Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([OH:21])=O)=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:43]([O:45][CH2:46][CH2:47][O:48][NH2:49])=[CH2:44]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([NH:49][O:48][CH2:47][CH2:46][O:45][CH:43]=[CH2:44])=[O:21])=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(I)cc1F
Reaction time: 1.5 h

Procedure:
To a suspension of 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (41 mg, 0.10 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (1.5 mL) was added EDCI (40 mg, 0.21 mmol) at room temperature. The resulting mixture was stirred for 1.5 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (21 mg, 0.20 mmol) and TEA (0.030 mL, 0.22 mmol) was added to the activated ester at room temperature. After stirring for 1.5 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3 (2×), and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide that was used directly without further purification. The title compound was prepared by the procedure previously described in Example 1 (step J) using the crude 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (40% yield over two steps). MS APCI (−) m/z 461 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.98 (t, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.78 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CC([O-])(C)C.[K+].C(O)=O>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[Cl:18]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Clc1ccc(Nc2nc3ccccc3s2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=CO
Product: O=C(c1ccccc1Cl)N(c1ccc(Cl)cc1)c1nc2ccccc2s1
Yield: 67 %

Procedure:
A mixture of 39.1 mg (0.15 mmol) Benzothiazol-2-yl-(4-chloro-phenyl)-amine in 0.5 ml THF, 45.2 mg (0.18 mmol) 2-chlorobenzoyl chloride in 0.18 ml THF and 0.17 ml of a 1 M solution of KOtBu in THF was heated to 50° C. for 16 h. After addition of 0.5 ml formic acid the mixtures are subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 40.1 mg (67%) of the title compound. MS (m/e): 399.3 (MH+, 100%).
Reaction SMILES: S([O-])(O)=O.[Na+].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C(=O)C>[C:17]1([C:16]2[NH:11][C:9](=[O:10])[C:8]3[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1ccccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2ccccc2)nc2ccccc12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
Sodium hydrogen sulfite (0.8 g, 7.5 mmol) was added to a solution of 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and benzaldehyde (32) (0.8 g, 7.3 mmol) in N,N-dimethylacetamide (DMAC) (20 ml). The mixture was heated with stirring at 150° C. for 2 h and then poured into ice water (200 ml). The precipitate was collected, washed with water, and then dried in vacuo. After recrystallization from EtOH, 41 was obtained (1.5 g, 92.6%) as pale yellow needles. Yield, mp, and spectral data are given in Table 1.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>CCO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[N:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc2c(c1)C(=NOCc1ccccc1)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A mixture of (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (150 mg, 0.35 mmol), NH2OCH2Ph (94 mg, 0.76 mmol) and pyridine (61 μl, 0.700 mmol) in EtOH (10 ml) was heated to reflux. After 2 h, the solution was cooled down to RT and evaporated under vacuum. The crude residue was triturated with Et2O/H2O 90/10 to give (E)-3-{1′-benzyl-4-benzyloxyimino-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide (55 mg) as a 70/30 mixture of the two isomers (hydrochloride salts).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:38])([CH3:37])[C:9]([N:11]1[CH2:14][CH:13]([C:15]2[CH:36]=[CH:35][C:18]3[C:19]4[N:20]=[C:21]([C:27]5[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=5)[S:22][C:23]=4[CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH2:12]1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]([CH3:38])([CH3:37])[C:9]([N:11]1[CH2:12][CH:13]([C:15]2[CH:36]=[CH:35][C:18]3[C:19]4[N:20]=[C:21]([C:27]5[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=5)[S:22][C:23]=4[CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH2:14]1)=[O:10]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)C3)ccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)N)C3)ccc1-2
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of (2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (203 mg, 0.36 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred for 1 hour then concentrated in vacuo. The residual solid was triturated with ether, filtered off and air-dried before being dissolved in DCM. The organic solution was washed (aqueous saturated sodium bicarbonate solution, followed by water and then brine), dried (MgSO4) and concentrated in vacuo. The residue was freeze-dried from MeOH/H2O to give 469 as a white solid (116 mg, 71%). LCMS: RT=8.13 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1 H, d, J=8.19 Hz), 8.06 (1 H, s), 7.18 (1 H, dd, J=8.24, 1.86 Hz), 7.00 (1 H, d, J=1.82 Hz), 5.82-5.74 (1 H, m), 4.79 (1 H, s), 4.42 (1 H, s), 4.33 (2 H, t, J=5.13 Hz), 4.19 (1 H, s), 3.77-3.70 (2 H, m), 3.39 (2 H, t, J=5.02 Hz), 1.74 (2 H, s), 1.50 (6 H, d, J=6.59 Hz), 1.17 (6 H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[NH2:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1O.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:14]3[CH:15]=[C:16]([OH:17])[CH:18]=[CH:19][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc2nc(-c3cccc(Br)c3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
14.1 ml (107 mmol) of 3-bromobenzoic chloride and 1.7 g (10.5 mmol) of 4-aminoresorcinol hydrochloride were introduced into a three-necked flask provided with a thermometer and a cooling condenser, and the mixture was heated at 90° to 145° C. for 30 minutes. To the residue, an aqueous solution of sodium hydroxide and methanol were added into a homogeneous solution which was then stirred at room temperature for 2 hours. The reaction solution was extracted twice with ethyl acetate and washed with 1N hydrochloric acid then with a saturated sodium chloride solution. Distilling off the excessive ethyl acetate, the obtained precipitate was recrystallized with THF/water. There was obtained 0.68 g (2.35 mmol) of 2-(3-bromophenyl)-6-hydroxybenzoxazole, and the yield was 16.6%.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[N+]([O-])(O)=O.[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:12][C:10]1[S:11][C:7]([C:5]2[CH:4]=[CH:3][N:38]=[C:36]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:34][CH:33]=3)[N:37]=2)=[C:8]([CH3:17])[N:9]=1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Solvent: O=[N+]([O-])O
Product: Cc1nc(N)sc1-c1ccnc(Nc2ccc(N3CCOCC3)cc2)n1

