Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].F[C:9]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=1[C:11]#[N:12]>CN(C=O)C>[CH:17]([C:14]1[CH:15]=[CH:16][C:9]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])=[C:10]([CH:13]=1)[C:11]#[N:12])=[O:18]
Reactant: CC[C@@H](C)O
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C)Oc1ccc(C=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.7 %

Procedure:
(2R)-2-Butanol (0.99 g, 0.013 mol) was dissolved in DMF (50 ml) and the solution cooled to 0° C. To this was added sodium hydride, 60% dispersion in mineral oil (1.54 g, 0.036 mol) in a portion-wise manner, the mixture was stirred at 0° C. for 10 minutes after complete addition. 2-Fluoro-5-formylbenzonitrile (2.0 g, 0.013 mol) was then added and the reaction mixture allowed to warm to room temperature (slowly within the ice bath) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then cooled to 0° C., quenched with brine and diluted with EtOAc (˜25 ml). The mixture was partitioned and the organic fraction extracted with water (˜30 ml), the combined organics were dried by passing through a phase separating cartridge and evaporated to dryness under reduced pressure to give the crude product. The crude residue was purified on a 40+M Biotage cartridge, eluting with a 20 to 50% mixture of EtOAc in hexane. This gave the title compound (310 mg) as a yellow oil. δH (d6-DMSO, 400 MHz): 9.88 (1H, s), 8.30 (1H, s), 8.15 (1H, d), 7.49 (1H, d), 4.73-4.81 (1H, m), 1.63-1.79 (2H, m), 1.33 (3H, d), 0.95 (3H, t).
Reaction SMILES: C(O)C.[O:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[C:20](Cl)[N:19]=1>O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:18]([NH2:17])=[N:19][C:20]([N:14]3[CH2:13][CH2:12][N:11]([C:9]([CH:5]4[O:4][CH2:8][CH2:7][CH2:6]4)=[O:10])[CH2:16][CH2:15]3)=[N:21][C:22]2=[CH:23][C:24]=1[O:30][CH3:31]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CCO
Solvent: O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a solution of absolute ethanol (272 ml), water (68 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 32 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 48 hours. The crystals were collected by filtration, washed with absolute ethanol and dried in vacuo at 40° C. to yield 36.44 g (85.5%) of Terazosin.HCl dihydrate. See Trial M in Table I. Trial N was performed using a 10% volume of water.
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:19]1([C:25]2[NH:26][C:27](=[O:36])[N:28]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C[O:40][CH2:39]C1>>[O:36]=[C:27]1[N:28]([CH:30]2[CH2:31][CH2:32][N:33]([C:39]([NH:1][C@H:2]([CH2:8][C:9]3[CH:18]=[CH:17][C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[CH:10]=3)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:40])[CH2:34][CH2:35]2)[N:29]=[C:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:26]1
Reactant: CCOC(=O)[C@H](N)Cc1ccc2c(c1)CCCC2
Reactant: C1CCOC1
Reactant: O=c1[nH]c(-c2ccccc2)nn1C1CCNCC1
Product: CCOC(=O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1
Temperature: 0 °C

Procedure:
A mixture of 15 mL THF, 0.830 g (3.4 mmol) ethyl (R)-2-amino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate and 0.63 g (3.8 mmol) CDT was stirred for 1 h in the ice bath and for 1 h at RT. Then 0.83 g (3.4 mmol) 5-phenyl-2-piperidin-4-yl-2,4-dihydro-[1,2,4]triazol-3-one was added and the mixture was refluxed for 3 h. The reaction mixture was evaporated down under reduced pressure, the residue was combined with 15% K2CO3 solution, the precipitate was suction filtered and dried.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:49])[C:12]([CH2:14][O:15][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(O)(=O)C>O>[CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:49])[C:12]([CH2:14][O:15][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[NH:23][C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Oc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2n1
Yield: 80.4 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.78 g of 5-{4-(5-isopropoxy-3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 103) was treated with 12 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 0.40 g of the title compound, melting at 210°-212° C.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([N+:17]([O-])=O)=[C:13]([O:15][CH3:16])[CH:14]=1)[CH3:4]>C(O)C.O.[Fe]>[CH2:3]([O:5][C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([NH2:17])=[C:13]([O:15][CH3:16])[CH:14]=1)[CH3:4]
Reactant: CCOC(=O)/C=C/c1cnc([N+](=O)[O-])c(OC)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C=C/c1cnc(N)c(OC)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
Iron (1.6 g) and ammonium chloride (3 g) were added to the suspension of (E)-3-(5-methoxy-6-nitropyridin-3-yl)acrylic acid ethyl ester (787 mg) in ethanol (40 mL) and water (8 mL) obtained above, and the reaction solution was heated to reflux for 1 hour. After the reaction solution was allowed to be cooled to room temperature, deposited substance was filtered by celite. Ethyl acetate and saturated sodium bicarbonate water were added to the filtrate, and the organic layer was partitioned. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 2:1), and 506 mg (66%) (E)-3-(6-amino-5-methoxypyridin-3-yl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:6]
Reactant: NCCN1CCCCC1
