Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1C=CC(C)=CC=1CC=O.[CH3:15][O:16][C:17](=[O:30])[C:18]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:15][O:16][C:17](=[O:30])[C:18]1[CH:23]=[C:22]([CH2:4][CH:3]=[O:2])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCOc1ccc(Br)cc1C(=O)OC
Reactant: COC(=O)c1ccc(C)cc1CC=O
Product: CCCCOc1ccc(CC=O)cc1C(=O)OC
Yield: 30 %

Procedure:
The title compound (30%) is prepared essentially according to the preparation of 4-Methyl-2-(2-oxo-ethyl)-benzoic acid methyl ester using 5-bromo-2-butoxy-benzoic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.61 (d, 1H), 7.26-7.23 (dd, 1H), 6.94-6.92 (d, 1H), 4.02-3.99 (t, 2H), 3.85 (s, 3H), 3.62 (d, 2H), 1.80-1.76 (m, 2H), 1.52-1.47 (m, 2H), 0.96-0.93 (t, 3H).
Reaction SMILES: C[N:2]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:3]([C:8](Cl)=[O:9])[CH2:4][C:5](=[O:7])[OH:6].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[C:37]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)=[O:38].[C:46](#N)C>C(Cl)(Cl)Cl>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([C:37]([C:30]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=2[NH:28][C:8](=[O:9])[C@H:3]([CH2:4][C:5]([O:6][CH3:46])=[O:7])[NH:2][C:11]([O:13][CH2:14][CH:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:12])=[O:38])=[CH:40][CH:41]=1
Reactant: CC#N
Reactant: COc1ccc(N)c(C(=O)c2ccc(Cl)cc2)c1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](CC(=O)O)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(OC)cc1C(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl N-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-α-aspartyl chloride (Int. J. Peptide Protein Res. 1992, 40, 13-18) (93 g, 0.24 mol) was dissolved in CHCl3 (270 mL) and [2-amino-5-(methyloxy)phenyl](4-chlorophenyl)methanone (53 g, 0.2 mol) (for a preparation see Reference compound B) was added. The resulting mixture was stirred at 60° C. for 1 h before being cooled and concentrated at 60% in volume. Ether was added at 0° C. and the resulting precipitate was filtered and discarded. The filtrate was concentrated under reduced pressure and used without further purification.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH2:21])=[O:15]>CC(C)=O>[CH3:12][O:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:10]([NH:9][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])=[S:11])=[O:15]
Reactant: COC(=O)c1sccc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COC(=O)c1sccc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of benzoyl isothiocyanate (1038 mg, 6.36 mmol) in acetone (3 mL) was added to absolution of 3-aminothiophene-2-carboxylic acid methyl ester (500 mg, 3.18 mmol) in acetone (3 mL). The mixture was stirred at room temperature for 10 hours and then concentrated, and the residue was purified by silica gel chromatography (Hex/EtOAc=10/1) to obtain 3-{[(phenylcarbonylamino) thioxomethyl]amino}thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCO[C:17]([CH3:19])=O.[CH2:20](Cl)Cl>>[CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]([OH:12])[CH2:20][CH:17]=[CH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: ClCCl
Reactant: O=CCCOCc1ccccc1
Agent: Cl
Product: C=CC[C@H](O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Enantioselective allylation of 3-benzyloxypropionaldehyde to give (3S)-1-benzyloxy-hex-5-en-3-ol: To a cooled (−10° C.) solution of(4R,5R)-2-Allyl-1,3-bis-(4-bromo-benzyl)-2-chloro-octahydro-benzo[1,3,2]diazasilole (1.0 mmol) in CH2Cl2 (5 mL) was added 3-benzyloxypropionaldehyde (1.0 mmol). The reaction mixture was transferred to a freezer (−10° C.) and maintained at that temperature for 20 h. To this cooled solution was added 1N HCl and EtOAc, and the mixture was vigorously stirred at room temperature for 15 min. The layers were separated and the aqueous layer was extracted with EtOAc 3 times. The combined organic layers were diluted with hexane, dried (MgSO4), filtered, and concentrated. Purification of the residue by chromatography on silica gel gave (3S)-1-benzyloxy-hex-5-en-3-ol in 87% yield and 98% ee.
Reaction SMILES: [CH2:1]([OH:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(=O)CCCCC1.CCCCCCCCCCCC>>[CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC=Cc1ccccc1
Solvent: O=C1CCCCC1
Solvent: CCCCCCCCCCCC
Product: O=CC=Cc1ccccc1

