Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:7](=[O:16])[CH:6]=1.I([O-])(=O)(=O)=[O:19].[Na+]>O1CCCC1>[S:13]1[CH:14]=[CH:15][C:11]([N:8]2[CH:9]=[CH:10][C:5]([CH:4]=[O:19])=[CH:6][C:7]2=[O:16])=[CH:12]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1ccn(-c2ccsc2)c(=O)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccn(-c2ccsc2)c(=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-(2-dimethylamino-vinyl)-1-thiophen-3-yl-1H-pyridin-2-one (3.8 mmol) in 50% aqueous tetrahydrofuran (130 mL) is added sodium periodate (2.4 g, 11 mmol). After 17 hours of stirring at room temperature, the reaction mixture is filtered. The filtrate is washed 3× with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide 1-thiophen-3-yl-2-oxo-1,2-dihydro-pyridine-4-carbaldehyde as a yellow powder (0.27 g, 34% over 2 steps).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Li+].[I-].[Na+].[C:12]([C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30]Cl)[CH2:24][CH2:23]2)[CH:19]=[C:18]([CH:32]2[CH2:34][CH2:33]2)[N:17]=1)([CH3:15])([CH3:14])[CH3:13]>CN(C)C=O>[C:12]([C:16]1[N:17]=[C:18]([CH:32]2[CH2:33][CH2:34]2)[CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][S:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:24][CH2:23]2)[N:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Sc1ncccn1
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCCl)CC2)n1
Agent: [I-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCSc3ncccn3)CC2)n1
Temperature: 60 °C
Yield: 113 %

Procedure:
0.4 g of 2-mercapto-pyrimidine (3.57 mmol) were dissolved in 20 ml of dimethylformamide. After addition of 0.09 g of lithium hydroxide (3.57 mmol) and 0.27 g of sodium iodide (1.78 mmol), the reaction mixture was stirred at 60° C. and 1.2 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclopropyl-pyrimidine (3.56 mmol) were added in portions. The reaction mixture was stirred at 60° C. for 1 h, and, after evaporation of dimethylformamide, the residue was partitioned between 30 ml of ethyl acetate and 15 ml of saturated aqueous sodium chloride solution and 15 ml of water. The aqueous phase was re-extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was re-dissolved in 30 ml of ethyl acetate and treated with 4 N hydrochloric acid in dioxane. The precipitated hydrochloride salt was collected by filtration and dried to yield 1.66 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O.C1CCN(CCOC(C2C=CC(Cl)=CC=2)C2C=CC=CC=2)CC1.Cl.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:16]([O:15][C:13]([N:6]1[CH2:7][C@H:8]([NH2:10])[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: Clc1ccc(C(OCCN2CCCCC2)c2ccccc2)cc1
Agent: [Al+3]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (2S,4R)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [Marusawa, H.; Setoi, H.; Sawada, A.; Kuroda, A.; Seki, J.; Motoyama, Y.; Tanaka, H. Bioorganic & Medicinal Chemistry (2002), 10(5), 1399-1415] (1.0 g, 4 mmol) in THF (5 ml) was added to an ice-cooled suspension of LAH (0.6 g, 15 mmol) in THF (5 ml) under Ar. The reaction was stirred for 1 h after which time it was quenched by cautious addition of water. The resulting precipitate was filtered, rinsed with EtOAc and the organics concentrated. The crude (2S,4R)-4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.7 g, 3 mmol) thus obtained was then dissolved in CH2Cl2 (15 ml), saturated NaHCO3 (15 ml) was added followed by acetic anhydride (0.3 ml, 3 mmol) and the mixture stirred for 2 h. The reaction mixture was then separated, the organic phase dried (Na2SO4) and concentrated affording crude (2S,4R)-4-acetylamino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.62 g, 79%). Treatment of this with a 4 N solution of hydrochloric acid in dioxane afforded the title product (0.5 g, quant) as a yellow powder. MS: 159.1 (MH+).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13].C(O)(=O)C>C(OCC)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([CH2:11][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:13])=[CH:15][CH:16]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 5 °C

Procedure:
21.7 g (0.72 mol) of sodium hydride (80% strength, 20% mineral oil) are weighed into a liter of diethyl ether p.a. and 85.5 g (127 ml, 0.72 mol) of diethyl carbonate (VK 22-010) are subsequently added. A solution of 100 g (0.72 mol) of 4-fluoroacetophenone in 300 ml of diethyl ether are added dropwise to this solution at boiling heat over a period of 4 hours (vigorous, mechanical stirrer necessary; a viscous paste is formed). The mixture is then heated to reflux for a further hour, then cooled to about 5° C. and a solution of 50 ml of acetic acid and 100 ml of Et2O is next added dropwise under N2 at this temperature. About 500 ml of H2O are subsequently added dropwise and the organic phase is separated off. The aqueous phase is extracted once again using Et2O (2×400 ml), and the combined ethereal phases are washed with NaHCO3 solution, dried over MgSO4 and concentrated. The residue is distilled over a short Vigreux column.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=O)=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:30]C#N)[CH:27]=[CH:28][CH:29]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]3=[N:20][O:22][C:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=4)=[C:16]3[CH:15]=2)=[CH:12][CH:11]=[N:10]1
Reactant: N#CCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Product: Fc1cccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4F)cc23)c1

