Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.O=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][O:18][C:17]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:29][C:16]1=2.[H-].[Na+]>C(COC)OC>[CH3:13][O:12][C:10]([CH:9]=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][O:18][C:17]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:29][C:16]1=2)=[O:11]
Reactant: O=C1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C=C1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
1.1 ml of methyl diethylphosphonoacetate dissolved in 10 ml of dimethoxyethane was added to 1.84 g of 11-oxo-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and 0.3 g of 64% by weight sodium hydride suspended in 20 ml of dimethoxyethane and the mixture was refluxed under heating for 5 hours. The solvent was removed from the reaction mixture, the residue was dissolved in ethyl acetate and the organic layer was washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. After the solvent was removed from the solution, the residue was applied to silica gel column chromatography to obtain 2.3 g of 11-methoxycarbonylmethylene-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine as a brown oily product.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:27]([OH:28])=[CH:26][C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:7]=2[CH:6]=1)=[CH:15][C:14]([Br:20])=[C:13]([C:21]([F:24])([F:23])[F:22])[C:12]=4[F:25])=[O:4].C(O)C.O.[Li+].[OH-]>C(OCC)(=O)C>[Br:20][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:25])[C:13]=1[C:21]([F:22])([F:23])[F:24])[NH:10][C:9]1[C:8]3[CH:26]=[C:27]([OH:28])[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[CH2:19][CH2:18][C:17]2=1
Reactant: COC(=O)c1cc2c(cc1O)-c1[nH]c3c(F)c(C(F)(F)F)c(Br)cc3c1CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc2c(cc1O)-c1[nH]c3c(F)c(C(F)(F)F)c(Br)cc3c1CC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A sample of 8-Bromo-10-fluoro-2-hydroxy-9-trifluoromethyl-5,11-dihydro-6H-benzo[a]carbazole-3-carboxylic acid methyl ester (28.9 mg, 63.4 μmol) is treated with ethanol (0.3 mL) and water (0.5 mL) followed by LiOH (4 mg, 190 μmol). The reaction is then stirred at 50° C. overnight. The reaction is then diluted with ethyl acetate and extracted with 1 M HCl. The organics are then dried over MgSO4, filtered and the solvent is removed. The resulting residue is purified using a UV triggered HPLC to afford 22 mg of the title compound as a white solid; 1H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 7.76 (s, 1H), 7.32 (s, 1H), 3.00 (m, 2H), 2.95 (2, H); LC/MS calculated for [M+H]+ C18H11F4NO3: 445.1, found: 445.9.
Reaction SMILES: [F:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:20].[CH3:21]I.[H-].[Na+].[H][H]>C1COCC1.C(Cl)Cl.O>[F:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:21])[C:3]1=[O:20]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F
Reactant: CI
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Yield: 45.6 %

Procedure:
To a well stirred solution of 3.0 g (0.01 mol) of 3-fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one, 75 ml of dry THF and 25.56 g (0.18 mol, 11.2 ml) of methyl iodide was added a suspension of 0.48 g (0.02 mol) of sodium hydride in 20 ml of THF. There was an immediate evolution of hydrogen. The contents of the flask were stirred under a nitrogen atmosphere for exactly 2 hours. The product mixture was poured into approximately 100 ml of water and methylene chloride added to extract the product. The organic layer was separated and washed twice with ca. 50 ml portion of fresh water, and then allowed to dry over magnesium sulfate. Evaporation of the solvent under reduced pressure gave 1.38 g of a yellow crystalline material. Recrystallization from hot heptane gave 0.97 g of an off-white powder identified as 3-fluoro-1-(N-methyl)-7-chloro-5-phenyl-1,4-benzodiazepin-2-one: 1H nmr (DMSO-d6): δ 7.2-7.72 ppm (m, 8H), δ 5.8 ppm (d, 1H, 56 Hz), δ 3.37 (m, 3H, N-methyl); 19F nmr (DMSO-d6) δ -160.14 ppm (d, J = 56 Hz).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][NH:5][C:4]2[CH:10]=[CH:11][S:12][C:3]1=2.P(Cl)(Cl)([Cl:15])=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:15][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c[nH]c2ccsc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cnc2ccsc2c1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A stirred mixture of 7-oxo-4,7-dihydro-thieno[3,2-b]pyridine-6-carbonitrile (0.668 g, 3.8 mmol) and 6 ml of phosphorus oxychloride was heated to reflux for 2 h, and then cooled to room temperature. The residue was added to ice water and dichloromethane, and the resulting mixture was neutralized by addition of solid NaHCO3 carefully. The organic layer was separated, washed with H2O, dried over MgSO4, and concentrated in vacuum to give 0.526 g (71%) of a red-brown solid. 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 7.82 (d, J=6 Hz, 1H); LC-MS (ESI) m/z 195.0 (M+1).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25](O)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])C)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.[CH:37]1[CH:38]=[CH:39][C:40]2N(O)N=[N:43][C:41]=2[CH:42]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:34][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([NH2:28])=[CH:30][CH:31]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[CH2:13][C:15]1[C:40]2[C:41](=[CH:42][CH:37]=[CH:38][CH:39]=2)[NH:43][CH:16]=1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)O
Reactant: NCc1ccc(N)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)Cc1ccccc1)C(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.5 %