Procedure:
1.5 g (11.2 mmol) of cinnamyl alcohol (trans-3-phenyl-2-propen-1-ol), 36 g (367 mmol) of cyclohexanone, 0.5 g of catalyst and 1.5 g of dodecane (as GC standard) were heated under argon. After the end of the reaction time, the reaction mixture was analyzed by gas chromatography and the yield was determined. The results are summarized in Table 5 below:
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of compound 99 (0.35 g, 0.776 mmol) was treated with 20% TFA in CH2Cl2 (20 mL) at 0° C. and stirring was continued for 1 h at the same temperature. The solvent was evaporated and crude was diluted with 10% aq. NH3 (15 mL) and product was extracted into CH2Cl2 (3 20 mL). The combined CH2Cl2 layer was washed with brine (10 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 100 (0.2 g, 74%) as a solid. mp 167-169° C.: 1H NMR (DMSO-d6) δ: 1.39-1.47 (m, 2H), 1.88-1.96 (m, 3H), 2.33 (s, 3H), 2.40-2.46 (m, 1H), 2.57-2.61 (m, 1H), 6.01 (s, 1H), 6.19 (brs, 2H), 6.65 (dd, 1H, J=1.5, 8.2 Hz), 7.09 (dd, 1H, J=4.2, 4.9 Hz), 7.20 (s, 1H), 7.28-7.31 (m, 2H), 7.59 (d, 1H, J==4.2 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.87 (s, 1H); ESI-MS m/z (%): 351 (MH+, 66), 320 (54), 160 (63), 119 (100); ESI-HRMS calculated for C20H23N4S (MH+), Calculated: 351.1654. Observed: 351.1637.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1.C(OCC)(=O)C>C(O)(C(F)(F)F)=O.ClCCl>[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Brc1csc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1sc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add dropwise fuming nitric acid (90%, 8.6 mL, 183 mmol) to a mixture of 3-bromo benzo[b]thiophene (39 g, 183 mmol) in TFA (100 mL) and dichloromethane (400 mL) at 0° C. The reaction turn greenish, then yellow precipitates. To this reaction mixture, add dichloromethane (200 mL) and the reaction stir at 0° C. for 30 min. Then pour the reaction into ice-water (2L). Extract with dichloromethane (3×500 mL) and the organic layer dry over MgSO4. Evaporation give a yellow solid. The resulting yellow solid triturate with diethyl ether to give a yellow solid. (Total: 34.8 g, 73%). Mass spectrum (m/e): 259(M+1); 1HNMR(300 MHz, DMSO-d6) δ ppm: 7.70(tt, 2H), 8.04(d, 1H), 8.17(d, 1H). 13CNMR(75 MHz, DMSO-d6) δ ppm: 112.5, 124.8, 126.9, 127.9, 131.3, 137.0, 137.2, 166.1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[C:9]1([P:15](Cl)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][P:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:16])[O:4][N:3]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1noc(N)c1C
Solvent: c1ccncc1
Product: Cc1noc(NP(=O)(c2ccccc2)c2ccccc2)c1C

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)diphenyl phosphinic amide was prepared by the method of Example 1 with 3,4-dimethyl-5-amino isoxazole (0.22 g, 2.0 mmol), diphenyl phosphinic chloride (0.6 ml, 3.0 mmol) and pyridine (5 ml). Flash chromatography (5% methanol/chloroform) followed by recrystallization from ethyl acetate and hexanes provided 0.38 g (61%) of white crystals, m.p. 167-170° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:17])[C:13]=2[C:14](O)=O)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:14]1[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[N:8]=[C:9]2[CH:10]=[N:11][N:12]([CH3:17])[C:13]=12.[Cl:20][C:14]1[C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=[C:9]2[CH:10]=[N:11][N:12]([CH3:17])[C:13]=12
Reactant: Cn1ncc(Nc2cccc(F)c2)c1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1ncc2nc3cc(F)ccc3c(Cl)c21
Product: Cn1ncc2nc3cccc(F)c3c(Cl)c21
Temperature: 25 °C
Yield: 40 %
Yield: 24 %

