Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25]>CCOC(C)=O>[F:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Yield: 97.9 %

Procedure:
To a solution of 1-methylpiperazine (6.91 g, 69 mmol) and Et3N (6.98 g, 69 mmol) in EtOAc (60 mL) was added 1,2-difluoro-4-nitrobenzene (10.02 g, 63 mmol) dropwise with stirring and the mixture was stirred at rt overnight. The reaction mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (14.75 g, 98%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=[O:18])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:23][C:24]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccc(SC2CCC2)n1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 92.4 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.044 g, 0.20 mmol) obtained in Step C of Preparation Example 37 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.046 g, 0.20 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.069 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[N:15]=2)[CH:3]=1.CO.[NH3:24]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C)c(C)n1
Solvent: CO
Product: Cc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
In a 50 mL round bottom flask, ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (929 mg, 3.03 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). The flask was sealed and stirred for 2 h at room temperature. Solvents evaporated and solid residue dried in high vacuum to give 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (841 mg, 100% yield) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 11.37 (br. s., 1H), 9.11 (s, 1H), 8.09 (br. s., 1H), 7.32 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 5.59 (br. s., 1H), 2.43 (s, 3H), 2.19 (s, 3H); LC-MS 278.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6](C)=[N:7][C:8]=1S)#[N:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([NH:14][NH2:15])=[N:7][CH:8]=1)#[N:2]
Reactant: NN
Reactant: CNc1nc(C)nc(S)c1C#N
Solvent: CCO
Solvent: O
Product: CNc1nc(NN)ncc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-cyano-4-methylamino-2-methyl-sulfanyl-pyrimidine (25.86 g) from Example 3 and hydrazine hydrate (52 mL) in ethanol (250 mL) was heated at reflux with stirring for 3 hours. The reaction mixture was cooled to room temperature and the insoluble product was collected by filtration, washed with cold aqueous ethanol (1:1) to give 23 g of the title compound. Crystallization from ethanol afforded an analytically pure sample of 5-cyano-2-hydrazino-4-methylamino-pyrimidine, mp 247°-249° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12](=[O:28])(=[O:27])[NH:13][C:14]3[C:19]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:26])[N:11]=[C:4]2[N:3]=1.[H-].[Na+].O1CCC[CH2:32]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12](=[O:28])(=[O:27])[N:13]([CH3:32])[C:14]3[C:19]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:26])[N:11]=[C:4]2[N:3]=1
Reactant: CCOCCOc1cccc(Cl)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOCCOc1cccc(Cl)c1N(C)S(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
1.5g of 5,7-dimethyl-2-(N-[2-chloro-6-(2-ethoxyethoxy)phenyl]-sulphamoyl)-1,2,4-triazolo[1,5-a]pyrimidine (prepared using the procedures described in Preparation Example 1, Variant A, were stirred in dry tetrahydrofuran under dry nitrogen at ambient temperature. To the pale yellow solution was added 60% sodium hydride and a white floccular solid formed over 60 minutes. The tetrahydrofuran was removed and the sodium salt resuspended in dry dimethyl formamide. 0.5g of methyl iodide was added and the mixture stirred under nitrogen overnight at ambient temperature. After concentration of the reaction mixture the residue was treated with water and extracted twice with 20ml of ethyl acetate. The organic phases were combined, dried over magnesium sulphate, filtered and concentrated. The crude product was then purified by flash chromatography to give 1.1g (71% yield) of 5,7-dimethyl-2-(N-methyl-N-[2-chloro-6-(2-ethoxyethoxy)phenyl]-sulphamoyl)-1,2,4-triazolo[1,5-a]pyrimidine (Compound No. 26) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[CH:43]=[N:42][N:41]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.94 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.53 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:9), and was recrystalized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 135) (858.7 mg) as yellow crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].CC(C)([O-])C.[K+:18]>C(OC(C)C)(C)C>[Cl:1]/[C:2](/[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8]/[O-:9].[K+:18]
Reactant: CCOC=O
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Product: CCOC(=O)/C(Cl)=C\[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
A mixture of ethyl 2-chloroacetate (220.8 g; 1802 mmol) and ethyl formate (133.5 g; 1802 mmol) was added slowly to a suspension of potassium t-butoxide (202.2 g; 1802 mmol) in diisopropyl ether (2000 mL) at 0° C. (maintaining the temperature <20° C.) with mechanical stirring. The mixture was stirred at ambient temperature for 24 hours. The solids were collected by filtration and washed with diisopropyl ether (500 mL) and acetonitrile (2×1500 mL). The material was dried under vacuum to give the product (270 g) which was used without further purification.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C)[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][Cl:12].[C:14]([O:17]C1C=CC(N)=CC=1)(=[O:16])[CH3:15]>>[C:14]([O:17][C:6]1[CH:7]=[CH:2][C:3]([NH:9][C:10](=[O:13])[CH2:11][Cl:12])=[CH:4][CH:5]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Oc1ccc(N)cc1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Product: CC(=O)Oc1ccc(NC(=O)CCl)cc1