Procedure:
To a solution of N-(benzylsulfonyl)-D-isoleucyl-L-methionine (100 mg, 0.24 mmol) and 4-aminobenzylamine (59 mg, 0.48 mmol) in dichloromethane (5 ml), HOBt (44 mg, 0.29 mmol) and EDC HCl (56 mg, 0.29 mmol) were added and stirred at room temperature under a nitrogen stream. After 12 hours, the reaction mixture was concentrated under reduced pressure and water was added to the residue. The precipitated product was collected by filtration, washed with water and then dried. The resulting crude product was applied to column chromatography (Fuji Silysia NH-DM-1020; mobile phase: dichloromethane:methanol=10:1) to give N-(benzyl-sulfonyl)-D-tryptophyl-N1-(4-aminobenzyl)-L-methioninamide (108 mg, 0.21 mmol; yield 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[CH:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([N:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([N:17]=[C:18]([C:20]([NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:21])[N:19]=2)[CH:16]=1
Reactant: CCOC(=O)c1nc2ccc(Br)cn2n1
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2nc3ccc(Br)cn3n2)cc1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using p-tolylmethanamine and ethyl 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36]>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH2:36][CH:35]=[CH2:34])=[O:14]
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1- oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesuihfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.
Reaction SMILES: Cl.Cl.[N:3]1[C:12]2[NH:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][NH2:15].C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[O:32](C(OC(C)(C)C)=O)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O>C(#N)C.C(OCC)(=O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])[CH2:14][CH2:13][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:12]=2[N:3]=1)[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: NCCc1ccc2c(n1)NCCC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(CCc1ccc2c(n1)NCCC2)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 10-7 (2.0 g, 7.8 mmol) and N,N-diisopropylethylamine (6.8 mL) in acetonitrile (50 mL) at 0° C. was added ethyl bromoacetate (0.975 mL, 8.6 mmol). The mixture was stirred at 50° C. for 15 h, then cooled to 25° C. and BOC2O (1.7 g, 7.8 mmol) was added. After 1 h, the mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 50-60% EtOAc/hexanes) gave 10-8 as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([O:18][CH3:19])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[C:20](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([O:18][CH3:19])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:20])=[O:9]
Reactant: COc1ccc(C(=O)O)c(NCCCCl)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1NCCCCl
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.3 %

