Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]3[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:6](=[O:8])[N:7]=1.[NH3:28]>CO>[NH2:28][C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]3[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:6](=[O:8])[N:7]=1
Reactant: N
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncc(C#N)c(-c4cccnc4)c3c2)S1
Solvent: CO
Product: N#Cc1cnc2ccc(C=C3SC(N)=NC3=O)cc2c1-c1cccnc1

Procedure:
Similar procedure as described in example 41c was used, starting from 6-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile (example 63e), and ammonia in methanol to give 6-(2-amino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile. Flash chromatography using a small amount of trifluoroacetic acid as a cosolvent gave 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-pyridin-3-yl-quinoline-3-carbonitrile; compound with trifluoro-acetic acid. LC-MS m/e 358 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=O)[CH2:15][CH2:16][CH:17]1[CH2:20][CH:19]([N:21]([CH2:23][C@@H:24]2[C@@H:31]3[C@@H:27]([O:28][C:29]([CH3:33])([CH3:32])[O:30]3)[C@H:26]([N:34]3[C:38]4[N:39]=[CH:40][N:41]=[C:42]([NH:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=5[O:53][CH3:54])[C:37]=4[CH:36]=[CH:35]3)[CH2:25]2)[CH3:22])[CH2:18]1>C(O)(=O)C>[CH3:54][O:53][C:46]1[CH:47]=[C:48]([O:51][CH3:52])[CH:49]=[CH:50][C:45]=1[CH2:44][NH:43][C:42]1[C:37]2[CH:36]=[CH:35][N:34]([C@H:26]3[C@H:27]4[C@H:31]([O:30][C:29]([CH3:33])([CH3:32])[O:28]4)[C@@H:24]([CH2:23][N:21]([CH3:22])[CH:19]4[CH2:18][CH:17]([CH2:16][CH2:15][C:14]5[NH:13][C:3]6[CH:4]=[CH:5][C:6]([O:8][C:9]([F:12])([F:10])[F:11])=[CH:7][C:2]=6[N:1]=5)[CH2:20]4)[CH2:25]3)[C:38]=2[N:39]=[CH:40][N:41]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(OC(F)(F)F)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Yield: 66.7 %

Procedure:
A solution of N-(2-amino-4-(trifluoromethoxy)phenyl)-3-(3-((((3 aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (2 g, 2 mmol) in Acetic acid (4 ml) was stirred overnight at 60° C. The volatiles removed in vacuo and remaining residue purified by flash chromatography (DCM/7N NH3 in MeOH 92:8) to give the desired compound (1 g) as a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH3:51])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C(Cl)Cl.C1COCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH3:51])[CH2:45][N:46]2[CH2:49][CH:48]([OH:50])[CH2:47]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: CN[C@@H](C)CN1CC(O)C1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 19 %

Procedure:
DIPEA (0.217 mL, 1.25 mmol) was added to a stirred suspension of 4-bromobenzoic acid (0.075 g, 0.37 mmol) and TBTU (0.120 g, 0.37 mmol) in DCM (2 mL) at rt. The suspension was stirred for 20 min before it was cooled on an ice-bath. A solution of (S)-1-(2-(methylamino)propyl)azetidin-3-ol (Compound M11) (0.06 g, 0.42 mmol) in THF (1.5 mL) was added over 10 min. The ice-bath was removed and the reaction was stirred at rt over night. DCM (3 mL) was added and the mixture was washed with NaHCO3 (8% aq., 3 mL). The aqueous layer was extracted with DCM (2×3 mL). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (23 mg, 17%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 1.01-1.11, 2.17-2.24, 2.33-2.38, 2.45-2.77, 3.15-3.56, 4.03-4.20, 4.44-4.53, 5.18-5.28, 7.27-7.34, 7.59-7.66. Some signals overlap with solvent. HRMS (M+H)+: calculated 327.0708. found 327.0722.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[C:17]([OH:23])=[CH:16][C:15]=2[CH3:24])=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:15]([CH3:24])=[CH:16][C:17]([O:23][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:18]3[C:22]=2[CH2:21][CH2:20][CH2:19]3)=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(O)c2c(c1Oc1ccc(OCc3ccccc3)c(Cc3ccc(F)cc3)c1)CCC2
Product: CCOC(=O)COc1cc(C)c(Oc2ccc(OCc3ccccc3)c(Cc3ccc(F)cc3)c2)c2c1CCC2

