Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:21][CH:22]([OH:33])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[NH2:19])=[CH:14][N:13]=1)C1C=CC=CC=1>C(O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][CH2:21][CH:22]([OH:33])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[N:13][CH:14]=1)(=[O:20])[NH2:19]
Reactant: COc1ccccc1OCC(O)CN(CCOc1ccc(C(N)=O)cn1)Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1OCC(O)CNCCOc1ccc(C(N)=O)cn1

Procedure:
A solution of 17.3 g of 1-[N-benzyl-N-[2-(5-carbamoyl-2-pyridyloxy)-ethyl]-amino]-3-(2-methoxy-phenoxy)-2-propanol in 180 ml of ethanol is hydrogenated analogously to Example 1, giving 1-[2-(5-carbamoyl-2-pyridyloxy)-ethylamino]-3-(2-methoxy-phenoxy)-2-propanol, which melts at 132°-133° C. after crystallisation from ethanol. It forms a neutral fumarate as a hemihydrate which melts at 98°-105° C. after crystallisation from methanol.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[C:20](Cl)[N:21]=[CH:22][C:15]=2[N:14]([CH3:30])[C:13]1=[O:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[C:20]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[CH:32]([CH3:34])[CH3:33])[N:21]=[CH:22][C:15]=2[N:14]([CH3:30])[C:13]1=[O:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)CC(O)c1c(Cl)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: CC(C)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CC(O)c1c(-c2ccccc2C(C)C)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-(1-hydroxy-3-methylbutyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (See Compound 48, step 1, 130 mg, 0.277 mmol), 2-isopropylphenyl boronic acid (90.8 mg, 0.554 mmol), aq. 2M K3PO4 (0.68 ml, 1.35 mmol) in dioxane (1 mL) and water (0.2 mL) was added Pd(dppf)Cl2 (8 mg, 0.01 mmol). The reaction was degassed with nitrogen (3×), heated at 120° C. (MW) for 1.5 h, cooled to RT, diluted with EA (10 mL) and water (2 mL) and filtered. The filtrate was concentrated to a residue which was purified by Prep TLC PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-5-(1-hydroxy-3-methylbutyl)-6-(2-isopropylphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (22 mg, 14.3% yield) as a colorless oil. LCMS: MH+ 554 and TR=2.415 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](OS(C(F)(F)F)(=O)=O)=[C:12]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.O1CCC[CH2:34]1.C[Zn]C.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.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:34])=[C:12]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2=C(OS(=O)(=O)C(F)(F)F)c3ccc(OC)cc3C3CCCCC23)cc1
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn]C
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C2=C(C)c3ccc(OC)cc3C3CCCCC23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Combine trifluoro-methanesulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,10a-hexahydro-phenanthren-9-yl ester (0.523 g, 1.12 mmol), Pd-tetrakis (45.0 mg, 0.04 mmol), and tetrahydrofuran (10.0 mL), and stir under nitrogen atmosphere at 0° C. After 15 minutes, add dimethylzinc (3.5 mL, 3.44 mmol) dropwise. Allow the reaction to warm to room temperature and stir for 18 hours, then heat reaction at 40° C. for 3 hours. Add ethyl acetate and water. Wash the organic phase with brine, dry over anhydrous sodium sulfate, concentrate, and chromatograph eluting with 0% to 20% ethyl acetate/hexanes to yield the titled compound (0.224 g, 60%) as a white solid. TLC Rf=0.30 in 5:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.32 (s, 1H), 7.20 (d, 2H, J=8.8 Hz), 6.95 (m, 3H), 6.79 (m, 1H), 3.88 (m, 6H), 3.21 (m, 1H), 2.46 (m, 2H), 1.97 (s, 3H), 1.74 (m, 1H), 1.55 (m, 3H), 1.38 (m, 1H), 1.15 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=3[CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(C)ccc3C)cccc2c1N
Yield: 83.1 %