Procedure:
To a mixture of 2-[(3-chloropropyl)amino]-4-methoxy-3-nitrobenzoic acid (1.77 g, 6.13 mmol) and potassium carbonate (847 mg, 6.13 mmol) in N,N-dimethylformamide (18 mL) was added iodomethane (0.38 mL, 6.10 mmol) at room temperature. After stirring at room temperature for 14 hr, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×5) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (1.60 g, 5.29 mmol, 86%) as a yellow amorphous.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[I-].[CH3:19][O:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH2:31][N+](C)(C)C)=[CH:26][N:27]2[CH3:30])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:31][C:25]2[C:24]3[C:28](=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[N:27]([CH3:30])[CH:26]=2)[CH2:14][CH2:13]1
Reactant: c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Reactant: COc1ccc2c(C[N+](C)(C)C)cn(C)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(CN3CCC(CNc4nc5ccccc5[nH]4)CC3)cn(C)c2c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
After adding anhydrous acetonitrile (2 ml) to a mixture of (1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine (20 mg, 0.09 mmol), (6-methoxy-1-methyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (0.1 mmol) and anhydrous potassium carbonate (5 mg, 0.11 mmol), the mixture was stirred at 50° C. for 12 hours. The mixture was cooled to room temperature and then passed through a silica gel short column and purified by preparative HPLC to obtain (1H-benzimidazol-2-yl)-[1-(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-piperidin-4-ylmethyl]-amine. The compound was identified by LC-MS.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=2)[N:10]=1.Cl.Cl.[NH2:20][CH:21]1[CH2:28][CH:27]2[N:29]([CH3:30])[CH:23]([CH2:24][CH2:25][CH2:26]2)[CH2:22]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:30][N:29]1[CH:23]2[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:28][CH:21]([NH:20][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[N:10][C:9]=13)=[O:17])[CH2:22]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3ccco3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccco4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
A mixture of 2-furan-2-ylbenzoxazole-4-carboxylic acid (51 mg, 0.22 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (59 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59 mg, 0.31 mmol) and 1-hydroxybenzotriazole (84 mg, 0.62 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.14 mL, 1.1 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-furan-2-ylbenzoxazole-4-carboxamide (49 mg, 61%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.94 (d, J=6.0 Hz, 1H), 8.22 (dd, J=7.5, 1.0 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.68 (dd, J=8.0, 1.0 Hz, 1H), 7.46 (t, J=4.0 Hz, 1H), 7.35 (d, J=4.0 Hz, 1H), 6.79-6.66 (m, 1H), 4.58-4.53 (m, 1H), 3.12 (d, J=10.0 Hz, 2H), 2.66-2.59 (m, 2H), 2.55 (s, 3H), 2.18-1.98 (m, 3H), 1.68-1.49 (m, 3H), 1.22-1.17 (m, 2H); MS (ESI+) m/z 366 (M+H); HPLC>99% (AUC), tR=12.12 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][CH:24](OC)[O:25]C)[CH:20]=[CH:19][C:18]=3[N+:29]([O-:31])=[O:30])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:19][C:18]=3[N+:29]([O-:31])=[O:30])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(Cc1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)c1)OC
Solvent: O
Solvent: O=CO
Product: NC(=O)c1sc(Nc2cc(CC=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of 0.200 g (0.43 mmole) of 4-(3-chloro-phenyl)-2-[5(2,2-dimethoxy-ethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.9a) and 3 mL of 96% formic acid was stirred at room temperature for 1 hour. The solution was poured into water and the resulting precipitate was collected by filtration, washed with water and air-dried to give 0.135 g of 4-(3-chloro-phenyl)-2-[2-nitro-5-(2-oxo-ethyl)-phenylamino]-thiazole-5-carboxylic acid amide (VI.9b) as an orange solid. A mixture of 0.135 g of 4-(3-chloro-phenyl)-2-[2-nitro-5-(2-oxo-ethyl)-phenylamino]-thiazole-5-carboxylic acid amide (VI.9b), 0.10 mL of N-methylpiperazine, 0.10 mL of glacial acetic acid, 0.50 g of sodium triacetoxyborohydride and 10 mL of dichloromethane was stirred at room temperature for 16 hours. To the mixture was carefully added 1 mL of 1M hydrochloric acid and stirring was continued at room temperature for 30 minutes. The mixture was partitioned between 30 mL of dichloromethane and 30 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed once with 30 mL of water, then 30 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 15:85-20:80) to give an orange foam. Trituration with diethyl ether gave 0.100 g of 4-(3-chlorophenyl)-2-{5-[2-(4-methyl-piperazin-1-yl)-ethyl]-2-nitro-phenylamino}-thiazole-5-carboxylic acid amide (VI.9c) as an orange solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([N+:11]([O-:13])=[O:12])[CH3:10])[C:3]([OH:5])=[O:4].S(Cl)([Cl:17])=O.[CH3:19]O>>[ClH:17].[NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([N+:11]([O-:13])=[O:12])[CH3:10])[C:3]([O:5][CH3:19])=[O:4]
Reactant: CO
Reactant: CC(C)(CCC[C@H](N)C(=O)O)[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CCCC(C)(C)[N+](=O)[O-]
Product: Cl

