Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[O:13])[CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:23]([N:11]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:30])=[O:2])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)=[O:13])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc(CN(Cc2ccccc2)C(=O)Nc2ccc(C#N)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(NC(=O)N(Cc2ccccc2)Cc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Dissolved to 3-[1-benzyl-3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid methyl ester (106 mg, 0.27 mmol) in 1:1 mixture of THF/MeOH (4 mL). To this was added a 15% NaOH solution and the mixture stirred overnight at room temperature. LC-MS analysis indicated the desired carboxylic acid. Concentrated the mixture and the residue was suspended in 5 mL of H2O and made acidic by the addition of 5% HCl, resulting in a white ppt., which was filtered and dried to give 101.6 mg of 3-[1-benzyl-3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13][CH:12]=1>CO>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:13][CH:12]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: Nc1ccccc1C(=O)O
Solvent: CO
Product: O=C(O)c1ccccc1N=Cc1ccnc2ccccc12
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A solution of anthranilic acid (5.46 g) in methanol was added to a melt of quinoline-4-carbaldehyde (6.26 g) and the mixture was heated on a water bath for 6 hours. The mixture was cooled to room temperature and the solid material was isolated by filtration and washed with methanol, affording 2-[(quinolin-4-ylmethylene)-amino]-benzoic acid (10.33 g). This intermediate (10.3 g) was dissolved in THF and ethanol, and sodium borohydride (1.41 g) was added portion-wise. The reaction mixture was stirred at room temperature for 3 hours. More sodium borohydride (1.41 g) and a small amount of methanol were added and stirring continued at room temperature for 4 hours. The mixture was evaporated under reduced pressure and transferred to a separatory funnel with EtOAc and water. Layers were separated and the aqueous layer was neutralised by addition of 4M hydrochloric acid. The resulting precipitated material was isolated by filtration, washed with water and dried in vacuo, affording the title compound (7.1 g). 13C-NMR (DMSO-d6) δ 170.4, 150.3, 150.3, 147.6, 144.8, 133.4, 131.7, 129.6, 129.2, 126.5, 126.1, 123.5, 118.5, 114.6, 112.9, 111.2, 42.7.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:15](=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][CH:18]=[N:17]3)[N:14]=[C:13]([CH:25]=O)[CH:12]=1)(C)(C)C.Cl.[NH2:29][OH:30].[OH-].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl.O>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:15](=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][CH:18]=[N:17]3)[N:14]=[C:13]([CH:25]=[N:29][OH:30])[CH:12]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C=O)nc2c1ccc1cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NCCOc1cc(C=NO)nc2c1ccc1cccnc12
Temperature: 25 °C

Procedure:
A solution of [2-(2-formyl-[1,10]phenanthrolin-4-yloxy)-ethyl]carbamic acid tert-butyl ester (0.52 g, 1.4 mmol) was stirred for 1 hour at room temperature in a mixture of trifluoroacetic acid (5 mL) and methylene chloride (10 mL). The solvent was removed and the residue was dried and redissolved in ethanol (5 mL). A solution of hydroxylamine hydrochloride (0.88 g, 12.7 mmol) in water (7 mL) was added followed by the addition of 10% NaOH until a white precipitate formed. The mixture was heated to reflux for 1 hour, cooled down to room temperature and the white precipitate filtered, washed with cold water and dried. The title compound was isolated as a pale solid (37.0 mg, 9%)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[O:7][N:6]=[C:5]([CH:8](O)[CH3:9])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C(OCC)C>[Br:33][CH:8]([C:5]1[CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[O:7][N:6]=1)[CH3:9]
Reactant: CC(O)c1cc(C(F)(F)F)on1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(Br)c1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(5-Trifluoromethyl-isoxazol-3-yl)ethanol was dissolved in 35 ml of diethyl ether, and 2.93 g of triphenylphosphine and 3.71 g of carbon tetrabromide were then added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to silica gel column chromatography to obtain 1.14 g of 3-(1-bromoethyl)-5-trifluoromethylisoxazole.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)C.[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCC1(C(=O)[O-])CCCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A THF (5 mL) solution of 1-tert-butyl 3-ethylpiperidine-1,3-dicarboxylate (1 g, 3.89 mmol) was added dropwise to a THF (15 mL) solution of lithium diisopropylamide (5.83 mmol) in a nitrogen atmosphere at −78 degrees over 5 minutes. The mixture was raised to room temperature, and stirred for 50 minutes. The temperature of the reaction mixture was lowered to −78 degrees again, and methyl iodide (1.21 mL, 19.43 mmol) was added dropwise at −78 degrees over 5 minutes. The reaction mixture was then raised to room temperature, and stirred for 5 hours. After being added to a saturated ammonium chloride aqueous solution, the reaction mixture was stirred for a while, and extracted with diethyl ether. The organic layer was collected, washed once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (698 mg, 66%).
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:14])C.[OH:15]O>>[CH3:14][C:5]1[C:4](=[O:3])[C:13]2[C:8]([C:7](=[O:15])[CH:6]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: OO
Reactant: CCOc1c(C)ccc2ccccc12
Product: CC1=CC(=O)c2ccccc2C1=O