Procedure:
A mixture of 4-[(3-fluorophenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid (EXAMPLE 3, step 1, 470 mg, 2.00 mmol) in phosphorus oxychloride (10 ml) was refluxed for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed with water (30 ml) and saturated aqueous sodium bicarbonate (30 ml×2) and dried over magnesium sulfate. Removal of solvent gave a dark red residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:5) to afford 189 mg (40%) of the 9-chloro-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]quinoline as a pale yellow solid and 111 mg (24%) of the 9-chloro-8-fluoro-1-methyl-1H-pyrazolo[4,3-b]quinoline as a yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br-].CCO[CH2:14][CH3:15].[CH3:16]N(C=O)C>>[CH2:16]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH:14]=[CH2:15]
Reactant: Oc1ccccc1
Reactant: CN(C)C=O
Reactant: CCOCC
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=CCc1ccccc1O

Procedure:
Phenol 25 may be treated with NaH in DMF and then alkylated with an allylic bromide to give ether 30. Claisen rearrangement of 30 under thermal conditions gives ortho-allyl phenol 31. Oxidation of the double bond in 31 with OsO4/NMO followed by cleavage with NaIO4 provides the lactol 32. Jones oxidation then provides lactone 33.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH3:7].[NH2:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH2:4]([C:3]1[N:9]=[C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:20][CH2:21]3)=[N:14][N:15]2[CH:2]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)CBr
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCCCc1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 42 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 1-bromohexan-2-one in place of 1-bromobutan-2-one to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid in 42% yield. 1H NMR (300 MHz, CDCl3) δ 7.72-7.48 (m, 4H), 7.43 (s, 1H), 7.35-7.32 (m, 1H), 6.71 (d, J=9.9 Hz, 1H), 4.02-3.83 (m, 2H), 3.53 (m, 2H), 3.37-3.3 (m, 4H), 2.74-2.69 (m, 2H), 1.76-1.61 (m, 2H), 1.48-1.3 (m, 2H), 0.91 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.4, 154.3, 146.8, 135.7, 134.4, 132.3, 129.4, 127.0, 126.8, 126.76, 126.7, 126.6, 126.2, 125.4, 125.3, 121.8, 113.6, 109.3, 46.5, 46.3, 46.2, 41.1, 31.5, 28.8, 22.4, 13.9. MS (ES+) m/z 432.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:9]=[C:8]2[C:19]1[N:23]=[C:22]([CH2:24]OS(C)(=O)=O)[S:21][N:20]=1)#[N:2].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(OCC)(=O)C.[Cl:41]CCl>CCCCCCC>[ClH:41].[CH:13]1([CH2:12][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[C:1]#[N:2])[C:8]([C:19]3[N:23]=[C:22]([CH2:24][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[S:21][N:20]=3)=[CH:9]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCc1nc(-c2cn(CC3CCCCC3)c3c(C#N)cccc23)ns1
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cl
Product: N#Cc1cccc2c(-c3nsc(CN4CCCC4)n3)cn(CC3CCCCC3)c12

Procedure:
To a solution of methanesulfonic acid 3-(7-cyano-1-cyclohexylmethyl-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (120 mg, 0.28 mmol) in dichloromethane (3 ml) was added pyrrolidine (0.12 ml, 1.4 mmol) and the reaction subjected to microwave irradiation at 100° C. for 5 minutes. The reaction was purified directly by flash column chromatography eluting with dichloromethane then 25-50% (v/v) ethyl acetate in heptane to afford the title compound (71 mg, 0.175 mmol) as the free base. The free base (35 mg, 0.086 mmol) was dissolved in dichloromethane (2 ml) and hydrogen chloride (1M solution in diethyl ether) was added. The mixture was concentrated in vacuo to afford the title compound as a 1:1 hydrochloride salt. 1H NMR (400 MHz, CD3OD): 1.06-1.36 (7H, m), 1.62-1.80 (5H, m), 1.91-2.07 (1H, m), 2.09-2.34 (2H, br m), 3.35-4.20 (4H, br m), 4.42 (2H, d, J 7), 5.07 (2H, s), 7.37 (1H, t, J 8), 7.69 (1H, dd, J 7, 1), 8.23 (1H, s); 8.84 (1H, dd, J 8, 1) EsIMS: m/z 406.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.Cl.[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH2:37]>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:14](=[O:16])[N:37]([CH2:36][C:35]([O:34][CH3:33])=[O:38])[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: COC(=O)CN
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CC(=O)OC)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 139.3 %