Procedure:
The title compound was prepared in a similar manner to those described in Reference Example 11 using 7-[4-benzyloxy-3-(4-fluorobenzyl)phenoxy]-6-methylindan-4-ol instead of 2-hydroxy-5-(5-methyl-7-nitroindan-4-yloxy) benzaldehyde and using ethyl bromoacetate instead of benzyl bromide.
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:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.Cl.[CH2:23]([O:25][NH2:26])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([O:25][NH:26][C:19]([C:18]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:20])[CH3:24]
Reactant: CCON
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (100 mg, 0.252 mmol) in DMF (3 mL) was added O-ethyl hydroxylamine hydrochloride (37 mg, 0.378 mmol), HOBt (37 mg, 0.277 mmol) and EDCI (53 mg, 0.277 mmol). The reaction mixture was stirred at room temperature for 1 hour then DIPEA (91 μl, 0.529 mmol) was added and the reaction stirred at room temperature for 18 hours. Additional quantities, as at the start of the reaction, of O-ethyl hydroxylamine hydrochloride, HOBt, EDCI and DIPEA were added to the reaction and stirring was continued for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, the solid precipitate in the mixture was filtered off, washed with water to give the title compound (41 mg, 37%). LCMS (Method A): RT=9.65 min, [M+H]+=441. 1H NMR (DMSO-d6, 400 MHz): 13.19 (1 H, s), 11.51 (1 H, s), 9.97 (1 H, s), 7.66 (1 H, dd, J=10.35, 1.95 Hz), 7.46 (1 H, d, J=8.78 Hz), 7.42 (1 H, dd, J=8.47, 1.84 Hz), 7.25 (1 H, s), 7.02 (1 H, d, J=8.76 Hz), 6.91 (1 H, t, J=8.66 Hz), 3.86 (2 H, q, J=7.04 Hz), 1.15 (3 H, t, J=7.03 Hz).
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1]1([C:7]2([C:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[CH2:8][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: C1CCNC1
Product: O=C(N1CCCC1)C1(c2ccccc2)CC1

Procedure:
The title compound was prepared from 1-phenylcyclopropanecarboxylic acid and pyrrolidine using a similar procedure to that described for Description 8.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].F.[CH3:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1>>[CH3:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:2]([NH2:3])=[S:1])=[CH:9][CH:8]=1
Reactant: N#C[S-]
Reactant: Cc1cccc2ccccc12
Agent: F
Agent: [K+]
Product: Cc1ccc(C(N)=S)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
At a temperature and in the manner as described in Example 1, 39 g of potassium thiocyanate (0.4 mol) are stirred into 0.3 l of 98% hydrofluoric acid, 47 g of α-methylnaphthalene (0.33 mol) are added, and the mixture is stirred for 4 hours at room temperature. The reaction is then complete. Work-up is possible by stirring with ice, as described in the preceding Examples, or by distilling off the greater part of the hydrofluoric acid in a steel apparatus before stirring with ice. 64 g of 1-methyl-4-thionaphthamide having a melting point of 143° - 145° C are obtained, which corresponds to a yield of 97% of the theoretical yield, relative to α-methyl-naphthalene used.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C(OCC)(=O)C.CC(O)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Ic1cccs1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccs2)CC1
Yield: 77 %

Procedure:
A mixture of 2-iodothiophene (Aldrich Co., 1.0 g), 1-(tert-butoxycarbonyl)piperazine (Aldrich Co. (hereafter the same), 1.06 g), copper(I) iodide (45 mg), ethylene glycol (530 μl), potassium phosphate (2.02 g) and 2-propanol (5 ml) was heated under reflux for 20 hr. Ethyl acetate was added, and the mixture was filtered through a Celite (trademark) filter. The filtrate was washed 3 times with 28% aqueous ammonia, and then washed with saturated brine. The solvent was evaporated under reduced pressure to give a brown solid. The solid was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane (7:3)) to give 4-(2-thienyl)piperazine-1-carboxylic acid tert-butyl ester (984 mg, yield 77%).
Reaction SMILES: C([O:8][C:9]1[C:13](/[CH:14]=[CH:15]/[P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:12][N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][C:9]1[C:13]([CH2:14][CH2:15][P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])=[CH:12][N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccccc1)OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOP(=O)(CCc1cn(-c2ccccc2)nc1O)OCC
Yield: 77.2 %

