Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19](O)=[O:20].C1CCN2C(=NCCC2)CC1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:24]([O:23][C:17]([C:18]1[C:19](=[O:20])[O:1][C:2]([CH3:16])([CH3:15])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:22])[CH3:25]
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=O)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 62.6 %

Procedure:
A mixture of 2-hydroxy-2-methyl-1-(4-(methylsulfonyl) phenyl)propan-1-one (2.87 g, 11.8 mmol), ethyl hydrogen malonate (2.02 g, 15.3 mmol), CMC (6.51 g, 15.4 mmol) and DMAP (0.35 g, 2.8 mmol) was dissolved in 100 mL of CH2Cl2. The mixture was stirred for 14 h at room temperature, then DBU (4 mL, 27 mmol) was added, stirred 1 h, then partitioned-between CH2Cl2 and 1M HCl. The organic layer was washed with brine, filtered through cotton and evaporated. Purification by flash chromatography (90% ether/Hex) provided 2.50 g of the title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-allyloxy-8-acetyl -3-methylflavone (2.5 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.3 g of product m.p. 145-47° C., 1H-NMR (CDCl3)δ:1.77 (s, 3H); 2.20 (s, 3H); 4.73 (d, 2H, J=5.1 Hz); 5.25-5.45 (m, 2H); 5.91-6.02 (m, 1 H); 7.05 (d, 1H, J=16 Hz); 7.11 (d, 1H, J=8.9 Hz); 7.38-7.48 (m, 7H); 7.53-7.59 (m, 4H); 8.34 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH:1]1([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[C:9]2[C:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccccc2)nc1CCc1ccccc1)C1CCCCC1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccccc3)nc2CCc2ccccc2)C2CCCCC2)cc1
Yield: 47.2 %

Procedure:
Using cyclohexyl[1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl]methanol (0.50 g) synthesized in Example 15(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.35 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.37 g, 47%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])=[CH:4][CH:3]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
A neat solution of aniline (4.3 mL, 47 mmol) and p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol) in a round bottom flask equipped with a reflux condenser was heated to 90° C. and hexafluoroacetone trihydrate (7 mL, 50 mmol) added over 15 minutes via syringe. Following addition, the temperature was increased to 130° C. and the resulting solution stirred over 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organics were washed with saturated NaHCO3 solution then brine. The solution was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by flash chromatography (4:1 hexanes/EtOAc) to give the title product as a white crystalline solid (5.5 g, 45%). MS (ES+) m/z 260 (MH+).
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C@@H:11]([N:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@H:33]3[CH2:38][CH2:37][O:36][CH2:35][C@H:34]3[F:39])[N:27]=2)=[CH:22][C:21]1=[O:40])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C>O1CCOCC1.CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]([N:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@H:33]4[CH2:38][CH2:37][O:36][CH2:35][C@H:34]4[F:39])[N:27]=3)=[CH:22][C:21]2=[O:40])[CH2:10][OH:9])=[CH:13][C:14]=1[F:19]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(N[C@H]3CCOC[C@H]3F)n2)cc1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1cc(-c2ccnc(N[C@H]3CCOC[C@H]3F)n2)ccn1[C@H](CO)c1ccc(Cl)c(F)c1
Reaction time: 1 h