Procedure:
To a solution (400 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (10 g) in methylene chloride were added triphosgene (6.9 g) and triethylamine (12 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were further added triethylamine (24.8 mL) and glycine methyl ester hydrochloride (20.3 g), and the mixture was further stirred at room temperature for 1 hr, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (500 mL), sodium methoxide (14.6 g) was added, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (8.69 g, 60%).
Reaction SMILES: [CH2:1]1[N:6]([C:7]([N:9]=[C:10]([NH2:12])[NH2:11])=[NH:8])[CH2:5][CH2:4][O:3][CH2:2]1.Cl.[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18]>O>[CH2:5]1[N:6](/[C:7](/[NH2:8])=[N:9]/[C:10]([NH2:12])=[NH:11])[CH2:1][CH2:2][O:3][CH2:4]1.[CH2:5]1[N:6](/[C:7](/[NH2:8])=[N:9]/[C:10]([NH2:12])=[NH:11])[CH2:1][CH2:2][O:3][CH2:4]1.[C:14]([O-:21])(=[O:20])/[CH:15]=[CH:16]\[C:17]([O-:19])=[O:18]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: N=C(N=C(N)N)N1CCOCC1
Agent: Cl
Solvent: O
Product: N=C(N)/N=C(\N)N1CCOCC1
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
Alternatively, the free base of moroxydine is prepared, e.g.: 2.1 g. moroxydine hydrochloride is dissolved in 100 ml. water and treated with an anion exchange resin. The resulting solution is neutralized, for example, with maleic acid and evaporated to crystallization yielding moroxydine maleate.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][C:9]1[C:10]([O:17][CH2:18][C:19](Cl)=[O:20])=[N:11][C:12]([F:16])=[C:13]([Cl:15])[CH:14]=1>O.C1C=CC=CC=1>[Cl:8][C:9]1[C:10]([O:17][CH2:18][C:19]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:20])=[N:11][C:12]([F:16])=[C:13]([Cl:15])[CH:14]=1
Reactant: O=C(Cl)COc1nc(F)c(Cl)cc1Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)CNC(=O)COc1nc(F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution was prepared by admixing 2.93 grams (0.039 mole) of glycine with 4.67 grams (0.117 mole) of sodium hydroxide in 117 milliliters of water. To this solution was added 10.0 grams of (3,5-dichloro-6-fluoro-2-pyridyloxy)acetyl chloride in 30 milliliters of benzene. The mixture was allowed to stand at a temperature of ~2°-5° C. for about 10 minutes and the mixture was warmed to room temperature and stirred for about 30 minutes. The reaction mixture was diluted with additional benzene and the aqueous layer which formed was removed and acidified. The solid which precipated was removed by filtration, dried and recrystallized from 50 percent ethanol. The N-[(3,5-dichloro-6-fluoro-2-pyridyloxy)acetyl]glycine product was recovered in a yield of 5.0 grams and melted at 155°-157° C. and upon analysis was found to have carbon, hydrogen, chlorine and nitrogen contents of 35.7, 2.1, 24.2 and 8.7 percent, respectively as compared with the theoretical contents of 36.5, 2.4, 23.9 and 9.4 percent, respectively, calculated for the above named compound.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][NH:10][C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]([CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.Cl.N1C=CC=CC=1>O>[O:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[NH:10][CH2:9][C:8]1[C:3](=[O:2])[NH:4][C:5]([CH3:22])=[C:6]([CH2:20][CH3:21])[CH:7]=1
Reactant: CCc1cc(CNc2nc3ccccc3o2)c(OC)nc1C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1cc(CNc2nc3ccccc3o2)c(=O)[nH]c1C
Temperature: 150 °C