Procedure:
By condensation between N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (prepared from 1-(2-amino-4-methyl-thiazol-5-yl)-ethanone and N,N-dimethylformamide dimethylacetal) and N-(4-morpholin-4-yl-phenyl)-guanidine nitrate. Yellow solid. M.p. 300-304° C.: 1H-NMR (DMSO-d6) δ: 2.46 (s, 3H, CH3), 3.07 (m, 4H, CH2), 3.76 (m, 4H, CH2), 6.85 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 6.92 (m, 2H, Ph-H), 7.53 (br. s, 1H, NH), 7.67 (m, 2H, Ph-H), 8.30 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.25 (br. s, 1H, NH). MS (ESI+) m/z 369 [M+H]+ (C18H20N6OS requires 368.5).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][O:6][C:7](=[O:9])[CH3:8])=[O:3].[C:10]([O:15][CH2:16][CH2:17][OH:18])(=[O:14])[C:11]([CH3:13])=[CH2:12].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[O:4][CH2:5][O:6][C:7](=[O:9])[CH3:8]
Reactant: CC(=O)OCOC(=O)Cl
Reactant: C=C(C)C(=O)OCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCOC(=O)OCOC(C)=O
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of acetoxymethyl chloroformate (1.00 g, 0.0066 mol) and 2-hydroxyethyl methacrylate (0.86 g, 0.0066 mol) in methylene chloride (30 ml), pyridine (0.52 g, 0.0066 mol) was added at 0° C. After 10 min at 0° C. and 18 hours at 25° C. the reaction mixture was washed with aqueous hydrochloric acid (100 ml), aqueous saturated sodium hydrogen carbonate (100 ml) and water (100 ml). The solvent was removed under reduced pressure after drying (MgSO4). Flash chromatography (silicagel, hexane/ethyl acetate (3:2)) gave 1.05 g (65%) of the title product.
Reaction SMILES: [OH-:1].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[S:14][CH:13]=[CH:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:4]([C:15]1[CH:16]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3](=[O:2])[N:7]2[C:6]=1[C:11]1[CH:12]=[CH:13][S:14][C:10]=1[CH2:9][CH2:8]2)(=[O:1])[CH3:3]
Reactant: [OH-]
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1sccc1-2
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccsc1CC2

Procedure:
A solution of 1 g of 5,6-dihydro-3-hydroxy-2-phenyl-thiazolo[3,2-a]thieno[3,2-c]pyridinium hydroxide (internal salt) and 0.23 g of 3-butyl-2-one in 10 ml of toluene was stirred at room temperature for 48 hours. The solution was evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). There was obtained pure 10-acetyl-4,5-dihydro-8-phenyl-7H-thieno-[3,2-a]quinolizin-7 one of m.p. 181°-182° (from ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[CH3:25][OH:26].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:25][OH:26])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1
Reactant: CO
Reactant: Cc1ccc2nc(C)ccc2c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: Cc1ccc2nc(C)cc(CO)c2c1
Yield: 46 %