Procedure:
A 4.0M solution of hydrogen chloride (18.6 mL, 74.5 mmol) in dioxane was slowly added to a cold (0° C.) solution of 1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (8.6 g, 14.9 mmol) in MeOH (40 mL), and the mixture was stirred for 1 hour. The reaction mixture was concentrated, and the residue was taken up in saturated NaHCO3 and extracted with ethyl acetate (2×). The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:4) to give 1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one as a solid (4.58 g, 66%; 97% e.e. by chiral HPLC (Chiral Tech, column OD-H, 4.6 mm×250 mm, 5u, 30% ethanol/70% hexanes, 1 mL/minute)). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=5.0 Hz, 1H), 7.41 (m, 2H), 7.21-7.09 (m, 3H), 6.89 (d, J=5.0 Hz, 1H), 6.76 (d, J=7.0 Hz, 1H), 6.20 (m, 1H), 5.55 (d, J=8.2 Hz, 1H), 4.75 (d, J=50 Hz, 1H), 4.38-4.18 (m, 4H), 4.05 (m, 1H), 3.69-3.53 (m, 2H), 3.12 (br, s, 1H), 2.08-1.84 (m, 2H); m/z (APCI-pos) M+1=463.1, 465.0.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:13][C:14]([F:43])([F:42])[C:15]1[CH:41]=[CH:40][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:36])(=[O:35])[NH2:34])=[O:25])=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[F:43][C:14]([F:13])([F:42])[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([NH:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:36])=[O:35])=[O:25])=[CH:40][CH:41]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
In a stream of nitrogen and at 0° C., 0.24 ml (1.10 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 451 mg (1.00 mmol) of 3-(4-trifluoromethylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 8 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 512 mg (yield: 84.6%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]2[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:13][S:12]2)=[C:6]([CH3:24])[CH:5]=1)(O)=[O:2].C(C1NC=CN=1)(C1[NH:28]C=CN=1)=O.O>C(Cl)Cl.N>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]2[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:13][S:12]2)=[C:6]([CH3:24])[CH:5]=1)(=[O:2])[NH2:28]
Reactant: Cc1cc(C(=O)O)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine (0.035 g, 0.10 mmol) in CH2Cl2 (5 mL) was added carbonyl diimidazole (0.047 g, 0.29 mmol). The mixture was allowed to stir at room temp. for 2 h, then anh NH3 (approximately 30 drops) was condensed into the solution at −78° C. The resulting mixture was warmed to room temp. overnight, then treated with H2O (20 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL), sequentially washed with H2O (20 mL) and a saturated NaCl solution (20 mL), dried Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (40% EtOAc/hexane) to give (4S)-2-(4-carbamoyl-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine as a white solid (0.027 g, 73%): mp 130-131° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[C:41](Br)[CH:40]=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[C:41]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:40]=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1
Reactant: Cc1ccn(-c2ccc(Br)cc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccc(-n2ccc(C)n2)c([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)c1
Temperature: 80 °C

Procedure:
To a solution of (S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (180 mg, 0.24 mmol) in ethanol (2 mL) was added Pd(PPh3)2Cl2 (34 mg, 0.048 mmol), KHCO3 (242 mg, 2.4 mmol). A balloon of CO was fitted and the reaction mixture was heated to 80° C. for 20 h, then cooled to RT. The reaction was quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH/AcOH) provided (S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:35])[NH:10][C@H:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1>ClC1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]=[C:9]([NH:10][C@H:11]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:12][NH:13][C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[S:35][C:6]=2[CH:7]=1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=S)Nc2ccc(Br)cc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)OC(C)(C)C)cc1
Temperature: 4 °C
Yield: 28.1 %