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCN1CCCCC1)c1ccc(OCCCN2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-Fluoro-4-(3-piperidin-1-yl-propoxy)-benzoic acid (70 mg, 0.25 mmol) and 1-(2-aminoethyl)piperidine (450 □L, 0.3 mmol) in DMF (5 mL) was added EDC (58 mg, 0.3 mmol), HOBT (40 mg, 0.3 mmol), and diisopropylethyl amine (52 □1, 0.3 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (Biotage 12 M, elute 90/10/1 CH2Cl2/MeOH/NH4OH) to yield the title compound. MS (ES+) 392.3
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL, 13.5 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (110 mg, 0.57 mmol) in dichloromethane (2 mL). After 2 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 346.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10](C(=O)C)[C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15](CCBr)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O.[CH2:32](O)C>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:32])[C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)c1cc2c3c(CCBr)cccc3n(C(C)=O)c2cn1
Reactant: C1COCCN1
Solvent: O
Product: CCOC(=O)c1cc2c([nH]c3cccc(N4CCOCC4)c32)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen, a solution of 0.19 g of 9-acetyl-5-bromoethyl-beta-carboline-3-carboxylic acid ethyl ester in 5 ml of ethanol is mixed with 1 ml of morpholine and stirred overnight at room temperature. After addition of water the crystallizate is suctioned off and recrystallized from ethanol/diethylether. 0.11 g (64%) is obtained. Melting point 285° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12](=[O:29])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[C:18]([C:38]4[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=4)[CH:19]=[CH:20][CH:21]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12](=[O:29])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=C1CN(S(=O)(=O)c2ccccc2)CC(c2cccc(Br)c2)N1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)CC(=O)N3c3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 4-benzenesulfonyl-6-(3-bromo-phenyl)-1-phenyl-piperazin-2-one (100 mg), (3-methylsulfonylphenyl) boronic acid (46.7 mg) and tetrakis(triphenylphosphine)palladium(0) (24.5 mg) in 1,2-dimethoxyethane (2mL) was added potassium carbonate (73.3 mg). The reaction mixture was stirred at 80° C. overnight. Additional amounts of (3-methylsulfonylphenyl) boronic acid (21 mg), potassium carbonate (58.6 mg) and tetrakis(triphenylphosphine)palladium(0) (24.5 mg) were added and stirring was continued at 80° C. for 3 h. To the reaction mixture water and ethyl acetate were added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×2). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, n-heptane/ethyl acetate 1:3, followed by ISOLUTE Flash NH2, n-heptane/ethyl acetate 1:1) to yield 58 mg (50%) of 4-benzenesulfonyl-6-(3′-methanesulfonyl-biphenyl-3-yl)-1-phenyl-piperazin-2-one as a white foam, MS: 547.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.C(=O)=[O:29].C[Li].[CH2:33]([Li])[CH2:34][CH2:35]C>O.CC(C)=O.C1COCC1>[OH:29][C:34]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2)([CH3:35])[CH3:33]
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Reactant: O=C=O
Reactant: [Li]CCCC
Agent: [Li]C
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.0 g) and THF (10 ml) was cooled to −78° C. (dry ice bath), and a solution of methyllithium (2.0 ml; 1.6 M in diethyl ether) was added dropwise. One minute after the addition had ended, a solution of butyllithium (1.4 ml; 2.5 M in toluene) was added dropwise. One minute after the addition had ended, acetone (0.14 g) was added. After warming to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 1:2 heptane/ethyl acetate). The product was thus obtained with the molecular weight of 409.53 (C25H31NO4); MS (ESI): 410 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=4)=[O:24])[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>N1C=CC=CC=1>[C:34]([C:31]([C:27]1[CH:26]=[C:25]([C:23]([NH:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[O:15][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:39]([CH:36]4[CH2:38][CH2:37]4)=[O:40])[S:3][C:4]=3[C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[O:24])[CH:30]=[CH:29][CH:28]=1)([CH3:32])[CH3:33])#[N:35]
Reactant: COC(=O)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(N)sc12
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: COC(=O)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of methyl 2-amino-6-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]-1,3-benzothiazole-7-carboxylate (0.92 g, 1.88 mmol) in pyridine (5 mL) was added cyclopropanecarbonyl chloride (371 μL, 4.1 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended in methanol (10 mL), sodium carbonate (250 mg) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was successively purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0) and silica gel column chromatography (ethyl acetate/n-hexane=40/60→60/40), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (706 mg, 68%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=1.C1COCC1.CO>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cn3)c2cc1OC