Procedure:
Using method B, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (250 mg, 0.702 mmol) and 2,5-dimethylphenylboronic acid (150 mg, 1.00 mmol) were reacted to afford the title compound (195 mg, 83% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.87 (m, 1H), 7.75-7.64 (m, 2H), 7.23-7.07 (m, 3H), 3.44 (apparent quartet, J=7.0 Hz, 2H), 2.35 (s, 3H), 2.01 (s, 3H), 1.64 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=335 HPLC 1.98 min.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[O:14][CH2:15][C:16]#[N:17]>>[C:16]([CH2:15][O:14][C:13]1[CH:12]=[C:11]([NH:10][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:20]=[CH:19][CH:18]=1)#[N:17]
Reactant: N#CCOc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: N#CCOc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (325 mg, 1.70 mmol) was coupled to (3-amino-phenoxy)-acetonitrile (172) (250 mg, 1.69 mmol) using Method C. The residue was purified by column chromatography eluting with a stepped gradient of 10-30% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@@:6]12[CH2:13][CH2:12][C@@H:11]1[CH2:10][CH2:9][CH2:8][C:7]2=O)[CH3:2].[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@:6]12[CH2:13][CH2:12][C@H:11]1[CH2:10][CH2:9][C:8]1[C:17]3[C:16]([NH:22][C:7]=12)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:2]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C[C@@]12CC[C@@H]1CCCC2=O
Product: CCOC(=O)C[C@]12CC[C@H]1CCc1c2[nH]c2ccccc12
Yield: 16.6 %

Procedure:
cis-2-Oxobicyclo[4.2.0]octane-1-acetic acid ethyl ester (3.5 g, 17.01 mmol) and phenylhydrazine (1.9 mL, 18.8 mmol) were allowed to react according to the procedure of Example 2. Flash chromatography (SiO2, 10% EtOAC/petroleum ether) afforded 0.798 g (16%) of cis-1,2,2a,3,4,9-hexahydro-9bH-cyclobuta[a]carbazole-9b-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])[CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:3]=1.[CH3:28]C(C)([O-])C.[K+].CCOC(C)=O>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:9])([CH3:12])([CH3:16])[CH3:28]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCCCCCCC1C=C(Cl)C=CN1C(=O)Oc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC1C=C(Cl)C=CN1C(=O)OC(C)(C)C
Temperature: -42 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a stirred solution of the 4-Chloro-1-(phenoxycarbonyl)-2-n-undecyl-1,2-dihydropyridine (5.31 g, 13.62 mmol) in 157 ml of THF at −42° C. was added dropwise over 15 minutes a 11.0M solution of potassium t-butoxide (54.5 ml, 54.5 mmol). The resulting orange solution was stirred for 1 h at −42° C. The cooling bath was removed, and the reaction mixture was allowed to stir for 20 min while being slowly warmed to room temperature. Water (40 ml) and ether (80 ml) were added and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with cold 1.0 N NaOH (2×35 ml), and brine. The organic phase was dried over MgSO4, filtered through Celite, and concentrated by evaporation to give the crude product. Column chromatography with 5% EtOAc in hexanes afforded 3.5 g (83%) of the product as a colorless oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) d 6.92-6.61 (pair of br d, 1H), 5.53 (pair of br d, 1H), 5.55 (br s, 1H), 5.25-5.11 (pair of br d, 1H), 4.82-4.63 (br m, 1H), 1.53 (s, 9H), 1.24 (br s, 20H), 0.83 (t, 3H); 13C NMR (75 MHz) 152.6 (s), 151.8 (s), 127.7 (s), 127.5 (s), 117.8 (s), 117.4 (s), 106.6 (s), 106.2 (s), 81.7 (s), 54.1 (s), 53.2 (s), 34.3 (s), 33.8 (s), 31.9 (s), 29.7 (s), 29.6 (s), 29.5 (s), 29.3 (s), 28.1 (s), 24.3 (s), 22.7 (s), 14.1 (s) ppm; FT-IR 2954, 2926, 2855, 1717, 1633, 1369, 1390, 1171, 1145, 1129, 1054 cm−1.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[CH3:23])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(F)C=2C)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:25]1([CH2:24][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[CH3:23])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(F)c2C)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Cc1c(F)cccc1NCC1CCCC1
Product: Cc1c(F)cccc1N(CC1CCCC1)C(=O)Nc1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-fluoro-2-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-fluoro-2-methyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]([C:6](=[O:7])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:23][C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In this example 5.0 grams (0.019 mole) of t-butyl 2,4-dichlorophenoxymethyl ketone and 2.1 ml (0.022 mole) of 3-pyridinecarboxaldehyde are added to 50 ml of methanol containing 0.1 g of sodium methoxide. The mixture is then stirred at room temperature for 5 hours and then evaporated to remove the methanol solvent, affording a semi-solid residue. The residue was then partitioned between diethyl ether and water. The separated ethyl ether phase was then extracted sequentially with 1N. aqueous sodium hydroxide, washed three times with water and then one time with brine. The diethyl ether phase was then dried over magnesium sulfate, filtered, then concentrated in vacuo affording a yellow oil. The yellow oil was then chromatographed on silica gel eluting with hexane ethyl acetate mixtures. The chromatographed fractions were combined by a thin layer chromatographed profile and then concentrated by evaporation affording the title compound as a viscous oil, 5.9 g.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([CH:9](O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:7][N:6]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([C:4]2[C:8]([CH:9]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:7][N:6]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-n2cc(C(O)CC(C)C)c(C3CC3)n2)cc1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COc1ccc(-n2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C3CC3)n2)cc1
Yield: 12 %