Procedure:
2-Methyl-1,4-naphthoquinone was prepared in much the same manner as in Example 1, except that 18.6 g of 1-ethoxy-2-methylnaphthalene (86% content) was used in place of 1-methoxy-2-methylnaphthalene and the amount of 35% hydrogen peroxide was increased to 36.0 g. The yield was 9.3 g (58.1%).
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)C.C(=O)=O>C(O)C(C)C>[F:25][C:22]([F:23])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)CO
Product: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (10.7 g) was heated to 100° C., and dissolved in isobutanol (15 mL). An isobutanol (25 mL) solution of 1-ethoxycarbonyl-4-(4-trifluoromethoxyphenoxy)piperidine (12.03 g) was dropwise added thereto while noticing generation of carbon dioxide gas. After the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours; then the solvent was concentrated; and toluene (40 mL) was added to the obtained residue. The toluene solution was washed with water (40 mL×2), and then the solvent was concentrated under reduced pressure to obtain a target compound as a light orange solid substance. The yield amount was 5.73 g (98% based on trifluoromethoxyphenol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[C:17]=1[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(F)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cccc(F)c1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 52 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 2,3-difluorophenylboronic acid (Aldrich; 529 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2,3-difluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (450 mg, 39%) as a colorless oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[C@H:30]([CH:31]=[O:32])[CH2:29][O:28][C:27]1([CH3:34])[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:35][C:36]1[CH:41]=[C:40]([CH2:42][CH2:43][N+:44]([O-:46])=[O:45])[CH:39]=[C:38]([F:47])[CH:37]=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[C@@H:30]([C@@H:31]([OH:32])[C@@H:43]([N+:44]([O-:46])=[O:45])[CH2:42][C:40]2[CH:41]=[C:36]([F:35])[CH:37]=[C:38]([F:47])[CH:39]=2)[CH2:29][O:28][C:27]1([CH3:34])[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])COC1(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 37.7 %

Procedure:
Add tetrabutylammonium fluoride in 5 minutes (50 mL, 50 mmol, 1.0 M solution in tetrahydrofuran) to a solution of (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (200 g, 873.362 mmol) and 1,3-difluoro-5-(2-nitroethyl)-benzene (164 g, 877.005 mmol) in tetrahydrofuran (1.2 L) at 8° C. Allow to warm to room temperature and stir for 14 hours. Partition between ethyl acetate (4 L) and saturated aqueous sodium chloride (1.5 L). Wash the organic layer with saturated aqueous ammonium chloride, saturated aqueous sodium chloride, water, dry (magnesium sulfate), filter and concentrate to give 379 g of a crude waxy pale orange solid. Recrystallize in dichloromethane/hexanes to give the title compound (137.15 g, 37.7%).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O1CCOCC1.O.[Cu]Br>[Br:22][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: N#Cc1cc(F)ccc1-c1cc(N)ccc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(F)ccc1-c1cc(Br)ccc1F
Temperature: 2 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
5′-Amino-4,2′-difluorobiphenyl-2-carbonitrile (23 g, 100 mmol) was dissolved in hot 1,4-dioxane (20 ml) then treated with a chilled (5° C.) solution of hydrobromic acid (200 ml of a 48% solution in water). The resulting suspension was cooled to 2° C. (internal temperature) before adding a solution of sodium nitrite (6.9 g, 100 mmol) in water (14 ml) at such a rate that the internal temperature did not exceed 4° C. Once addition was complete the reaction was stirred at <4° C. for 1 h before pouring the reaction into a cooled (5° C.) solution of copper(I) bromide (21.5 g, 150 mmol) in 48% aqueous hydrobromic acid (75 ml). The resulting dark mixture was left to stir at ambient temperature for 15 min then heated at 50° C. for 40 min. After cooling to ambient temperature the mixture was diluted with water (1l) and then extracted with ethyl acetate (2×400 ml). The organics were combined then washed with 10% ammonium hydroxide (500 ml), water (500 ml), brine (400 ml) and, dried (MgSO4). Filtration and evaporation to dryness gave a brown oil, which crystallised on standing. Purification of this residue by dry flash chromatography (silica gel, 2-4% EtOAc/isohexane) furnished 5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile as a white solid (27.5 g, 94%): 1H NMR (360 MHz, CDCl3) δ7.11 (1H, dd, J 9, 9 Hz), 7.37-7.58 (5H, m).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2C=1C(O)=O)[CH2:8][CH2:9][CH3:10].CN(C=O)C>C(Cl)Cl>[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:1]=1[C:2]([Cl:4])=[O:3])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1oc2ccccc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Oxalyl chloride (6 mL, 68.8 mmol) was added under nitrogen at room temperature to a solution of 2-butyl-benzofuran-3-carboxylic acid (3.00 g, 13.7 mmol), prepared in the previous step, in 40 mL of methylene chloride. After the addition 10 μL of DMF was added and the reaction stirred at room temperature for 3 h. The solvent and the excess oxalyl chloride were removed under reduced pressure. To remove any residual oxalyl chloride the residue was taken up in benzene and then concentrated under reduced pressure to give 2-butyl-benzofuran-3-carbonyl chloride (3.00 g, 92%) as a white solid that was used in the next step without additional purification.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.[CH2:16]([CH:18]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]([NH:32][C@@H:33]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:34](O)=[O:35])=[O:31])=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:41][C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)[CH2:19][CH3:20])[CH3:17].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:5][C:34]([C@@H:33]([NH:32][C:30]([C:28]2[CH:27]=[CH:26][C:25]3[N:21]([CH:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[C:22]([CH2:41][C:42]4[S:43][CH:44]=[CH:45][CH:46]=4)=[N:23][C:24]=3[CH:29]=2)=[O:31])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:35])[CH2:4][CH2:3][CH2:2]1
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)O)ccc21
Reactant: NC1CCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)NC3CCC3)ccc21
Temperature: 25 °C
Yield: 65.7 %