Procedure:
Compound 56 was prepared in the manner of compound 3 substituting compound 55 for compound 1 in part A of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[CH:59][CH:58]=1>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:56][C:57]2[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[CH:61][CH:62]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Reaction time: 2 h

Procedure:
A solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.9 mg, 0.130 mmol) in dichloromethane (3 ml) were added DIPEA (66.8 mg, 0.514 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (78.2 mg, 0.324 mmol). The mixture was stirred for 20 mins under argon before methyl 4-(4-aminophenyl)butanoate (24.7 mg, 0.128 mmol) was added. After 2 hrs, the reaction mixture was diluted with dichloromethane and extracted with water then with sat. NaHCO3, water, and sat. NaCl. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral methyl 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoate (79.2 mg., 96%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 642.2. found: 642.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11]Cl)[CH:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][CH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CCl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNCc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 99.3 %

Procedure:
A mixture of 4-chloro-2-chloromethyl-1-nitro-benzene (85 g, 0.41 mol), glycine ethyl ester hydrochloride (70 g, 0.50 mol) and triethylamine (121.4 ml, 0.8665 mol) in ethanol (1000 ml) was heated at reflux for 8 h. The solvent was evaporated and the residue was triturated in warm tert-butyl methyl ether. The ammonium salts were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (111 g, 99%) as an amorphous brown solid which was used in the next step without purification. MS m/e: 273 (M+H+).
Reaction SMILES: [C:1](OOC(=O)C1C=CC=CC=1)(=[O:8])C1C=CC=CC=1.[Br-].[Br-].O1CCOCC1.[CH3:27][C:28]1[C:33](C)=[CH:32][C:31]2[N:35]([CH2:45][CH:46]([O:62]C(C)=O)[CH:47]([O:58]C(C)=O)[CH:48]([O:54]C(C)=O)[CH2:49][O:50]C(C)=O)[C:36]3[C:43](=[N:44][C:30]=2[CH:29]=1)[C:41](=[O:42])[NH:40][C:38](=[O:39])[N:37]=3>O1CCOCC1>[CH3:27][C:28]1[C:33]([CH2:1][OH:8])=[CH:32][C:31]2[N:35]([CH2:45][C@@H:46]([OH:62])[C@@H:47]([OH:58])[C@@H:48]([OH:54])[CH2:49][OH:50])[C:36]3[C:43](=[N:44][C:30]=2[CH:29]=1)[C:41](=[O:42])[NH:40][C:38](=[O:39])[N:37]=3
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(Cn1c2nc(=O)[nH]c(=O)c-2nc2cc(C)c(C)cc21)OC(C)=O
Agent: [Br-]
Solvent: C1COCCO1
Product: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@@H](O)[C@@H](O)[C@@H](O)CO)c2cc1CO