Procedure:
Diethyl (E)-2-(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)ethenylphosphonate (0.89 g), 5% palladium on carbon (1.0 g) and tetrahydrofuran (50 mL) were subjected to catalytic reduction under a hydrogen atmosphere and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated to give diethyl 2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethylphosphonate as colorless crystals (0.54 g, yield 76%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL), cooled in an ice bath, was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of benzenesulfonyl chloride (0.155 g, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then diluted with water (15 mL) and the aqueous layer extracted with DCM (3×30 mL) and the combined organic extracts dried over a phase separating column and concentrated. MeOH (ca. 0.5 mL) was added to the residue which resulted in the precipitation of a solid. The solid was filtered, washed with MeOH (2 mL) and dried, to afford the title compound (88 mg). LCMS (A) m/z: 425 [M+1]+, Rt 1.40 min (basic).
Reaction SMILES: Cl.C([N:9]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[CH2:15]2)[CH2:10]1)C1C=CC=CC=1.Cl.O1CCOCC1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:10]1[C@H:11]2[C@H:16]([CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH2:12]2)[CH2:17][NH:9]1
Reactant: c1ccc(CN2C[C@H]3Cc4ccccc4C[C@H]3C2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: c1ccc2c(c1)C[C@H]1CNC[C@H]1C2
Reaction time: 48 h
Yield: 64.9 %

Procedure:
To a solution of cis-2-benzyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole hydrochloride (210 mg, 0.80 mmol) in 10 mL of ethanol was added palladium hydroxide (210 mg, 20 wt % on carbon) and 4 N hydrochloric acid solution in dioxane (1 mL, 4 mmol). The mixture was placed on a Parr apparatus, the vessel was pressurized to 50 psi with hydrogen, and the mixture was shaken for 2 days. TLC of the mixture showed very little reaction, so the same amounts of palladium hydroxide and hydrochloric acid were added again. The vessel was pressurized to 50 psi with hydrogen, and the mixture was shaken for an additional 3 days. TLC of the mixture showed that the reaction was still incomplete, and so the same amounts of palladium hydroxide and hydrochloric acid were added, the vessel was pressurized to 50 psi with hydrogen, and the mixture was shaken for an additional 6 days. The mixture was filtered through celite, and the cake was rinsed with methanol. The filtrate was stripped, the residue was taken up in 20 mL of 1 N sodium hydroxide, and the aqueous was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and stripped to yield 90 mg of an amber oil, which was purified by flash chromatography, eluting with ethyl acetate followed by 20% methanol/chloroform. Obtained 35 mg of a colorless oil. Yield=25%. NMR (300 MHz, CDCl3) δ 7.17-7.09 (m, 4H), 3.17-3.16 (m, 2H), 2.79 (bd, 2H, J=9 Hz), 2.58-2.43 (m, 6H), 2.36 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:16][CH2:15][CH:14]1[CH2:17][OH:18].[OH-].[Li+]>>[O:13]1[CH2:16][CH2:15][CH:14]1[CH2:17][O:18][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCC1CCO1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC2CCO2)nc1
Temperature: 75 °C
Yield: 42 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 42% yield starting from ethyl 6-chloronicotinate and oxetan-2-ylmethanol. The reduction was performed using 3 equiv of lithium hydroxide while heating to 75° C. for 3.5 h. The final aqueous solution was extracted with ethyl acetate in order to collect the product; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, 1 H), 8.16 (dd, 1 H), 6.96 (dd, 1 H), 4.96-5.06 (m, 1 H), 4.41-4.57 (m, 4 H), 2.64-2.75 (m, 1 H), 2.46-2.56 (m, 1 H); S (ESI) m/z 210[M+H+], m/z 208[M−H+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:42][CH2:43]I>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]([O:23][CH2:43][Cl:42])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)OCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(N-benzyloxycarbonyl-L-valyloxy)propanoic acid (5.2 g, 16.08 mmole) in 1,4-dioxane (50 ml) was added a 40% solution of tetrabutylammonium hydroxide (10.43 g, 16.08 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 40 ml dichloromethane and chloroiodomethane (28.4 g. 160 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. Ethyl acetate (100 ml) was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 2.2 g=35%
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][CH2:15][C:16]1[C:23]([F:24])=[C:22]([F:25])[C:19]([CH2:20]O)=[C:18]([F:26])[C:17]=1[F:27].[CH3:28][C:29]([CH3:39])=[CH:30][CH:31]1[CH:33]([C:34]([OH:36])=[O:35])[C:32]1([CH3:38])[CH3:37]>C1(C)C=CC=CC=1>[CH3:28][C:29]([CH3:39])=[CH:30][CH:31]1[CH:33]([C:34]([O:36][CH2:20][C:19]2[C:18]([F:26])=[C:17]([F:27])[C:16]([CH2:15][O:14][CH3:13])=[C:23]([F:24])[C:22]=2[F:25])=[O:35])[C:32]1([CH3:38])[CH3:37]
Reactant: CC(C)=CC1C(C(=O)O)C1(C)C
Reactant: COCc1c(F)c(F)c(CO)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COCc1c(F)c(F)c(COC(=O)C2C(C=C(C)C)C2(C)C)c(F)c1F
Temperature: 25 °C