Procedure:
Into a reaction vial were placed 10 mg of cyclobutylamine, 20 mg of HOAt, 53 mg of (S)-2-{[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoic acid. Then 0.11 ml DIPEA in 1 ml DMF were added, followed by 67 mg PyBrOP in 0.5 ml DMF. The reaction was shaken at RT over night, then filtered and purified by HPLC to yield 39 mg (74%) of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyclobutylcarbamoyl-3-methyl-butyl)-amide.
Reaction SMILES: [Na:1].[C:2](#[N:6])[CH2:3][C:4]#[N:5].[CH2:7]([O:9][C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH3:8]>C(O)C>[Na:1].[C:4]([C:3]([C:2]#[N:6])=[C:13]([NH:12][C:10]([O:9][CH2:7][CH3:8])=[O:11])[S-:14])#[N:5]
Reactant: CCOC(=O)N=C=S
Reactant: N#CCC#N
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)NC([S-])=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium metal (1.01 g, 44 mmol) was dissolved in 40 mL of ethanol at ambient temperature. The resulting solution was cooled in an ice bath, and malononitrile (2.91 g, 44 mmol) was added. The ice bath was removed, and the mixture was stirred at ambient temperature for 30 minutes. After cooling to 0° C., ethoxycarbonylisothiocyanate (5.77 g, 44 mmol) was added, and the mixture was allowed to warm to ambient temperature overnight. The mixture was concentrated in vacuo, and the residue solidified upon repeated dilution with hexane and concentration in vacuo. The resulting yellow solids were collected and dried in vacuo, affording 10.74 g (100%) or sodium, 2,2-dicyano-1-ethoxycarbonylamino-ethenethiolate as a light yellow solid that contained 0.5 molar equiv. of ethanol as indicated by 1H NMR spectroscopy. 1H NMR (300 MHz, DMSO-d6) δ 4.36 (t, 0.5H, J=5.0 Hz (EtOH)), 4.03 (q, 2H, J=7.1 Hz), 3.43 (dq, 1H J=5.0, 6.7 Hz (EtOH)), 1.26 (t, 3H, J=7.3 Hz), 1.06 (t, 1.5H, J=7.0 Hz (EtOH)) ppm; MS (APCI, m/z): 197 [M−Na]−.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>CC#N>[CH3:23][O:22][C:20]([C:3]1[C:2]2[NH:1][C:28]([C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[O:25][CH3:24])=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:21]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(N)c(N)c1C(=O)OC
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)c1ccc2nc(-c3ccccc3OC)[nH]c2c1C(=O)OC
Yield: 71 %