Procedure:
Using 1-[3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]-3-methylbutan-1-ol (0.5 g) synthesized in Example 44(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.33 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (80 mg, 9%) was obtained as a white solid.
Reaction SMILES: [O:1]1C[CH:2]1[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[C:39](=[O:42])([O-])O.[Na+]>O1CCOCC1.O>[OH:1][CH:2]([CH2:39][OH:42])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:19][CH2:20]2)=[O:14])=[CH:32][CH:33]=1
Reactant: O=C([O-])O
Reactant: O=C(c1ccc(OCCCCC2CO2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(OCCCCC(O)CO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(4-Oxiranylbutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.6 g) is dissolved in a mixture of dioxane (30 ml) and water (10 ml). Thereto is added conc. sulfuric acid (0.1 ml) and the mixture is stirred at room temperature overnight. The mixture is neutralized with sodium hydrogen carbonate and then extracted with chloroform. The extract is dried with magnesium sulfate and the solvent is evaporated off. The resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol=50:1) to give 1-{1-[4-(5,6-dihydroxyhexyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.6 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH:13]=1>CO>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])[O:16][N:15]=1
Reactant: COC(=O)CCCCCCc1cc(-c2ccccc2OC)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1cc(CCCCCCC(=O)O)on1
Reaction time: 3 h
Yield: 99.3 %

Procedure:
Add 2 N sodium hydroxide (15 mL) to a solution of 7-[3-(2-methoxyphenyl)isoxazol-5-yl]heptanoic acid methyl ester (2.89 g, 8 mmol) in methanol (50 mL) at room temperature under nitrogen and stir for 3 hours. Remove the solvent under reduced pressure, dilute the residue with water (100 mL), and wash with methyl tert-butyl ether (100 mL). Acidify the mixture to pH 1 with 1 N HCl and extract with ethyl acetate (3×100 mL). Wash the combined organic extracts with water (100 mL) and brine (100), dry over sodium sulfate, and remove the solvent under reduced pressure to provide 7-[3-(2-methoxyphenyl)isoxazol-5-yl]heptanoic acid (2.41 g, 98%): APCI mass spectrum m/z 302 [C17H21INO4—H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:20][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH3:10])=[CH:13][CH:14]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCc1ccc(C(C)=O)cc1
Product: CCc1ccc(C(=O)C=Cc2ccc(Cl)cc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and 4-ethylacetophenone, 3-(4-chlorophenyl)-1-(4-ethylphenyl)prop-2-en-1-one was obtained as pale yellowish solid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.C([O:16][C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH:21]=[O:22])=O)(C)(C)C>C1COCC1>[CH3:23][C:20]1([CH3:24])[CH:21]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[O:22][C:17](=[O:16])[NH:19]1
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)NC(=O)OC1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A cold (−78 ° C.), stirred solution of (trimethylsilyl)acetylene (4.42 g, 45.0 mmol) In anhydrous THF (20 mL) was treated with nBuLi (18 mL, 45.0 mmol) under nitrogen. The colorless solution was stirred for 30 minutes and followed by the addition of 2(tert-butoxycarbonylamino)-2-methyl propionaldehyde (2.80 g, 15 mmol) in anhydrous THF (20 mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched with water. After removal of THF, tne residue was partitioned between ether (150 mL) and water (100 mL). The separated organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated to give the crude 4,4-Dimethyl-5-trimethylsilylethynyl-2-oxazolidinone (100%) as yellow oil which was carried to the next step.
Reaction SMILES: [C:1](O)(=O)/C=C\C(O)=O.[C:9]([O:16][CH3:17])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13].C1(=O)OC(=O)C=C1>CO.O>[C:12]([O:14][CH3:1])(=[O:13])/[CH:11]=[CH:10]\[C:9]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: O=C(O)/C=C\C(=O)O
Agent: O=C1C=CC(=O)O1
Solvent: O
Solvent: CO
Product: COC(=O)/C=C\C(=O)OC