Procedure:
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added to a mixture of 4-methoxymethyl-2,3,5, 6-tetrafluorobenzyl alcohol, 3- (2-methyl-1-propenyl) -2, 2-dimethylcyclopropanecarboxylic acid {containing the stereoisomers in a ratio of (1R)-trans form: (1R)-cis form: (1S)-trans form: (1S)-cis form=49:49:1:1} and toluene under ice-cooling. The resulting mixture is heated to room temperature and stirred at room temperature. The reaction mixture is poured into ice water to be separated. The organic layer thus separated is washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant residue is subjected to silica gel column chromatography to obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (hereinafter referred to as the present compound 6).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([O:20][CH2:21][C:22](Cl)=O)[CH3:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:19]([CH2:18][O:20][CH2:21][CH3:22])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41.1 %

Procedure:
A solution of 7-bromo-N4-isobutylquinoline-3,4-diamine (85 g, prepared according to Part F of Example 1) in anhydrous pyridine (413 mL) was immersed in an ice bath, and ethoxyacetyl chloride (36.9 g, 300 mmol) was added. The reaction was allowed to warm to room temperature and was then heated in an oil bath held at 85° C. for 3.5 h. The reaction mixture was concentrated under vacuum, and the residue was taken up in diethyl ether and washed with 2M Na2CO3 (2×) followed by H2O (1×). The organic layer was dried (MgSO4), filtered, and concentrated. Recrystallization of the resulting solid from boiling 15% ethyl acetate in hexanes afforded 43.0 g of 7-bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinoline as brown crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=3)[N:10]=2)=[CH:5][C:4]=1[N+:25]([O-])=O>CCO.C([O-])(O)=O.[Na+]>[NH2:25][C:4]1[CH:5]=[C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=3)[N:10]=2)[CH:7]=[CH:8][C:3]=1[N:2]([CH3:1])[CH3:28]
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N(C)C)c([N+](=O)[O-])c3)n2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N(C)C)c(N)c3)n2)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a suspension of methyl 4-{5-[4-(dimethylamino)-3-nitrophenyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate obtained in step 1 (150 mg; 0.39 mmol) in EtOH (15 mL) was added stannous chloride dihydrate (438.05 mg; 1.94 mmol) and stirred at 70° C. for 3 h, then at RT for 16 h. After this time, the solution was diluted with a saturated aqueous solution of NaHCO3 (75 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum to give the title compound. LC/MS (Method B): 357.3 (M+H)+. HPLC (Method A) Rt. 3.75 min (purity: 95.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][C:12]([O:14]C)=O)[NH2:10])=[CH:5][CH:4]=1.[CH3:16][N:17]=[C:18]=[O:19].C[O-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:11][C:12](=[O:14])[N:17]([CH3:16])[C:18](=[O:19])[NH:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CN(N)c1ccc(OC)cc1
Reactant: CN=C=O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(N2CC(=O)N(C)C(=O)N2)cc1

Procedure:
Methyl [1-(4-methoxyphenyl)hydrazino]acetate (1.50 g) was treated with methyl isocyanate (0.85 ml) and then with sodium methoxide (from sodium (0.33 g) in methanol (15 ml)) according to the method of Example 1. The product was purified by recrystallisation from ethyl acetate to give the title compound (703 mg), m.p. 179°-181°, t.l.c. (ether) Rf 0.5.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=O.Cl>CO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=C1COc2cc(O)ccc21
Reactant: COc1ccc(C=O)cc1C
Agent: Cl
Solvent: CO
Product: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Temperature: 25 °C
Yield: 39.9 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methyl-4-methoxybenzaldehyde 1.11 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.75 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].Cl.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: C[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [Na]
Product: COc1ccc(N2CCN(c3ccc(S(=O)(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-propionic acid, sodium salt and 4-(4-methoxy-phenyl)-piperazine dihydrochloride were condensed to give the title compound as a brown solid, mp=203-205° C.