Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH2:36]([Mg]Br)[CH:37]=[CH2:38].[Cl-].[NH4+]>O1CCCC1>[OH:35][C:32]1([CH2:38][CH:37]=[CH2:36])[CH2:31][CH2:30][CH:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: C=CC[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC1(O)CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.8 g) was dissolved in tetrahydrofuran (10 mL), and allylmagnesium bromide (1.0 M diethyl ether solution, 2.1 mL) was added at −78° C. The reaction mixture was warmed to room temperature, and the mixture was stirred for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.26 g, 30%).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=1[Cl:12].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:22]([NH:29][CH:15]([CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(=O)CCc1ccc(Cl)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccc(Cl)c(Cl)c1)NCc1ccccc1
Yield: 33.9 %

Procedure:
A mixture of acetic acid (0.29 ml, 5 mmol), the product of step (a) (700 mg, 2.5 mmol), benzylamine (0.56 ml, 5 mmol) and sodium cyanoborohydride (320 mg, 5 mmol) in ethanol (10 ml) was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous sodium carbonate (saturated). The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane (10:90) to give the title compound as an oil (310 mg). m/e (CI+) 366 (MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[CH2:23][CH2:22][CH2:21][CH2:20][C:14]=3[C:15](=[O:19])[O:16]2)=[CH:11][C:10]=1[O:24]C(=O)C)(=O)C>OS(O)(=O)=O>[OH:24][C:10]1[C:11]([N+:1]([O-:4])=[O:2])=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[O:16][C:15](=[O:19])[C:14]1[CH2:20][CH2:21][CH2:22][CH2:23][C:13]2=1
Reactant: CC(=O)Oc1cc2oc(=O)c3c(c2cc1OC(C)=O)CCCC3
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1oc2cc(O)c(O)c([N+](=O)[O-])c2c2c1CCCC2
Temperature: 25 °C

Procedure:
A solution of 5 M HNO3 in H2SO4 (1 ml) was added to solution of acetic acid 3-acetoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-2-yl ester (1.6 g) in concentrated sulfuric acid (20 ml) and stirred at room temperature for an hour. The mixture was treated with ice (150 g) and filtered. The product was purified by column chromatography on silica (10% methanol in dichloromethane). Yield: 50 mg, melting point 238-255° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][F:13])[CH2:10][F:11].CCN(C(C)C)C(C)C.[CH2:24](Cl)[O:25][CH3:26].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14][CH2:24][O:25][CH3:26])([CH2:10][F:11])[CH2:12][F:13]
Reactant: COCCl
Reactant: Cc1ccc(C(O)(CF)CF)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(CF)(CF)c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 11 h
Yield: 79.2 %

Procedure:
To a stirring solution of 2-(2-bromo-4-methylphenyl)-1,3-difluoropropan-2-ol (1.3 g, 4.9 mmol) in DCM (10 mL) at rt were successively added DIPEA (3.4 mL, 19.6 mol) and MOMCl (0.6 mL, 7.4 mmol) over a 10 min period. The solution was stirred 11 h at rt followed by addition of a saturated aqueous NH4Cl solution (20 mL). The aqueous phase was segregated, and the organic one was washed with water (20 mL), brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated to give pure 2-bromo-1-(1,3-difluoro-2-(methoxymethoxy)propan-2-yl)-4-methylbenzene (1.2 g, yield 80%) 1H NMR (400 MHz, CDCl3): δ 7.50 (s, 1 H), 7.38 (d, 1 H), 7.15 (d, 1 H), 5.15-5.12 (m, 1 H), 5.03-5.00 (m, 2 H), 4.91-4.88 (m, 1 H), 4.62 (s, 2 H), 3.43 (s, 3 H), 2.32 (s, 3 H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[NH:9]C(=O)C(C)(C)C)=[O:2]>Cl>[NH2:9][C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: CC(C)(C)C(=O)Nc1ccncc1C=O
Agent: Cl
Product: Nc1ccncc1C=O
Temperature: 25 °C
Yield: 56.5 %