Procedure:
A solution of diethyl [3,4-diamino-2-(methoxycarbonyl)phenyl]malonate (4.39 g, 13.5 mmol), 2-methoxybenzaldehyde (1.97 g, 14.5 mmol) and p-chloranil (6.10 g, 14.5 mmol) in MeCN (135 mL) was stirred at room temperature for 22 h. The resulting suspension was filtered and the solid recovered was washed with MeCN (filtrate 1 kept). The solid was dissolved in EtOAc (800 mL) and the resulting solution was successively washed with aqueous 1N NaOH solution (3×150 mL), water (150 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The resulting solid was triturated with hexane:EtOAc (1:1; 135 mL) to give the title compound (4.22 g) as a white solid (filtrate 2 kept). The filtrates 1 and 2 were combined and concentrated under reduced pressure. The residue was treated as the initial solid but the residue after washings was concentrated and purified by flash chromatography (10-40μ silica gel; hexane:EtOAc 1:1) before being triturated with hexane:EtOAc (3:2; 35 mL) to give an additional 0.72 g amount (total of 4.96 g, 83% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[NH2:27][C:28]([CH3:33])([CH3:32])[C:29]([NH2:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:31][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[N:27]=3)[C:9]=2[CH2:24][CH3:25])=[CH:6][CH:7]=1
Reactant: CC(C)(N)C(N)=O
Reactant: CCc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: Cl
Product: CCc1c(C2=NC(C)(C)C(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 24 was synthesized from 4c (1.0 g, 2.53 mmol) and 5i (0.56 g, 4.07 mmol) as a white solid (0.58 g, 50%) in a manner similar to that described in Example 53. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, 1H), 7.30 (d, 2H), 7.30˜7.27 (m, 2H), 7.07 (d, 2H), 7.00 (br s, 1H), 2.78 (q, 2H), 1.81 (s, 6H), 1.20 (t, 3H); ESMS m/z: 461.0 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]SC1C(C2C=NC=CC=2)=NNC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH2:18][N:19]([CH3:23])[CH2:20][CH2:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1c[nH]nc1-c1cccnc1)CCCc1ccccc1
Reactant: CSc1c[nH]nc1-c1cccnc1
Product: CN1CCC=C(c2n[nH]cc2C#CCCCc2ccccc2)C1
Yield: 95 %

Procedure:
Compound 44D was converted to compound 45D, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 95% (amorphous). LCMS (method A); Rt: 1.99 min, ([M+H]+=306). 1H-NMR (400 MHz, CDCl3): δ 7.58 (s, 1H), 7.31-7.18 (m, 5H), 6.79-6.73 (bs, 1H), 3.43-3.40 (m, 2H), 2.78 (t, J=7 Hz, 2H), 2.60 (bt, J=7 Hz, 2H), 2.45-2.37 (m, 7H), 1.95-1.87 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:40]Br)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[NH:25][C:24]2[C:26]([CH3:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:23]=2[C:22]=1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:40][N:25]2[C:24]3[C:26]([CH3:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:23]=3[C:22]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:21]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H](CBr)NC(=O)OCc3ccccc3)[nH]c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(C3CCCCC3)c3n(c2c1C)C[C@@H](NC(=O)OCc1ccccc1)COc1ccccc1-3
Temperature: 25 °C
Yield: 45 %

Procedure:
Methyl 5-{2-[((2S)-2-{[(benzyloxy)carbonyl]amino}-3-bromopropyl)oxy]phenyl}-6-cyclohexyl-3-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate was dissolved in DMF (0.034M) and NaH (1.1 eq., 60% in mineral oil) was added. The mixture was left stirring at RT. After 30 min all volatiles were evaporated i. vac. The residual material was purified by chromatography (PE:EtOAc, 8.5:1.5). The product was obtained as a colourless solid (45%). MS (ES+) m/z 559 (M+H)+.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH:13][C:22](=[O:24])[CH3:23])=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CCN)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CCNC(C)=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 69.2 %

Procedure:
To a mixture of N-(4-bromophenyl)-N-ethylethane-1,2-diamine dihydrochloride (1.044 g, corresponding to 2.33 mmol), pyridine (4 ml) and anhydrous dichloromethane (8 ml) was added dropwise acetic anhydride (0.28 ml, 2.92 mmol) at 0° C. After stirring at room temperature for 70 mins, the reaction mixture was diluted with dichloromethane (50 ml), washed twice with diluted aqueous sodium hydrogen carbonate solution and with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→1:0) to give N-{2-[(4-bromophenyl)(ethyl)amino]ethyl}acetamide (460 mg, overall yield of 2 steps 92%) as a white solid.