Procedure:
The title compound, light yellow solid (85 mg, 65%), MS (ISP) m/z=392.2 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH3:9][C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:11].B(F)(F)F.CCOCC>>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([C:10]([CH3:11])([CH3:9])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:2]=1
Reactant: C=C(C)CC(C)(C)C
Reactant: Cc1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: Cc1ccc(O)c(C(C)(C)CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2.67 h

Procedure:
Preparation was modified from the method of Kitchen, L. J., J. Am. Chem. Soc. 1948, 70, 1290. In a round-bottom flask to which were attached two addition funnels, a mixture of p-cresol (33.12 g, 306 mmol) and 33 mL 2,4,4-trimethyl-1-pentene was purged with nitrogen. The flask was cooled to 0° C., and 162 mL additional olefin (total amount of 2,4,4-trimethyl-1-pentene=1.23 mol, 4.0 eq.) was added dropwise, while a mixture of boron trifluoride etherate (5 mL, 40 mmol) and 30 mL nitrogen-sparged hexanes was added at the same time. The addition of olefin proceeded for 160 min, and subsequently the flask was allowed to warm to room temperature, and then was heated to 45° C. with stirring under nitrogen for 16 h. After cooling back to room temperature, the reaction was quenched by the addition of 121 g of 30% NaOH/H2O and 10 mL hexanes. After separation, the organic fraction was washed with water, and the combined aqueous fractions were washed with hexanes. The combined organic fractions were again washed with water and then distilled. The fraction distilling at 141° C. and 9-10 Torr was saved and analyzed. Yield: 30.56 g waxy white solid (45%). M.P.=42-5° C. 1H NMR was in accordance with literature (PCT Int. Appl. WO 2006120178 A1, inventors Olesen, Preben. H.; Hansen, H. C.; Christiansen, L. B.; Nielsen, F. E.; Petersen, A. K., to Novo Nordisk A/S).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:32][C@H:33]2[CH2:35][O:34]2)(=O)=O)=CC=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:32][C@H:33]2[CH2:35][O:34]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a stirred solution of 1-(4-(benzyloxy)-2-hydroxyphenyl)ethanone (3.36 g, 13.9 mmol) in anhydrous DMF (15 ml) was added NaH (0.62 g, 15.5 mmol). The mixture was allowed to stir at RT for 30 min, and a solution of (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (3.17 g, 13.9 mmol) in DMF was added dropwise at RT. The mixture was slowly heated to 60° C. and stirred for 3 h. The reaction was quenched by addition of water (80 ml) and extracted three times with EtOAc. The combined organic layers were extracted twice with aq 1 M NaOH and washed with water and brine. The organic layer was dried with Na2SO4 and concentrated. The crude product obtained was purified by column chromatography with EtOAc/heptane (1:1) as eluent to afford the title compound (2.64 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10].C(N(CC)CC)C.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[CH3:20][Si:19]([CH3:22])([CH3:21])[O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10]
Reactant: O=C1C=CC(=O)N1CCO
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-hydroxyethyl)maleimide (0.2 g, 1.41 mmol) in dry dichloromethane (10 ml) and triethylamine (0.22 ml, 1.57 mmol) at 0° C. was added chlorotrimethylsilane (TMS-Cl, 0.2 ml, 1.57 mmol). After stirring for 1 hour at room temperature, TLC analysis (ethyl acetate/petroleum ether 1:1) indicated one spot (Rf=0.67). Solvent was removed in vacuo and the residue was dissolved in dichloromethane and filtered through a small silica gel column eluting with dichloromethane. The fractions containing product were pooled and evaporated in vacuo to afford N-(2-trimethylsiloxyethyl)-maleimide (formula II) as colorless flakes (0.3 g; 100% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C(O[C:13](=[O:22])[CH2:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=O)C.CC#N.O>CO>[CH2:20]([O:19][C:17](=[O:18])[CH:15]=[C:14]1[C:13](=[O:22])[N:2]([CH3:1])[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:9]1)[CH3:21]
Reactant: CNc1ccccc1N
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Solvent: O
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)C=C1Nc2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-methyl-1,2-phenylenediamine (6.1 g, 4.99 mmol) in MeOH (50 mL) was added in portion of oxalacetic acid diethyl ester (9.9 g, 5.26 mmol). The mixture was then stirred at rt for 1 h. The precipitate was collected via filtration and was washed with small amount of methanol to yield a pale brownish solid as the pure product: 1H NMR (DMSO-d6) δ=11.1 (bs, 1H), 7.45–7.42 (m, 1H), 7.32–7.29 (m, 1H), 7.15–7.10 (m, 2H), 5.53 (s, 1H), 4.14 (q, J=9.0 Hz, 2H), 3.51 (s, 3H), 1.23 (t, J=9.0 Hz, 3H); HPLC (CH3CN—H2O-0.1% TFA) (short column): Rt=3.91 min.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:8]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32]>>[CH3:21][C:20]1([CH3:22])[N:16]([CH2:15][CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:5]3[S:6][C:2]([S:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:25])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)[C:17](=[O:24])[NH:18][C:19]1=[O:23]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(I)s2)n1
Reactant: Cc1ccccc1S
Product: Cc1ccccc1Sc1ccc(-c2ccnc(NCCN3C(=O)NC(=O)C3(C)C)n2)s1