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(N)cn3)c2cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 6,7-dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline (0.46 g, 1.41 mmol, 1.0 eq.), and THF (10 mL), MeOH (4 mL), DMF (2 mL), and TEA (2 mL). The 6,7-Dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline was dissolved completely in the above solution mixture, and was flushed with nitrogen for at least 5 minutes. The Pd/C (10% by weight) (0.090 g, 20% by weight) was then added. A balloon filled with H2 was connected to the flask after the nitrogen was vacuumed out. The reaction mixture was stirred at room temperature for 4 hours. The palladium was filtered out through Celite, and the filtrated was collected and concentrated via rotary evaporation. The resulting oil-like product was taken up into 5 mL of water and 1 mL of acetonitrile and lyophilized to yield 6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine as a light brown solid (0.411 g, 98.1%). 1H NMR (400 MHz, CDCl3): 8.54 (d, 1H), 7.85 (d, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.18 (dd, 1H), 6.96 (d, 1H), 6.61 (d, 1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.73 (s, 2H); MS (EI) for C16H15N3O3: 298 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][CH:9]=1.[CH2:17]([N:19](CC)CC)C.CN.C1COCC1>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[C:13]([C:14]([NH:19][CH3:17])=[O:16])=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: CCN(CC)CC
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Oxalyl chloride (1.01 mL, 11.6 mmol) was added to a suspension of 4-chloronicotinic acid (prepared according to F. Guillier et al. J. Org. Chem. 1995, 60, 292) (1.5 g, 7.7 mmol) in CH2Cl2 (15 mL) containing 2 drops of DMF. The mixture was stirred at room temperature for 1 h then evaporated to dryness, suspended in CH2Cl2 (10 mL) and re-evaporated. The residue was re-suspended in CH2Cl2 (10 mL), cooled to 0° C. and treated with triethylamine (3.23 mL, 23.2 mmol) dropwise followed by a 2M solution of methylamine in THF (7.7 mL, 15.4 mmol) dropwise. The resulting orange mixture was stirred at 0° C. for 20 min before being concentrated in vacuo. The residue was treated with sat. NaHCO3 (aq) (30 mL), extracted with CH2Cl2 10×25 mL) and the combined organic layers were dried (MgSO4) and evaporated to give an orange oil which crystallised. The solid was triturated with ether (10 mL), stirred for 30 min, then filtered and washed with 1:1 ether/pentane (20 mL) to give the title amide (986 mg, 75%) as an off-white solid; δH (CDCl3, 400 MHz) 3.07 (3H, d), 6.20 (1H, br), 7.37 (1H, d), 8.53 (1H, d), 8.86 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31]([OH:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31]([O:33][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a suspension of (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Aldrich) (1 g, 2.21 mmol) in methanol (6 mL) was added a solution potassium carbonate (153 mg, 1.1 mmol) in water (6 mL) dropwise. The mixture was stirred at room temperature for 1 hour, concentrated, and the residue slurried in toluene and evaporated to dryness 3 times and once from diethyl ether to give a white solid. The solid was mixed with DMF (6 mL), and bromomethyl-benzene (289 μL, 2.43 mmol) was added dropwise at room temperature. After 16 hours the mixture was diluted with water extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to give (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (0.92 g, 77%) as a foam.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:32])[C@H:11]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:12][C:13](=[O:27])[C@H:14]([CH2:25][OH:26])[NH:15][C:16](=[O:24])[C@H:17]([CH2:19][CH2:20][C:21](=[O:23])[NH2:22])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:33]1[CH:38]=[C:37]2N=N[N:41](O)[C:36]2=[CH:35][CH:34]=1.O.C(N1CC[O:49][CH2:48][CH2:47]1)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C.O>[ClH:1].[CH2:2]([O:9][C:10](=[O:32])[C@H:11]([CH2:28][CH:29]([CH3:30])[CH3:31])[NH:12][C:13](=[O:27])[C@H:14]([CH2:25][OH:26])[NH:15][C:16](=[O:24])[C@H:17]([CH2:19][CH2:20][C:21](=[O:23])[NH2:22])[NH:18][C:48](=[O:49])[CH2:47][NH:41][CH:36]1[CH2:35][CH2:34][CH2:33][CH2:38][CH2:37]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: CCN1CCOCC1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCC(N)=O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC1CCCCC1)C(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
N-(glutaminyl-serinyl)leucine benzyl ester hydrochloride (2.6 kg) (prepared as described in Step 3), N-Boc-L-cyclohexylglycine (1.414 kg) and HOBt hydrate (168 g) were dissolved in DMF (13.0 L). N-ethylmorpholine (1.266 kg, 11.0 M) and EDC hydrochloride (1.265 kg) were added and the mixture stirred at 20° C. for 3 hours. The solution was diluted with ethyl acetate (13.0 L) and water (26.0 L) added. The product precipitated and the slurry was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with 1:1 ethyl acetate/water (60 L) dried on the filter under nitrogen for 24 hours and dried in vacuo at 45°. The title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:13](Cl)(=[O:15])=[O:14])=[CH:3]1.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:13]([N:18]([CH3:19])[CH3:17])(=[O:15])=[O:14])=[CH:3]1
Reactant: CNC
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccccc21
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cn(C)c2ccccc2c1=O

Procedure:
A mixture of 1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (2.4 g) and a solution of dimethylamine in ethanol (33% w/w; 50 ml) was stirred at room temperature for 30 minutes. The precipitated solid was filtered off and then boiled with dichloromethane (100 ml). The mixture was filtered and the filtrate evaporated to dryness to provide a white solid which was crystallised from methanol to give the novel compound 1,N,N-trimethyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 225°-226°.