Procedure:
N-(3-Formyl-pyridin-4-yl)-2,2-dimethyl-propionamide (3.35 g) was dissolved in 3 N hydrochloric acid (50 ml) to prepare a solution which was stirred under reflux for 5.5 hr. The reaction solution was cooled to room temperature, and the reaction solution was then washed with diethyl ether and was neutralized with potassium carbonate powder. Diethyl ether was added thereto, the mixture was extracted, and the diethyl ether layer was dried over potassium carbonate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 4-amino-pyridine-3-carbaldehyde (1.12 g, yield 58%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7](Cl)[CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:51]([C:53]([OH:85])([CH2:83][CH3:84])/[CH:54]=[CH:55]/[C:56]1[CH:61]=[CH:60][C:59]([C:62]([CH2:80][CH3:81])([C:65]2[CH:70]=[CH:69][C:68](B3OC(C)(C)C(C)(C)O3)=[CH:67][CH:66]=2)[CH2:63][CH3:64])=[CH:58][C:57]=1[CH3:82])[CH3:52].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:6]=[C:7]([C:68]2[CH:67]=[CH:66][C:65]([C:62]([CH2:80][CH3:81])([C:59]3[CH:60]=[CH:61][C:56](/[CH:55]=[CH:54]/[C:53]([CH2:83][CH3:84])([OH:85])[CH2:51][CH3:52])=[C:57]([CH3:82])[CH:58]=3)[CH2:63][CH3:64])=[CH:70][CH:69]=2)[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Reactant: COC(=O)Cc1cc(F)cc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(F)cc(CC(=O)OC)c3)cc2)cc1C)CC
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
(3-Chloro-5-fluoro-phenyl)acetic acid methyl ester (Example 127-(1); 35 mg, 0.173 mmol), palladium acetate (2.7 mg, 0.012 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.4 mg, 0.023 mmol), potassium phosphate (73 mg, 0.345 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 55 mg, 0.115 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (57.7 mg, 97%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: BrBr
Reactant: CCc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(O)c(Br)c1
Reaction time: 1 h

Procedure:
A solution was prepared by dissolving 105 g of 4-ethylphenol into 500 ml of chloroform. The solution was cooled by ice water bath, followed by dropwise addition of 45 ml of bromine while stirring. The addition was took 1 hour. Then, the reaction mixture was cooled by an ice water bath while stirring for 4 hours, moved into a separatory funnel to wash with water, an aqueous solution saturated with NaCl, 10% water solution of sodium hydrogencarbonate and an aqueous solution saturated with NaCl in turn, and dried with magnesium sulfate anhydride. The solvent in the reactant was distilled off under reduced pressure to yield 173 g of light brown and oily 2-bromo-4-ethylphenol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:16][CH:15]3[CH:13]([CH:14]3[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(CC)CC.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][N:34]=1>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[CH:3]=[C:4]([C:9]([N:11]3[CH2:16][CH:15]4[CH:13]([CH:14]4[C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[CH2:12]3)=[O:10])[CH:5]=[CH:6][C:7]=2[CH3:8])=[O:38])=[CH:35][N:34]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(N)c4)CC32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(NC(=O)c5ccc(Cl)nc5)c4)CC32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To a solution of (3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone (150 mg, 0.47 mmol) and Et3N (0.25 mL, 1.8 mmol) in CH2Cl2 (4 mL) at 0° C. was added 6-chloronicotinoyl chloride (106 mg, 0.6 mmol). The ice bath was removed after the addition. The reaction mixture was stirred at room temperature for 1.5 h and then purified by flash column chromatography with EtOAc in hexane (60%, then 100%) to give the title compound as a white foam (0.172 g, 80% yield). MS [M+H]+: 462, 464.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:14][C:15]([F:33])([F:32])[C:16]([C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][C@H:24]([C:29](O)=[O:30])[CH2:23][CH2:22][C:21]=2[N:20]=1)([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:29]([CH:24]3[CH2:23][CH2:22][C:21]4[N:20]=[C:19]([C:16]([CH3:18])([CH3:17])[C:15]([F:33])([F:32])[F:14])[CH:28]=[CH:27][C:26]=4[CH2:25]3)=[O:30])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Reactant: CC(=O)N1CCc2ccc(N)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2ccc(NC(=O)C3CCc4nc(C(C)(C)C(F)(F)F)ccc4C3)cc21
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 64.1 %