Procedure:
The title compound was prepared from 1-{2-[4-(5-iodothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethyl-imidazolidine-2,4-dione and 2-methylthiophenol in a manner analogous to Example 259. MS (M+H)+ 454.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C@H:13]([NH:15][C@@H](C2C=CC=CC=2)C)[CH3:14])[CH:7]=1.C([O-])=O.[NH4+]>>[CH3:2][O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C@H:13]([NH2:15])[CH3:14])[CH:7]=1
Reactant: COC(=O)Cc1cccc(C[C@@H](C)N[C@H](C)c2ccccc2)c1
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Product: COC(=O)Cc1cccc(C[C@@H](C)N)c1
Temperature: 25 °C
Yield: 104.8 %

Procedure:
A solution of methyl-[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hydrochloride (Preparation 42) (7.69 g, 22.0 mmol) and ammonium formate (6.94 g, 110 mmol) was heated to 75° C. in the presence of 20% palladium hydroxide-on-charcoal (Pd(OH)2/C, 2.00 g). After 90 minutes the reaction mixture was cooled to room temperature, filtered through arbocel and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane (100 ml) and 880 ammonia (100 ml) and the organic phase separated. The aqueous phase was extracted dichloromethane (100 ml) and the combined organic extracts dried (magnesium sulfate) and reduced in vacuo to give the title compound as a colourless oil (4.78 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13](Cl)[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([N:4]([CH2:5][CH3:6])[CH2:1][CH3:2])[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)c1ccc([N+](=O)[O-])c(N2CCN(C(C)=O)CC2)n1
Reaction time: 1.25 h
Yield: 136.1 %

Procedure:
A solution of 51.22 g of N-acetylpiperazine in 200 ml of acetonitrile was added over 50 minutes at 0° C. to a mixture of 78 g of 2,6-dichloro-3-nitropyridine, 600 ml of acetonitrile and 66.3 g of potassium carbonate and after the mixture was allowed to return to room temperature, it was stirred for 75 minutes. The inorganic salts were filtered off and 180 ml of N,N-diethylamine and 76 g of potassium carbonate were added to the filtrate. The mixture was refluxed for 75 minutes and after cooling, the inorganic salts were filtered off. The filtrate was evaporated to dryness under reduced pressure and the 166.9 g residue were crystallized from 200 ml of ethyl acetate to obtain 87.4 g of the expected product melting at 120° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([OH:22])[C:11]([C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)=[CH:12][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CCOCC>[Cl:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([C:11]1[C:10]([OH:22])=[CH:9][C:8]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH:12]=1)=[O:21]
Reactant: COC(=O)C1=Cc2cc(C(=O)c3cccc(Cl)c3)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)C1=Cc2cc(C(=O)c3cccc(Cl)c3)c(O)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
12.1 g of 4-(m-chlorobenzoyl)-5-hydroxybenzocyclobutene- 1-carboxylic acid methyl ester are dissolved in 120 ml of ether; 100 ml of 2N aqueous sodium hydroxide solution are added and the whole is stirred well for 15 minutes at room temperature. The ether phase is separated off and washed with water. The strongly yellow-coloured aqueous phase is washed with ether. The combined aqueous phases are rendered acidic with concentrated hydrochloric acid and extracted thoroughly with methylene chloride. The combined methylene chloride extracts are dried over magnesium sulphate and concentrated by evaporation. Crystallisation of the residue from ether/petroleum ether yields 4-(m-chlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid in the form of yellow crystals having a melting point of 138°-139°.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9](Cl)[CH:10]=2)[S:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][OH:18]>>[NH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([O:18][CH3:17])[CH:10]=2)[S:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CO
Reactant: COC(=O)c1sc2ncc(Cl)cc2c1N
Agent: [Na]
Product: COC(=O)c1sc2ncc(OC)cc2c1N
Yield: 86 %