Procedure:
0.05 ml of SO2Cl2 is added to a solution of 250 mg of 11-1 in 5 ml of chlorobenzene cooled down to approximately 4° C., the temperature is allowed to rise to 20° C. and a further 0.05 ml of SO2Cl2 is added. The reaction medium is then diluted in dichloromethane and washed, the organic phase is dried, and evaporation is carried out under reduced pressure until a dry extract is obtained which is purified by chromatography, eluting with a CH2Cl2/AcOEt mixture 85/15. 70 mg of expected product is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH2:25][C:26]2[N:27]([CH2:31][C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[CH:28]=[CH:29][N:30]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>>[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[C:36]([Cl:38])[CH:35]=1)[CH2:31][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[CH2:25][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN(Cc2cccc(F)c2)Cc2nccn2Cc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cccc(CN(CCN2CCNCC2)Cc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of 4-{2-[[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (92 mg, 0.16 mmol) and 4N HCl/dioxane (5 mL) was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and water (5 mL) added. The pH of the solution was adjusted to pH 9 by addition of 1N NaOH and the mixture extracted with CH2Cl2 (2×20 mL). The combined CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo to afford [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-(2-piperazin-1-yl-ethyl)-amine (74 mg, 98%) as colorless a viscous oil: ESI MS m/z 476 [C24H28Cl2FN5+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:81])[C:30]([CH:71]([N+:78]([O-])=O)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([CH:61]([N+:68]([O-])=O)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43](=[O:60])/[CH:44]=[CH:45]/[C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[C:48]([O:58][CH3:59])[CH:47]=2)=[O:32])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Zn]>[CH3:59][O:58][C:48]1[CH:47]=[C:46](/[CH:45]=[CH:44]/[C:43]([O:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:31](=[O:32])[C:30]([CH:61]([NH2:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)([CH:71]([NH2:78])[C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:17](=[O:18])/[CH:16]=[CH:15]/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:81])=[O:60])[CH:51]=[CH:50][C:49]=1[O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCCOc1ccc(/C=C/C(=O)OCCCCCCCCOC(=O)C(C(=O)OCCCCCCCCOC(=O)/C=C/c2ccc(OCCCCC)c(OC)c2)(C(c2ccccc2)[N+](=O)[O-])C(c2ccccc2)[N+](=O)[O-])cc1OC
Agent: [Zn]
Product: CCCCCOc1ccc(/C=C/C(=O)OCCCCCCCCOC(=O)C(C(=O)OCCCCCCCCOC(=O)/C=C/c2ccc(OCCCCC)c(OC)c2)(C(N)c2ccccc2)C(N)c2ccccc2)cc1OC

Procedure:
Preparation can be carried out analogously to Synthetic Example 1 using 1.07 g (1.00 mmol) of bis[8-({(2E)-3-[3-methoxy-4-(pentyloxy)phenyl)prop-2-enoyl }oxy)octyl]2,2-bis(nitrobenzyl)malonate, 1.62 g (6.00 mmol) Ferric chloride hexahydrate and 0.65 g (10.00 mmol) Zinc powder yield bis[8-({(2E)-3 -[3-methoxy-4-(pentyloxy)phenyl)prop-2-enoyl}oxy)octyl]2,2-bis(aminobenzyl)malonate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([NH:14][CH3:15])=[CH:7][C:6]=1[F:16])[CH3:2]>[Ni].C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:14][CH3:15])=[CH:7][C:6]=1[F:16])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)c(NC)cc1F

Procedure:
Prepared analogously to example 156c from 2-fluoro-4-methylamino-5-nitro-benzoic acid ethyl ester and Raney nickel in THF.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:17])[CH:9]([NH2:16])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[CH2:19]([O:21][C:22]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:23]=1[C:24](=N)OCC)[CH3:20].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:17][C:24]([C:23]3[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:22]=3[O:21][CH2:19][CH3:20])=[N:16][CH:9]2[CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OC)cc1OCC
Reactant: NC(CC1CCCC1)C(N)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Yield: 62.7 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-3-cyclopentyl-propane-1,2-diamine (170 mg, 0.672 mmol) and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride (210 mg, 0.806 mmol) in ethanol (10 mL) was added triethylamine (82 μL, 0.806 mmol). The reaction mixture was heated at gentle reflux for 6 h. The solvent was removed and the residue was partitioned between water and methylene chloride. The product was extracted with methylene chloride (2×20 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with ethyl acetate then 5–10% methanol in ethyl acetate to give 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (174 mg, 63%, 4.5:1.0 ratio of cis:trans) as a white foam. HR-MS (ES, m/z) observed 413.1993, calculated for C24H30N2O2Cl [(M+H)+] 413.1991.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[N:17][C:18](Cl)=[CH:19][CH:20]=2)[N:15]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:14]=1)=[O:12])[CH3:9].Cl.Cl.[CH3:32][O:33][C@H:34]1[C@H:38]([NH:39][CH3:40])[CH2:37][NH:36][CH2:35]1>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[N:17][C:18]([N:36]3[CH2:37][C@@H:38]([NH:39][CH3:40])[C@H:34]([O:33][CH3:32])[CH2:35]3)=[CH:19][CH:20]=2)[N:15]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:14]=1)=[O:12])[CH3:9]
Reactant: CN[C@@H]1CNC[C@H]1OC
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@@H](NC)[C@H](OC)C3)ccc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
Triethylamine (18 ml) was added to a suspension composed of 7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (7.1 g) obtained in Example A-1 (4), trans-3-methoxy-4-methylaminopyrrolidine dihydrochloride (6.0 g) and acetonitrile (150 ml). The resulting reaction mixture was stirred at room temperature for 5 hours, and was then concentrated under reduced pressure. Then, an aqueous solution of sodium hydrogencarbonate was added, and the resultant mixture was extracted with chloroform. After the obtained extract was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent chloroform:methanol=6:1), and thus, there was obtained 1,4-dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (6.1 g).
Reaction SMILES: N#N.[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[CH2:4].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20]>C(Cl)(Cl)Cl>[C:19](=[O:20])([O:21][CH:22]=[CH2:23])[O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]=[CH2:4])=[CH:6][CH:7]=1
Reactant: C=COC(=O)Cl
Reactant: C=Cc1ccc(O)cc1
Agent: N#N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=COC(=O)Oc1ccc(C=C)cc1
Temperature: 5 °C