Procedure:
This example also refers to FIG. 1. A butane oxidation reactor (not shown) produces 100 moles per hour of maleic anhydride, of which 40 kmols are condensed by cooling the gases in condensers (not shown). The remaining 60 moles per hour are recovered as a 50 wt % aqueous solution of maleic acid from an absorber (2) in line 5 and mixed together with the crude maleic anhydride from the partial condensers (line 8). The aqueous maleic acid is fed to the mono-ester reaction column (9). Recycle methanol from the refining section is fed (line 16a) to the bottom of the column (9). More than 80% of the maleic acid is converted to mono-methyl maleate and the bottom product (line 17) contains less than 20 mol % water. Mainly water and methanol and a small amount of maleic acid in the overhead are fed (line 14) to the methanol column (25). The bottom product from the mono-ester reaction column (9) is fed to a reaction column (19) to react the mono-methyl maleate with methanol to produce di-methyl maleate. 300 moles per hour of methanol are fed (line 24) to the bottom of the reaction column (19). Essentially water free, fully converted di-methyl maleate is fed (line 26) to hydrogenation. Recycle methanol from the refining section is fed to the top of the reaction column as wash (line 16b) to minimise the di-methyl maleate and maleic acid in the overhead of the column. Methanol and water from the overhead (line 31) of the reaction column is fed to the methanol column (25) where the methanol is separated and recycled to the reaction column (line 24). Water and a small amount of recovered maleic acid and di-methyl maleate from the bottom of the methanol column are recycled to the absorber (2) in line 3. Thus in this arrangement the evaporator and the mono-ester reaction column duties are combined in a single unit which will reduce the equipment costs by eliminating the evaporation equipment.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CNCCOC
Product: COCCN(C)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and N-(2-Methoxyethyl)Methylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine, MS: 405 (MH+, 1Cl).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[C:8]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].S([O-])([O-])(=O)=O.O[NH3+:26].O[NH3+]>O>[C:8]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:26])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: [NH3+]O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(C#N)cc1
Temperature: 100 °C

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 1800 parts by weight of anhydrous sodium sulfate, 365 parts by weight of 4-tert-butylbenzaldehyde and 194 parts by weight of hydroxylammonium sulfate. Following evacuation to 25 mbar, the mixture is heated to 100° C. and stirred at this temperature for 2 hours. It is subsequently heated at 125° C. for 40 minutes, during which about 82 parts by weight of water are removed by distillation. The distillation of the nitrile is then initiated and controlled by successive reduction of the pressure to 10 mbar and raising of the jacket temperature to 170° C. 300 parts by weight of 4-tert-butylbenzonitrile are obtained with an outstanding purity of ~98-99% (HPLC), along with 18 parts by weight of a less pure fraction.
Reaction SMILES: [CH2:1]([N:3]1[C:15]([CH:16]=[O:17])=[C:14]2[C:5]([C:6](=O)[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2].[OH-].[NH4+].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[C:5]2=[N:4][N:3]([CH2:1][CH3:2])[C:15]([CH:16]=[O:17])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nc2c(=O)[nH]c3ccccc3c2c1C=O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1nc2c(Cl)nc3ccccc3c2c1C=O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
2-Ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carbaldehyde (1 g) was combined with phosphorus oxychloride (10 mL) and heated at 100° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, poured into a mixture of ammonium hydroxide and ice, and then stirred for 20 minutes. A solid was isolated by filtration and air dried to provide 4-chloro-2-ethyl-2H-pyrazolo[3,4-c]quinoline-1-carbaldehyde as a white powder. MS (APCI) m/z 260 (M+H)+.