Procedure:
Synthesis of 8α-hydroxyriboflavin was carried out by the method of McCormick (21). Briefly, riboflavin was added to a solution of acetic acid: acetic anhydride (1:1) and the yellow solution was stirred at room temperature for 24 hours. Tetra-acetylriboflavin (TAR) was extracted from the aqueous reaction mixture with CHCl3, followed by extraction with water and evaporation to give a yellow residue of essentially pure TAR. Dibenzoyl peroxide and dioxane dibromide in dioxane were added to a solution of TAR in dioxane, and the solution was refluxed. The crude bromo-TAR was separated from the reaction mixture on a C-18 Semi-Prep HPLC column (Beckman). The bromo-TAR was hydrolyzed to yield 8α-hydroxyriboflavin, which was separated by HPLC (System Gold, Beckman) through a linear gradient from 0.5% trifluoroacetic acid (TFA) in water to 0.5% TFA in acetonitrile for 50 minutes at a flow rate of 4 ml/minute.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].C(N)CCC.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH3:5])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1Br
Solvent: CCO
Solvent: CCCCN
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1Br
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Nitroethane (0.800 mL, 836 mg, 11.1 mmol) and n-butylamine (0.050 mL, 37 mg, 0.51 mmol) were added to a solution of 3-bromo-4-methoxybenzaldehyde (2.00 g, 9.30 mmol) in 2.0 mL of absolute ethanol. The solution was heated in a 95° C. oil bath for 8 h and then stirred overnight at room temperature. The ethanol was evaporated, the residue was stirred with 12 mL of 8% ether in hexane, and the supernatant was decanted. The undissolved material was stirred with 12 mL of 8% ether in hexane, and sufficient toluene was added to bring it into solution at 60° C. The crystals which separated at room temperature were recrystallized again from a solution of hexane (7 mL) and toluene (1.8 mL) at 55° C. cooled to room temperature to give 1-(3-bromo-4-methoxyphenyl)-2-nitropropene as 598 mg of yellow needles. All of the mother liquors were combined and evaporated, and the residue was purified by flash column chromatography on 85 g of silica gel eluting with 25% dichloromethane in hexane to give an additional 791 mg of 1-(3-bromo-4-methoxyphenyl)-2-nitropropene (total isolated yield of 55%). 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.68 (d, 1H, J=2 Hz),7.40 (dd, 1H, J=9, 2 Hz),6.97(d, 1H, J=9Hz), 3.96 (s, 3H), 2.47 (s, 3H). Mass spectrum (NH3CI): m/e=272 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([F:18])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([F:18])=[C:12]([CH:17]=3)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1F
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(F)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Yield: 39 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-fluorobenzoate obtained in Example (176b) (20.1 mg, 0.07 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (11.3 mg, 0.06 mmol), WSC hydrochloride (37.2 mg, 0.19 mmol) and HOBt (8.7 mg, 0.06 mmol), to obtain 11 mg of the title compound as a pale yellow solid (39%).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[O:23][CH2:24][CH:25]2[O:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][CH2:26]2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl>C1COCC1.[OH-].[Na+].CO>[O:30]1[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[O:27][CH2:26][CH:25]1[CH2:24][O:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[C:11]([NH:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:12]
Reactant: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCC2COc3ccccc3O2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CCCC1)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Yield: 50.5 %