Procedure:
To a solution of 10.0 g (63.6 mmol) of 2,6-dimethylquinoline and 29.1 g (127.5 mmol) of ammonium peroxodisulfate in a mixed solvent of methanol (140 mL)-water (110 mL) was added 4.0 mL of concentrated sulfuric acid and heated under reflux for 24 hours. After the reaction mixture was left to cool, methanol was evaporated under a reduced pressure. The remaining solution was adjusted to pH 10 by adding sodium carbonate, and then extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by column chromatography (silica gel 200 g, developing solvent: chloroform:ethyl acetate:triethyamine=1:1:0.01) to obtain 5.50 g (yield 46%) of (2,6-dimethylquinolin-4-yl)methanol. Its physical properties are shown below.
Reaction SMILES: [Cr](Cl)([O-])(=O)=[O:2].[NH+]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:12]=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1>>[O:12]=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[O:2]=[CH:7][CH:8]=[C:9]1[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1
Reactant: c1cc[nH+]cc1
Reactant: O=[Cr](=O)([O-])Cl
Agent: COC(=O)C1CCC(=O)CC1
Product: COC(=O)C1CCC(=CC=O)CC1

Procedure:
The epoxides used as the starting materials in the general process described above can be obtained from available starting materials using an appropriate series of reactions. Thus, methyl 4-hydroxybenzoate is hydrogenated using 5% rhodium on alumina as catalyst to give methyl 4-hydroxycyclohexanecarboxylate. This is then oxidized with pyridinium chlorochromate resulting in methyl 4-oxocyclohexanecarboxylate. The 2-carbon homologation of methyl 4-oxocyclohexanecarboxylate to give methyl 4-(oxoethylidene)cyclohexanecarboxylate is carried out using the method developed by A. I. Meyers. Acetaldehyde t-butylimine is metalated with lithium diisopropylamide and then treated with diethyl chlorophosphate to provide the lithioeneaminephosphonate. Addition of methyl 4-oxocyclohexanecarboxylate and subsequent acid hydrolysis gives methyl 4-(oxoethylidene)cyclohexanecarboxylate. The reduction of this oxoethylidene compound with sodium borohydride gives methyl 4-(2-hydroxyethylidene)cyclohexanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][NH2:26]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:26][NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[N:3]=1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1ccc(NNc2nc(Cl)nc3c2ncn3C2CCCC2)c(Cl)c1

Procedure:
2-Chloro-6-(2,4-dichlorophenyl hydrazino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,4-dichlorophenyl hydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][CH2:31][CH2:32][N:33]=[C:34]=S.C(Cl)CCl>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:34]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: COCCN=C=S
Solvent: CCO
Solvent: ClCCCl
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1Cc1ccccn1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(pyridin-2-ylmethyl)quinoline-3,4-diamine (35 mg, 0.093 mmol) was dissolved in ethanol (5 ml) and 2-methoxyethyl isothiocyanate (22 mg, 0.186 mmol) was added, then the solution was heated at 60° C. for 3 h, cooled and evaporated in vacuo. The residue was dissolved in THF (5.0 ml) and EDC (35.7 mg, 0.186 mmol) was added, then the solution was heated at 60° C. for 3 h, cooled and evaporated in vacuo and the residue purified by MDAP (formate) to give 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-N-(2-methoxyethyl)-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-amine (25 mg, 0.055 mmol, 58.5% yield) as a beige solid.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].CS(C)=O.[CH3:10][N:11]([O:16][CH3:17])[C:12](=[O:15])[CH2:13]Cl>C(Cl)Cl>[CH3:10][N:11]([O:16][CH3:17])[C:12](=[O:15])[CH2:13][O:3][C:1](=[O:4])[CH3:2]
Reactant: CON(C)C(=O)CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CON(C)C(=O)COC(C)=O
Temperature: 70 °C
Reaction time: 7 h
Yield: 75.2 %

Procedure:
A mixture of 23 g (0.28 mole) of sodium acetate, 200 ml of dimethylsulphoxide and 34.4 g (0.25 mole) of chloroacetic acid N-methyl-N-methoxy-amide (for its preparation, see DE-OS (German Published Specification) No. 2,753,182) was stirred at 70° C. for 7 hours. The mixture was then cooled to room temperature, 500 ml of methylene chloride were added and the inorganic salt was filtered off. The filtrate was evaporated in vacuo and the residue was distilled. 30.3 g (75% of theory) of acetoxyacetic acid N-methyl-N-methoxy-amide were thus obtained as a colourless liquid with a boiling point of 70° C./0.3 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[O:16]C(OCC)=O)=[O:5])[CH3:2].Cl>CN(C)C=O.O>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[CH:8]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]1=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1cc2cc(Cl)ccc2n1C(=O)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1C(=O)N(C(=O)OCC)c2ccc(Cl)cc21
Yield: 70 %