Procedure:
(S)-2-Amino-6-methyl-6-nitroheptanoic acid (20.5 g) was dissolved in methanol (177 ml) and thionyl chloride (7.34 ml) was gently added dropwise under ice-cooling. The mixture was refluxed under heating for 2.5 h, and methanol was concentrated under reduced pressure to give the objective compound (21.9 g).
Reaction SMILES: [CH2:1]([N:4]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:5]1=[O:6])[CH:2]=[CH2:3].C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[CH:41]1([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>CO.C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][C:19]([N:50]3[CH2:51][CH2:52][N:47]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)[CH2:48][CH2:49]3)=[O:21])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)ccc2cc(OCCCC(=O)O)ccc21
Reactant: C1CCC(N2CCNCC2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: C=CCn1c(=O)ccc2cc(OCCCC(=O)N3CCN(C4CCCCC4)CC3)ccc21
Reaction time: 5 h

Procedure:
Into 200 ml of chloroform were added 5.9 g of 1-allyl-6-(3-carboxypropoxy)carbostyril and 3.2 g of DBU. The outside of the reaction vessel containing the above mentioned mixture was ice-cooled and 2.8 g of isobutyl chloroformate was added dropwise to the mixture under stirring condition. After the addition operation the reaction mixture was stirred for 1 hour, then 3.7 g of N-cyclohexylpiperazine was added dropwise to the reaction mixture and the reaction was continued for 5 hours. After the reaction was compleated, the reaction mixture was washed with a 1% NaOH aqueous solution and water, then the organic layer was dried with anhydrous Na2SO4. The drying agent was removed by filtration and the mother liquor was concentrated. The residue thus obtained was treated by a silica-gel column chromatography (solvent used was a mixture of chloroform:methanol=30:1) to obtain elute. 4.2 Grams of 1-allyl-6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]carbostyril was obtained from the elute, in the form of a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Br:22]Br>ClCCl>[NH2:1][C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH2:9][C:10]([Br:22])([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=CCC(Br)(C(=O)OC)C=C1N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
10.5 g (50 mmol) dimethyl amino-terephthalate and 8.1 ml (100 mmol) pyridine are dissolved in 175 ml dichloromethane and at −16° C. a solution of 2.7 ml (52.5 mmol) bromine in 25 ml dichloromethane is added dropwise. It is stirred for 4 hours at 0° C. and then heated overnight to ambient temperature. The mixture is added to ice water, washed three times with water and then dried over magnesium sulphate and evaporated down. The crude product is recrystallised from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1)=[O:9]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.6 %

Procedure:
2-Chloropyridine-4-carbonyl chloride (1.58 g, 9.0 mmol) in DCM (10 ml) was added dropwise to a solution of methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (1.81 g, 7.5 mmol) and triethylamine (3.13 ml, 22.5 mmol) in DCM (10 ml) at 0° C. The reaction was stirred at room temperature for 20 h, the solvent evaporated under vacuum and the residue partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The aqueous was extracted with ethyl acetate (50 ml) and the combined organic phases washed with brine (50 ml), dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/ethanol/ammonia (300:8:1). The solvents were evaporated under vacuum to give methyl 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate (1.73 g, 61%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=3)[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: CC1NCCc2cc(O)c(O)cc21
Reactant: Cc1nc(Cl)nc(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)nc(N2CCc3cc(O)c(O)cc3C2C)c1C
Yield: 75.9 %

Procedure:
After 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(1.6 g, 4.98 mmol) and triethylamine(0.7 ml, 4.98 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(0.8 g, 4.53 mmol) in dimethylformamide, 1.1 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 76%)
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][C:9]=3[C:10](=O)[O:11][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[CH2:17]([Mg]Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([C:10]1([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]2[S:13][CH2:14][CH2:15][C:8]=2[C:7]2[C:2]([OH:1])=[CH:3][C:4]([CH3:16])=[CH:5][C:6]=2[O:11]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC[Mg]Br
Reactant: Cc1cc(O)c2c3c(c(=O)oc2c1)SCC3
Product: CCCCCCC1(CCCCCC)Oc2cc(C)cc(O)c2C2=C1SCC2

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexyl magnesium bromide, using the procedure described in Example 8, there is obtained 4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-7-methyl-4H-thieno [2,3-c][1]benzopyran. The benzopyran is then reacted with γ-pyrrolidinobutyric acid, hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.