Procedure:
A mixture of 2-methoxy-3-{[(benzoxazol-2-yl)amino]methyl}-5-ethyl-6-methylpyridine (80 mg, 0.269 mmol) and pyridine hydrochloride (335 mg, 2.9 mmol), under a nitrogen atmosphere, was warmed in an oil bath pre-heated to 150° C. for 5 minutes. This solidified mixture was cooled, diluted with water and the crude precipitated product collected by filtration. This material was dissolved in methylene chloride, filtered through a charcoal pad and then diluted with hexane. As the methylene chloride was boiled off the product crystallized out to give 40 mg (53%), m.p. 211°-213° C.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8].[CH2:22]([NH:25][C:26]([C:28]1[S:29][CH:30]=[CH:31][C:32]=1[NH:33][C:34]1[C:39]([Cl:40])=[CH:38][N:37]=[C:36](Cl)[N:35]=1)=[O:27])[C:23]#[CH:24]>>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH:20][C:36]3[N:35]=[C:34]([NH:33][C:32]4[CH:31]=[CH:30][S:29][C:28]=4[C:26](=[O:27])[NH:25][CH2:22][C:23]#[CH:24])[C:39]([Cl:40])=[CH:38][N:37]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: C#CCNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CN(C)CCCOC(=O)N1CCCOc2cc(N)ccc21
Product: C#CCNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCCN(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-prop-2-ynylcarbamoyl-thiophen-3-ylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid prop-2-ynylamide in an analogous manner to Example 1410. Product isolated as a yellow foam (116 mg, 68%). LCMS (m/e) 584 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 11.51 (s, 1H), 9.60 (s, 1H), 8.84-8.72 (m, 1H), 8.57-8.43 (m, 1H), 8.29 (s, 1H), 7.89-7.77 (m, 1H), 7.62-7.48 (m, 1H), 7.35-7.21 (m, 1H), 7.21-7.10 (m, 1H), 4.17-3.92 (m, 7H), 3.77-3.48 (m, 2H), 3.17-3.13 (m, 1H), 2.23-2.00 (m, 7H), 2.00-1.83 (m, 2H), 1.83-1.49 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].CO[C:16]1[CH:17]=[C:18]([CH2:24][C:25]#[N:26])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.[C:27]([O-:30])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:23][O:22][C:20]1[CH:19]=[C:18]([C:24]2[C:25](=[NH:26])[N:3]([CH2:1][CH3:2])[C:4]3[N:5]=[C:6]([S:12][CH3:13])[N:7]=[CH:8][C:9]=3[CH:10]=2)[CH:17]=[C:16]([O:30][CH3:27])[CH:21]=1
Reactant: COc1cc(CC#N)cc(OC)c1
Reactant: O=C([O-])[O-]
Reactant: CCNc1nc(SC)ncc1C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=N)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Yield: 76 %

Procedure:
To a solution of the product of Example 3, 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (37.0 g, 0.19 mol) and 3,5-dimethoxyphenylacetonitrile (37.0 g, 0.21 mol) in DMF (300 mL) was added portionwise anhydrous K2CO3 (130 g) with stirring. The reaction mixture was heated overnight at 105–110° C. and filtered hot. The insoluble salts were washed with DMF (100 mL), and water was added to the warm filtrate until the solution just turned turbid. Crystals developed upon seeding or inducement (scratching with a glass rod). The product was collected by filtration, washed with 100 mL DMF/H2O (25:75), washed with water, and dried in vacuo to afford 50.5 g (76%) of the titled compound. mp 93–95° C.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:8]2[CH:12]=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([CH2:13][CH:14]([CH3:15])[CH3:16])[S:10][C:9]=2[CH2:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1sc(CC(C)C)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1sc(CC(C)C)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 76.5 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-({cyclohexyl[2-ethyl-5-(2-methylpropyl)thiophen-3-yl]methyl}amino)benzoic acid (250 mg) synthesized in Example 83 (1) and ethyl 3-(methylamino)propanoate (98.5 mg) to give the title compound (232 mg, 76%).