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: C1CCNC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: C(#Cc1ccccc1Cc1nccc2ccccc12)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) and ethynylbenzene (204 mg, 2.0 mmol) in pyrrolidine (1.5 ml) was added to a solution of the compound of Example B25 (345 mg, 1.07 mmol) in pyrrolidine (1.5 ml) under nitrogen atmosphere, and the mixture was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (280 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[CH:20].N#N>C1(C)C=CC=CC=1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:20]#[C:19][C:18]([CH3:22])([CH3:21])[CH3:17])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1I
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)C#Cc1nc(Cl)ccc1N
Temperature: 70 °C
Yield: 87.9 %

Procedure:
To a solution of 6-chloro-2-iodo-pyridin-3-ylamine (16.0 g, 62.7 mmol) in toluene (160 mL) and water (80 mL) were added Et3N (12.7 g, 125 mmol), Pd(PPh3)2Cl2 (2.2 g, 3.1 mmol), CuI (238 mg, 1.3 mmol) and 3,3-dimethyl-but-1-yne (7.7 g, 94 mmol) successively under N2 atmosphere. The reaction mixture was heated at 70° C. for 3 hours and was allowed to cool to room temperature. The resulting mixture was extracted with ethyl acetate (150 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 6-chloro-2-(3,3-dimethyl-but-1-ynyl)-pyridin-3-ylamine (11.5 g, 88%), which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-hydroxybenzoate (0.200 g; 1.31 mmol), benzeneboronic acid (0.321 g; 2.63 mmol), copper acetate (0.477 g; 2.63 mmol) and pyridine (0.213 mL; 2.63 mmol) in dichloromethane (8 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:18][CH2:17][C:12]3([NH:16][CH2:15][CH2:14][CH2:13]3)[CH2:11]2)[CH:7]=[N:8][CH:9]=1)[CH3:2].C=O.[C:21](=O)(O)[O-].[Na+]>C(O)=O>[CH3:21][N:16]1[C:12]2([CH2:17][CH2:18][N:10]([C:6]3[CH:7]=[N:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:11]2)[CH2:13][CH2:14][CH2:15]1
Reactant: O=C([O-])O
Reactant: CCOc1cncc(N2CCC3(CCCN3)C2)c1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CCOc1cncc(N2CCC3(CCCN3C)C2)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a stirring solution of 7-(5-ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (360.4 mg, 1.4 mmol) in 37% aqueous solution of formaldehyde (4 mL) was added 98% formic acid (2 mL) under nitrogen. The reaction mixture was heated to reflux for 8 h. The reaction mixture was cooled to room temperature, then basified with saturated aqueous sodium bicarbonate to pH 8-9 and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to afford a viscous brown liquid. This was distilled using a Kugelrohr apparatus (2 mm, 180° C.) to give a very light cream-colored syrup (340 mg, 89.3%).
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:37])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1)=O)(C)(C)C.[ClH:38]>C(O)(C)C>[ClH:38].[NH2:8][C:9]1([CH3:37])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1
Reactant: COc1c(N2CC3(CC3)C(C)(NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Solvent: CC(C)O
Product: COc1c(N2CC(C)(N)C3(CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 55 °C
Yield: 92 %

Procedure:
7-[7-(tert-Butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in which configuration of the tert -butoxycarbonylamino group in the substituent at position 7 is the same as the one produced in Example 9 (267.2 g) was suspended in isopropyl alcohol (1.6 L), and 6N hydrochloric acid (405 mL, 2.43 mol) was added to the suspension while the suspension was stirred in an oil bath at 55° C. The mixture was stirred at the same temperature for 3.5 hours, and after allowing to cool to room temperature, isopropyl alcohol (2.4 L) was added. The reaction vessel was cooled in a water bath at 5° C., and the mixture was stirred at the same temperature for 13 hours. The precipitated crystals were collected by filtration and after air drying for several hours, the crystals were dried under reduced pressure at 40° C. to obtain 223.3 g (471 mmol, 92%) of the target compound as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8](=[O:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(O)COc1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
11.4 g (0.05 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-ol were added to a mixture of 14.7 g (0.05 mole) of potassium dichromate in 12.25 g of sulphuric acid and 73.5 g of water at 30° C., whereupon the temperature rose to about 45° C. The mixture was stirred overnight at room temperature and then extracted three times with ether. The combined organic phases were washed with sodium bicarbonate and water, dried over sodium sulphate and concentrated. 7.8 g (69% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one of melting point 58° C. were obtained. ##STR25##
Reaction SMILES: [K].[C:2]([CH:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[NH:24][NH2:25]>Cl>[C:5]([C:4]1[C:2]([NH2:3])=[N:25][N:24]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:20])([F:22])[F:21])=[CH:16][C:15]=2[Cl:23])[C:10]=1[NH2:11])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C#N)C#N
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [K]
Product: CCOC(=O)c1c(N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Yield: 38.4 %

Procedure:
Ethyl dicyanoacetate potassium salt (35.2 g) was added to a stirred suspension of 2,6-dichloro-4-trifluoromethylphenylhydrazine (49 g) in hydrochloric acid (0.9M; 220 ml) and the mixture was stirred and boiled under reflux for 18 h, then cooled to precipitate a solid which was filtered off, triturated with diethyl ether (250 ml) and dried to give an off-white solid which was recrystallized from ethyl acetate-hexane to give 4-carboethoxy-3,5-diamino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (29.2 g), m.p. 196-197° C., in the form of an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Temperature: 0 °C
Yield: 97 %

Procedure:
To a solution of methyl 2,2′-dimethyl-1,1′-biphenyl-4-carboxylate of Step A (24.7 g, 103 mmol) in tetrahydrofuran:methanol (5:1, 200 mL) was added 1N sodium hydroxide (108 mL, 108 mmol) and the reaction mixture was heated at reflux for 1 hour. The cooled reaction mixture was then concentrated in vacuo to remove organic solvents. The resulting aqueous solution was cooled to 0° C. and 2N hydrochloric acid (60 mL, 120 mmol) was added slowly followed by water (60 mL) to facilitate stirring of the precipitated product. The suspension was stirred for 1 hour at 0° C., then filtered to afford the title compound (22.6 g, 97%) as a white solid, m.p. 140-143° C. MS [(−)ESI, m/z]: 225 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32](F)=[CH:31][C:30]=3[C:36]([F:39])([F:38])[F:37])(=[O:28])=[O:27])[CH2:23][N:22]2[C:40]2[N:41]([CH:46]3[CH2:49][CH2:48][CH2:47]3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14]>CN(C=O)C>[C:13]([C:15]1([NH:18][C:19]([C@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:31][C:30]=3[C:36]([F:37])([F:39])[F:38])(=[O:27])=[O:28])[CH2:23][N:22]2[C:40]2[N:41]([CH:46]3[CH2:49][CH2:48][CH2:47]3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14]
Reactant: OCC(F)(F)F
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
2,2,2,-Trifluoroethanol (10 ul, 137 umol; CAS Reg. No. 75-89-8 99) and cesium carbonate (45 mg, 137 umol) were added to a solution of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (37 mg, 69 umol; example 388 g) in DMF (500 ul) under an argon atmosphere. The reaction mixture was stirred for 72 h at ambient temperature and partitioned between ice water/brine 1/1 and iPrOAc. The layers were separated and the aqueous layer was extracted one more time with iPrOAc. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give a yellow foam which was purified by preparative chiral HPLC to give the title compound (6 mg, 10 umol; 14%) as colorless oil. MS (ESI): m/z=620.2 [M+H]+.