Procedure:
A 500 ml round bottom flask equipped with a reflux condenser, a mechanical stirrer , a thermometer, a dropping funnel and an efficient N2 blanket, is charged with 30.0 g (0.25 mole) of 4-vinylphenol, 21.8 g of pyridine and 300 ml of chloroform. The contents are then cooled down to 5 degrees C., and 25,3 g of vinyl chloroformate is added dropwise via the dropping funnel with constant stirring and the temperature maintained at 5 degrees or below. The temperature is then allowed to rise to ambient temperature and the mixture stirred overnight. The reaction mixture is then passed through a silica gel column and dried over magnesium sulfate and filtered. After the solvent is removed under pressure, the named product is recovered.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([NH2:33])[CH2:29][CH2:30][O:31][CH3:32]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:33]=[C:28]([CH2:29][CH2:30][O:31][CH3:32])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][S:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: COCCC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 134 mg (0.910 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 185 mg (49% of theory)
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([N:7]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:25]4[C:26]([CH3:30])=[C:27]([CH3:29])[S:28][C:24]=4[N:23]4[C:31]([CH3:34])=[N:32][N:33]=[C:22]4[C@H:21]([CH2:35][C:36]([OH:38])=[O:37])[N:20]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=[N:8]1)[CH3:6].[CH3:39][O:40][CH:41](O)[CH3:42]>>[CH2:5]([N:7]1[C:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:25]4[C:26]([CH3:30])=[C:27]([CH3:29])[S:28][C:24]=4[N:23]4[C:31]([CH3:34])=[N:32][N:33]=[C:22]4[C@H:21]([CH2:35][C:36]([O:38][CH2:42][CH2:41][O:40][CH3:39])=[O:37])[N:20]=3)=[CH:17][CH:18]=2)=[CH:10][CH:9]=[N:8]1)[CH3:6]
Reactant: COC(C)O
Reactant: CCn1nccc1Nc1ccc(C2=N[C@@H](CC(=O)O)c3nnc(C)n3-c3sc(C)c(C)c32)cc1
Solvent: O=S(Cl)Cl
Product: CCn1nccc1Nc1ccc(C2=N[C@@H](CC(=O)OCCOC)c3nnc(C)n3-c3sc(C)c(C)c32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (230 μL) and the intermediate synthesized in Example 151, (S)-4-[4-(2-ethyl-2H-pyrazol-3-ylamino)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-acetic acid (500 mg), were successively added to methoxy ethanol (10 mL) at 0° C., and the mixture was stirred at room temperature for 1 day. After completion of the reaction, the mixture was partitioned by adding water and ethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol=100:1) to give the title compound (410 mg).