Procedure:
96 mg 1-{[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carbonyl]-amino}-cyclopentanecarboxylic acid methyl ester in 0.5 ml THF, 0.62 ml of 2 M sodium hydroxide and 1.4 ml methanol were reacted in a microwave at 120° C. for 6 min. The reaction was then acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated to yield 47 mg of 1-{[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carbonyl]-amino}-cyclopentanecarboxylic acid.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[Si:22]([O:5][CH2:4][CH2:3][C@H:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CCCCCCCCCCC[C@@H](O)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCC[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of diol compound 9 (2.28 g, 10 mmol) in N,N-dimethyl formamide (50 mL) at 0° C. was added sequentially imidazole (1.63 g, 24 mmol), and t-butyldimethylsilyl chloride (1.65 g, 11 mmol), and the reaction mixture was stirred for 2 h. After completion of the reaction (TLC). The mixture was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), dried and concentrated to give a colorless oil, which after purification by flash chromatography, afforded the pure monosilyl compound 10 as an oil (Rf 0.71, silica, ethyl acetate and hexane, 1:10, 2.80 g, 84%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:22]3[CH:21]=[CH:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[C:17]=3[N:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=23)=[CH:5][CH:4]=1.Cl.[NH+]1C=CC=CC=1.O>C(Cl)(Cl)Cl>[CH:27]1[C:14]2[C:15]3[N:16]=[C:17]4[C:22]([CH:21]=[CH:20][C:19]5[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=54)=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=4)[C:10]=3[CH:11]=[CH:12][C:13]=2[CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Oc1ccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc1
Temperature: 210 °C
Reaction time: 72 h

Procedure:
In a pressure vessel a mixture of 18 (1.00 g, 2.6 mmol, 1 eq) and pyridiniumhydrochloride (1.75 g, 15.1 mmol, 5.8 eq) was heated to 210° C. under an inert atmosphere and vigorously stirred at this temperature over a three days period. The mixture was allowed to cool down to room temperature. The solidified melt was dissolved in chloroform (50 mL) and water (50 mL) and treated in an ultrasonic bath for 5 minutes. The layers were separated and the aqueous layer was extracted with chloroform (3×50 mL). Afterwards, the combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution (5×50 mL) followed by water (3×50 mL) and dried over magnesium sulphate. Evaporation of the solvent at 40° C. led to an old rose coloured solid. The product was directly used in the next step without any further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:17][C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]=1[CH2:27][NH:28][CH3:29]>>[Cl:17][C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]=1[CH2:27][N:28]([CH3:29])[C:14](=[O:16])/[CH:13]=[CH:12]/[C:7]1[CH:8]=[N:9][C:10]2[NH:11][C:2](=[O:1])[CH2:3][CH2:4][C:5]=2[CH:6]=1
Reactant: CNCc1oc2ccccc2c1Cl
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 56 %

Procedure:
According to the method of example 43d, 3-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid (203 mg, 0.8 mmol) and (3-chloro-benzofuran-2-ylmethyl)methylamine (172 mg, 0.88 mmol) were coupled to yield the title compound (176, 56%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.21-7.64 (m, 6H), 4.84-5.08 (rotamers, 2s, 2H), 3.22 (s, 3H), 2.91-2.96 (m, 2H), 2.52-2.59 (m, 2H); MS (ESI) m/e 396 (C21H18ClN3O3+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:8]=[C:7]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ccc2[nH]cc(-c3cccnc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(-c2cccnc2)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
5-Nitro-3-(3-pyridyl)-1H-indole (0.60 g) was added portionwise to a stirredsuspension of sodium hydride (0.11 g of 60% dispersion in mineral oil) in dry N,N-dimethylformamide (10 ml) at room temperature, and the mixture wasstirred for 30 minutes. Ethyl 4-bromobutanoate (0.40 g) was added and the mixture was stirred for 18 hours. Further sodium hydride (0.11 g of 60% dispersion) was added, the mixture was stirred for 30 minutes and then further ethyl 4-bromobutanoate (0.40 g) was added. Stirring was continued for an additional 4 hours and then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed twice with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed using dichloromethane/methanol (100:1) as eluent. The product fractions were combined and evaporated, and the residue was triturated with ether to give the title compound (0.51 g), m.p. 76°-78° C. Found: C,64.92; H,5.48; N,11.95. C19 H19N3O4 requires: C,64.58; H,5.42; N,11.89%.