Procedure:
Sodium metal (0.46 g, 20 mmol) was added to methanol (20 mL) and allowed to react until metallic sodium was consumed. To the solution was added the product from Example 32A (0.485 g, 2.0 mmol) and the reaction was heated to reflux for 2 h. The reaction was quenched in sat. aq. NH4Cl and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to yield 0.410 g (86%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3H), 4.02 (s, 3H), 6.74 (d, 1H), 7.77 (d, 1H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].Cl[C:7]1[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:13][C:9]=2[N:10]=[CH:11][N:12]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.ClCCl.O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[C:8]3[C:7]([O:4][CH2:3][CH2:2][CH2:1][OH:5])=[N:12][CH:11]=[N:10][C:9]=3[O:13][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=1
Reactant: OCCCO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCO)c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Put 1.13 g (14.85 mmol) 1,3-propanediol in 30 ml THF. Add 833 mg (7.42 mmol) potassium tert.-butylate and stir for 15 min at RT. Then cool to 0° C. and add a solution of 1.0 g (2.97 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 15 ml THF dropwise over a time of 30 min. Then leave to return to RT and stir for a further 2 h. Dilute with dichloromethane and water, acidify with 10% citric acid solution and separate the phases. Extract the aqueous phase once with dichloromethane. Combine the organic phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate, concentrate by evaporation and purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 7:3→1:1). 772 mg (69.0% of theor.) of the target compound is obtained.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>C1COCC1>[N:16]1[CH:17]=[CH:18][C:13]([CH:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[OH:19])=[CH:14][CH:15]=1
Reactant: Brc1cccs1
Reactant: O=Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccncc1)c1cccs1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a stirred solution of 2-bromothiophene (10 g, 61.34 mmol) in dry THF (42 mL) was added n-butyl lithium (42.0 mL, 67.48 mmol) dropwise at −78° C. and the mixture was stirred at same temperature for 30 min. Then a solution of isonicotinaldehyde (6.56 g, 61.34 mmol) in dry THF (30 mL) was added dropwise and continued stirring at −78° C. for another 2 h. The reaction mixture was quenched with NH4Cl solution (10 mL), diluted with water (200 mL) and extracted with diethyl ether (2×200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was triturated with mixture of hexane and diethyl ether to get the desired compound as an off-white solid (4 g, 34%); 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J=4.9 Hz, 1.5 Hz, 2H), 7.45-7.38 (m, 3H), 6.97-6.93 (m, 2H), 6.45 (d, J=4.4 Hz, 1H), 5.97 (d, J=4.4 Hz, 1H).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)#[N:2]>C(O)C.[Pt]=O>[C:1]([CH2:3][CH:4]1[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][CH2:5]1)#[N:2]
Reactant: N#CC=C1CCC2(CC1)OCCO2
Agent: O=[Pt]
Solvent: CCO
Product: N#CCC1CCC2(CC1)OCCO2
Reaction time: 4 h

Procedure:
The above nitrile (2.15 g) is treated with platinum oxide (0.1 g) in ethanol (200 ml) and hydrogenated at 3 atmospheres pressure over 4 hours. Removal of the catalyst and concentration of the solvent gives 8-cyanomethyl-1,4-dioxaspiro[4.5]decane as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].Cl.Cl.[CH3:11][O:12][C:13](=[O:41])[CH2:14][CH:15]([NH2:40])[CH:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[C:31]([CH3:39])[CH:30]=3)=[CH:23][CH:22]=2)[CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:41])[CH2:14][CH:15]([NH:40][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7])[CH:16]1[O:20][N:19]=[C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[C:31]([CH3:39])[CH:30]=3)=[CH:25][CH:26]=2)[CH2:17]1
Reactant: COC(=O)CC(N)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CC(NC(=O)c1ccco1)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reaction time: 2 h
Yield: 100 %

Procedure:
Furan-2-carbonyl chloride ((0.07 g, 0.54 mmol) was added to a mixture of 3-amino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester di-hydrochloride salt (0.22 g, 0.45 mmol) from step 10e, methylene chloride (10 mL) and aqueous sodium carbonate (5 mL) under a nitrogen atmosphere at room temperature. The reaction was stirred vigorously for 2 h, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 3-[(furan-2-carbonyl)-amino]-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester (0.23 g, 100%) as an oil. MS found: (M+H)+=514.