Procedure:
To a mixture of 1-acetyl-6-amino-indoline (32 mg, 0.18 mmol), (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (40 mg, 0.14 mmol) was added HATU (79 mg, 0.21 mmol) in NMP (0.7 mL), followed by N,N-diisopropylethylamine (73 μL, 0.42 mmol). After 1.3 h, the reaction was heated to 60° C. After 25 h, the material was filtered and purified by reverse-phase HPLC (40-75% ACN in 0.1% HCO2H/H2O). The fractions were stirred with MP-carbonate resin (1.0 g, 3.0 mmol/g) overnight, filtered and concentrated to afford the amide (40 mg, 64%) as a solid foam. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.21 (d, J=1.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.38 (dd, J=1.8, 8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 4.09 (t, J=8.5 Hz, 2H), 3.08 (t, J=8.5 Hz, 2H), 3.02-2.85 (m, 4H), 2.85-2.74 (m, 1H), 2.18-2.12 (m, 1H), 2.16 (s, 3H), 1.93-1.82 (m, 1H), 1.55 (s, 6H); m/z=446.5 (M+1)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:2]1.[CH3:15][C:16]1([CH3:33])[O:20][CH:19]([CH2:21]OS(C2C=CC(Cl)=CC=2)(=O)=O)[CH2:18][O:17]1.CC(C)([O-])C.[Na+].O>O1CCOCC1>[CH3:15][C:16]1([CH3:33])[O:20][C@H:19]([CH2:21][N:1]2[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:2]2)[CH2:18][O:17]1
Reactant: O=C(Nc1cc[nH]n1)c1ccccc1
Reactant: CC1(C)OCC(COS(=O)(=O)c2ccc(Cl)cc2)O1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)c3ccccc3)n2)O1
Temperature: 10 °C
Yield: 49.8 %

Procedure:
N-(1H-Pyrazol-3-yl)-benzamide (2.5 g, 20 mmol) and 4-Chloro-benzenesulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (6.75 g, 22 mmol) were dissolved in anhydrous 1,4-dioxane (30 ml). Sodium tert-butoxide (2.28 g, 23.8 mmol) was added in one portion at room temperature. The yellow suspension was heated to reflux with agitation for 23 hrs. The mixture was cooled to 10° C., water (80 ml) was added. The mixture was extracted with ethyl acetate (30 ml*2), the organic layer was washed with 1N NaOH (20 ml), 10% aqueous NaCl (40 ml*2). The organic layer was dried over Na2SO4, concentrated under reduced pressure to give the crude product as oil. Purified by silicon column (hexane/EA=5:1 to hexane/EA=3:1) to give off-white solid (3 g), yield: 50%. 1H-NMR (400 MHz, d6-DMSO): δ 10.86 (s, 1H), 7.99-8.01 (d, 2H), 7.67 (s, 1H), 7.47-7.58 (m, 3H), 6.63 (s, 1H), 4.4-4.42 (m, 1H), 4.16-4.38 (m, 2H), 4.01-4.05 (m, 1H), 3.75-3.78 (m, 1H), 1.33 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]1[S:13][C:14]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:16]=[C:12]([NH:11][C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:9])[S:13][C:14]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Agent: Cl
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1cccnc1
Yield: 60.6 %

Procedure:
In a manner similar to that in Example 1, by using nicotinoyl chloride hydrochloride (356 mg, 2.00 mmol) in place of isonicotinoyl chloride hydrochloride and using 2-amino-4-(2-furyl)-5-morpholinothiazole (251 mg, 1.00 mmol) obtained in Step 1 of Example 29 in place of Compound a obtained in Reference Example 1, the entitled Compound 31 (216 mg, 61%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16](=O)[NH:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:27])=O.Cl.N>O>[Cl:27][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3nc[nH]c(=O)c23)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: N
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Suspend 135 g (424 mmol) 5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4(3H)-one at RT in 675 ml (7241 mmol) phosphoryl chloride and heat the mixture to boiling (evolution of HCl). After 1 h, cool the dark solution to RT and add dropwise to a vigorously stirred mixture of 2.25 liter water and 4.05 liter conc. ammonia solution (25 wt. %) (heating to 55-75° C., pH>9). At the end of addition, cool to RT and extract the mixture three times with 1.0 liter dichloromethane each time. Combine the organic phases, dry, and concentrate by vacuum evaporation. Stir the residue with diethyl ether, filter with suction and dry at high vacuum. 134.4 g (94.1% of theor.) of the title compound is obtained.
Reaction SMILES: CC1(C)CO[C:5]2([CH:7]=[C:6]2[CH:8]([OH:22])[C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13])[O:4]C1.S(=O)(=O)(O)O.O>C(OCC)C.O1CCCC1>[C:18]([O:17][C:15]([NH:14][C@@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:8]([C:6]1[C:5](=[O:4])[CH:7]=1)[OH:22])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)C1=CC12OCC(C)(C)CO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)c1cc1=O
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a solution of 8.80 g of 2-((2S)-2-tert-Butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone 2,2-dimethyl-1.3-propanediyl acetal obtained in Example 5 in 100 ml of diethyl ether and 20 ml of tetrahydrofuran were added 0.2 ml of 2 N sulfuric acid and 1 ml of water, and the mixture was stirred for 30 minutes. After subsequent addition of 300 ml of ether, the resulting product was washed sequentially in 50 ml of an aqueous 0.01 N sodium hydroxide solution and an aqueous saturated brine. After drying over magnesium sulfate, the product was filtered and concentrated, followed by purification by silica gel column chromatography (eluent; hexane: ethyl acetate =1:2) to produce the objective product (3.15 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]2[CH:18]=[C:19]([CH3:21])[O:20][C:3]=12>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]2[CH:18]=[C:19]([CH3:21])[O:20][C:3]=12
Reactant: CCCCCC1C=Cc2c(c(F)c(F)c3oc(C)cc23)O1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCc2c(c(F)c(F)c3oc(C)cc23)O1