Procedure:
To a solution of ethyl-5-chloro-2-[(ethoxycarbonyl)oxy]-1H-indole-1-carboxylate, intermediate 49, (36.87 g, 118.28 mmol) in N,N-dimethylformamide (100 ml) 4-dimethylaminopyridine (14.45 g, 118.28 mmol) was added portionwise at 0-5° C. such that the internal temperature did not exceed 5° C. A thick suspension was obtained, which was repeatedly diluted with N,N-dimethylformamide (total volume: 350 ml) to ease up stirring. After two hours at 0-5° C. a solution of hydrogen chloride (fuming, 37%; 9.8 ml) in water (480 ml) was added at such a rate that the internal temperature could be kept below 15° C. The precipitate was filtered, washed with water at 0-5° C. (2×100 ml) and dried to yield the title compound (27.45 g, 70%) as off-white powder (HPLC purity: 94%). MS (ESI+): 312.2; MS (ESI−): 310.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+]([O-])=O.FC1C=C(F)C=CC=1[N+:25]([O-:27])=[O:26].N1CCOCC1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:25]([O-:27])=[O:26])=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1F
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1N1CCOCC1

Procedure:
4-(3-Fluoro-4-nitrophenyl)morpholine: A solution of 2,4-difluoronitrobenzene (10.0 mL, 91 mmol) and morpholine (17.4 mL, 200 mmol) in THF (100 mL) was stirred at RT under nitrogen for 2 h. The solvent was removed and the residue was partitioned between EtOAc and water. The organic layer was washed brine, dried over MgSO4, and concentrated. The resulting solid was purified by SiO2 chromatography with 20-50% EtOAc in hexane to give 4-fluoro-2-morpholinonitrobenzene (18.1 g) and 55a (1.81 g, 8% yield); [M+H]+=227.10.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C.ClCCl>[Si:16]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CON(C)C(=O)C1CC(O)C1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Yield: 50 %

Procedure:
Into a solution of 3-hydroxy-N-methoxy-N-methylcyclobutanecarboxamide (0.6 g, 0.004 mol in DMF (10 mL) was added tert-butylchlorodiphenylsilane (3 mL, 0.01 mol), followed by 1H-imidazole (1 g, 0.02 mol). The mixture was stirred at rt over night. The reaction was diluted with dichloromethane and washed with sat. NaHCO3, water and brine. The organic layers were dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-30% EtOAc/Hex) to give the desired product (0.7 g, 50%) as cis- and trans-isomer mixtures. LCMS calculated for C23H32NO3Si(M+H)+: 398.2; Found: 398.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8](=[CH:11]Cl)[CH:9]=O.[NH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.C(C=C)=O>C(Cl)Cl.CN(C)C=O>[Cl:7][C:8]1[CH:9]=[N:13][C:14]2[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[C:15]=2[CH:11]=1
Reactant: NC1CCCC(=O)C1
Reactant: O=CC(Cl)=CCl
Agent: C=CC=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCc2ncc(Cl)cc21

Procedure:
In reaction 3 of Scheme 1, a solution of oxalyl chloride in methylene chloride is added dropwise to a solution of chloromalondialdehyde III in methyene chloride and a phase transfer catalyst, such as dimethylformamide, under inert reaction conditions. The reaction mixture is stirred at room temperature until conversion to the corresponding 2,3-dichloroacrolein is complete. In reaction 4 of Scheme 1, a solution of 1-amino-cyclohexan-3-one VI in dimethylformamide is added dropwise to the above acrolein to form the corresponding 3-chloro-5,6,7,8-tetrahydroquinolin-5-one VII. The reaction, generally carried out overnight, will be in the temperature range between about 60° C. to about 80° C., preferably about 70° C.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([CH2:48][NH2:49])[CH2:44][CH2:43]2)[CH2:37][CH2:36]1.[OH-].[Na+]>ClCCl>[C:16]([O:15][C:13](=[O:14])[NH:1][C@@H:2]([C:10](=[O:12])[NH:49][CH2:48][CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH:38]2[CH2:37][CH2:36][O:35][CH2:40][CH2:39]2)[CH2:47][CH2:46]1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCC1CCN(CC2CCOCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A solution consisting of 10 g of Boc-D-Phe-OH, 40 ml of dichloromethane and 4.6 ml of N-methylmorpholine is slowly dripped into a solution of 5.4 ml of isobutyl chloroformate in 60 ml of dichloromethane cooled to 0° C., at a rate such that the inner temperature does not exceed 5° C. The resulting mixture is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of dichloromethane is dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 5 hours. After a process control, 100 ml of 1M NaOH is added to the mixture, the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate compound (12) is crystallised from ethyl acetate, to obtain 14.29 g of white solid. Yield 83%.