Procedure:
2.8 g (9.58 mmol) of 4,5-difluoro-2-methyl-7-pentyl-7H-furo[3,2-f]chromene are hydrogenated for a few minutes in toluene using elemental hydrogen in the presence of Pd/C (5% Pd). The reaction soln. is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=2:1). The further purification is carried out by recrystallisation from ethanol, giving 4,5-difluoro-2-methyl-7-pentyl-8,9-dihydro-7H-furo[3,2-f]chromene as a colourless solid having an m.p. of 61° C. (Δ∈=−6.7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Thus, in a typical procedure, p-chlorobenzene sulfonyl chloride (24 g, 0.115 mol) was added to 250 ml H2O and the resulting suspension was cooled to 0° C. and stirred for 1 hour. Sodium sulfite (15.1 g, 0.120 mol) was then added and the reaction kept at 0° C., and a pH of 7.5 was maintained by addition of 15 percent NaOH using a pH-stat. After two hours the reaction was allowed to warm to 25° C. and stirred for an additional five hours. The resulting clear solution was filtered, the filtrate cooled to 0° C. and 12N HCl at 0° C. was added to the filtrate. The resulting precipitate was collected by filtration and dried under vacuum, to give p-chlorobenzenesulfinic acid as a white solid, 17.3 g (85 percent) mp 94°-96° C. (lit 93°-96° C.). The salt was generated by slurrying the acid in an EtOH/NaOH solution containing an excess of base. The sodium salt was purified by recrystallization from EtOH. Other metal sulfinate catalysts useful according to the present invention are similarly prepared.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH2:24])=[N:13][N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=1>ClCCl.C(N(CC)CC)C>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:24][C:1](=[O:5])[CH2:2][CH:3]=[CH2:4])=[N:13][N:14]2[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:10][CH:9]=1
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(=O)Nc1nn(C(=O)OC(C)(C)C)c2cc(Cl)ccc12
Temperature: 19 °C
Reaction time: 16 h

Procedure:
0.45 cm3 of predistilled crotonyl chloride is added to 1 g of 6-chloro-1-[(1,1-dimethylethoxy)carbonyl]-1H-indazole-3-amine described previously, in 40 cm3 of dichloromethane and 1.05 cm3 of triethylamine. The mixture is stirred at about 19° C. for 16 hours. The medium is then concentrated under reduced pressure (20 kPa; 40° C.). The residue is taken up in 100 cm3 of ethyl acetate and 50 cm3 of distilled water. The organic phase is then washed with 50 cm3 of saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under the conditions already described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.). After drying (90 Pa; 45° C.), 120 mg of N-(6-chloro-1-[(1,1-dimethylethoxy)carbonyl]-1H-indazol-3-yl)-3-butenamide are obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:9]([CH3:20])[C:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH3:20])[CH:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1)[OH:11])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(C(=O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1(C(O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.5 %

Procedure:
A solution of ethyl 1-[2-(dibenzylamino)propanoyl]cyclopropanecarboxylate (1.31 g) in methanol (60 mL) was cooled to 0° C., 90% sodium borohydride (350 mg) was added, and the mixture was stirred at room temperature for 17 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue s was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→1/1) to give the title compound as a colorless oil (yield: 1.31 g, 99%).